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Item 1A. Risk Factors

2025-02-27 compared with 2024-02-28 · 465 added, 298 removed, 1188 unchanged (39% of the section changed)

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● Our projections regarding the market opportunities for our products and product candidates may not be accurate, and the actual market for our products and product candidates may be smaller than we estimate;

● We may be unable to establish effective marketing and sales capabilities or enter into agreements with third parties to market and sell our products and product candidates, if they are approved, and as a result, we may be unable to generate significant product revenues;

● We have limited commercial experience and may be unable to establish effective marketing and sales capabilities or enter into agreements with third parties to market and sell our products and product candidates, if they are approved, and as a result, we may be unable to generate significant product awareness, and the lack of awareness may limit the revenues that we generate;

● If our products or product candidates do not achieve broad market acceptance, the revenues that we generate from their sales will be limited;

● Our products and product candidates may face competition sooner than anticipated;

● As a condition of approval, the FDA may require that we implement various post-marketing requirements and conduct post-marketing studies, any of which would require a substantial investment of time, effort, and money, and which may limit our commercial prospects;

● As a condition of approval, the FDA and foreign regulatory authorities may require that we implement various post-marketing requirements and conduct post-marketing studies, any of which would require a substantial investment of time, effort, and money, and which may limit our commercial prospects;

● We will need to grow the size and capabilities of our organization, and we may experience difficulties in managing this growth;

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● Development of a product candidate intended for use in combination with an already approved product may present more or different challenges than development of a product candidate for use as a single agent;

● A Fast Track product designation, BTD, or other designation to facilitate product candidate development may not lead to faster development or a faster regulatory review or approval process, and it does not increase the likelihood that our product candidates will receive marketing approval;

● While lifileucel has received ODD for melanoma stages IIB-IV and for cervical cancer patients with tumors greater than 2 cm, there is no guarantee that we will be able to maintain this designation, receive these designations for any of our other product candidates, or receive or maintain any corresponding benefits, including periods of exclusivity;

● We may encounter substantial delays in our clinical trials or may not be able to conduct our clinical trials on the timelines we expect and we may be required to conduct additional clinical trials or modify current or future clinical trials based on feedback we receive from the FDA;

● A Fast Track, breakthrough therapy, or regenerative medicines advanced therapy product designations, or other designation to facilitate product candidate development may not lead to faster development or a faster regulatory review or approval process, and it does not increase the likelihood that our product candidates will receive marketing approval;

● While in the U.S.

lifileucel has received orphan drug designation for melanoma stages IIB-IV and for cervical cancer patients with tumors greater than 2 cm, there is no guarantee that we will be able to maintain this designation, receive these designations for any of our other product candidates, or receive or maintain any corresponding benefits, including periods of exclusivity;

● We may encounter substantial delays in our clinical trials, not be able to conduct our clinical trials on the timelines we expect, and be required to conduct additional clinical trials or modify current or future clinical trials based on feedback we receive from the FDA and foreign regulatory authorities;

● It may take longer and cost more to complete our clinical trials than we project, or we may not be able to complete them at all;

● Our clinical trials may fail to demonstrate adequately the safety and efficacy of our product candidates, which would prevent or delay regulatory approval and commercialization;

● We are required to pay substantial royalties and lump sum benchmark payments under our license or acquisition agreements with the NIH, Moffitt, Novartis, Clinigen, and Cellectis, and we must meet certain milestones to maintain our license rights;

● We are required to pay substantial royalties and lump sum benchmark payments under our license or acquisition agreements with the NIH, Novartis, Clinigen, and Cellectis, and we must meet certain milestones to maintain our license rights;

● We rely on and collaborate with governmental, academic, and corporate partners or agencies to approve, improve, and develop TIL cell therapies for new indications for use in combination with other therapies and to evaluate new TIL manufacturing methods, the results of which, because the manufacturing processes are not within our control, and may be incorrect or unreliable;

● Our business could be adversely affected by the effects of health epidemics, including the COVID-19 pandemic, in regions where we or third parties on which we rely have significant manufacturing facilities, concentrations of clinical trial sites or other business operations.

The COVID-19 pandemic could materially affect our operations, including at our headquarters in San Carlos, California and at our manufacturing facility in Philadelphia, Pennsylvania, which have previously been subject to state executive orders and shelter-in-place orders, and at our clinical trial sites, as well as the business or operations of our other manufacturers, contract research organizations, or CROs, or other third parties with whom we conduct business;

● We are currently operating in a period of economic uncertainty and capital markets disruption, which has been significantly impacted by geopolitical instability, ongoing military conflicts between Russia and Ukraine and Israel and Hamas and record inflation.

Our business, financial condition and results of operations could be materially adversely affected by any negative impact on the global economy and capital markets resulting from the conflict in Ukraine and the Middle East, geopolitical tensions or record inflation;

● Climate change or legal, regulatory or market measures to address climate change may negatively affect our business, results of operations, cash flows and prospects;

● Environmental, social and governance matters may impact our business and reputation.

● We have global operations, which expose us to additional risks, and any adverse event could have a material adverse effect on our results of operations and financial condition;

Risks Related to Government Regulation:

● We are subject to extensive regulation, which can be costly, time consuming and can subject us to unanticipated delays;

even after obtaining regulatory approval for some of our products and/or product candidates, those products and/or product candidates may still face regulatory difficulties;

● The FDA regulatory approval process is lengthy and time-consuming, and we may experience significant delays in the clinical development and regulatory approval of our product candidates;

● Obtaining and maintaining regulatory approval of our product candidates in one jurisdiction does not mean that we will be successful in obtaining regulatory approval of our product candidates in other jurisdictions;

● We are subject to extensive regulation, which can be costly and time consuming and can subject us to unanticipated delays in obtaining regulatory approvals for our products and/or product candidates, and even after obtaining regulatory approval for some of our products and/or product candidates, those products and/or product candidates may still face regulatory difficulties;

● The FDA and foreign regulatory approval process is lengthy and time-consuming, and we may experience significant delays in the clinical development and regulatory approval of our product candidates;

● Political uncertainty may have an adverse impact on our operating performance and results of operations, and uncertainty surrounding the potential legal, regulatory, and policy changes by a new U.S.

presidential administration may directly affect us and the global economy;

● Obtaining and maintaining regulatory approval of our product candidates in one jurisdiction does not mean that we will be successful in obtaining or maintaining regulatory approval of our product candidates in other jurisdictions;

● Coverage and reimbursement may be limited or unavailable in certain market segments for our product candidates, which could make it difficult for us to sell our product candidates profitably.

● Governments outside the U.S.

tend to impose strict price controls, which may adversely affect our revenues, if any.

The summary risk factors described above should be read together with the text of the full risk factors below in this section entitled “ Risk Factors ” and the other information set forth in this Annual Report on Form 10-K, including our consolidated financial statements and the related notes, as well as in other documents that we file with the SEC.

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Until recently, we did not have products approved for commercial sale and have not generated significant revenue from operations.

With the closing of the acquisition of the worldwide rights to Proleukin ® in May 2023, we began to have commercial sales.

With the recent approval of the BLA, we began to generate revenue from the sale of our product Amtagvi ® in the second quarter of 2024.

Furthermore, following the acquisition of the worldwide rights to Proleukin ® in May 2023, or the Acquisition, we began to generate revenue from the sales of Proleukin ® .

However, Proleukin ® revenues are dependent upon continued use in manufacturing and clinical settings by us and other cell therapy companies.

We recognize revenue from product sales in accordance with ASC Topic 606, Revenue from Contracts with Customers, or ASC 606.

Under ASC 606, revenue is recognized when a customer obtains control of promised goods or services in an amount that reflects the consideration which the entity expects to receive in exchange for those goods or services.

To the extent the transaction price includes variable consideration, we estimate the amount of variable consideration that should be included in the transaction price using the most likely method based on historical experience, as well as applicable information currently available.

In the U.S., products are sold principally to hospitals and clinics, as well as distributors and wholesalers, and outside of the U.S.

to hospitals and clinics.

Contractual performance obligations are usually limited to transfer of control of the product to the customer.

In the case of Amtagvi ® , revenue is recognized upon infusion, while for Proleukin ® , transfer of control occurs either upon shipment or upon receipt of the product after considering when the customer obtains legal title to the product.

Revenue is measured as the amount of consideration we expect to receive in exchange for transferring our products and is generally based on a list of fixed prices less allowances for chargebacks, product returns, rebates and discounts.

Our payment terms to customers range from 45 to 105 days;

payment terms differ by customer and by product.

Revenue is reduced at the time of recognition for expected chargebacks, discounts, rebates, and sales allowances, collectively referred to as gross to net adjustments, or GTN adjustments.

In the U.S., these GTN adjustments are attributable to various commercial arrangements and government programs.

In addition, non-U.S.

government programs include different pricing schemes such as cost caps and volume discounts.

Cash discounts are recorded as a reduction to receivables and settled through the issuance of credits, typically within one month.

All other GTN adjustments are recorded as a liability and settled through cash payments to the customer.

Significant judgement is required in estimating GTN adjustments considering legal interpretations of applicable laws and regulations, historical experience, payer channel mix, current contract prices under applicable programs, processing time lags, and inventory levels in the distribution channel.

As of December 31, 2024, we had an accumulated deficit of $2.4 billion.

In addition, during the year ended December 31, 2024, we incurred a net loss of $372.2 million.

While we are beginning the commercial launch of our product, Amtagvi™, we do not expect to generate any meaningful product sales until later in 2024.

We expect to incur significant additional operating losses in the future as we expand our development and clinical trial activities in support of demonstrating the effectiveness of our products.

While we are executing the U.S.

launch of our first internally developed product, Amtagvi ® , we may not generate any meaningful product sales until later, and we expect to incur significant additional operating losses in the future as we expand our development and clinical trial activities in support of demonstrating the effectiveness of our product candidates.

Our ability to achieve long-term profitability is dependent upon obtaining regulatory approvals for our products and successfully commercializing our products alone or with third parties.

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In June 2023, we entered into a new open market sale agreement, or the 2023 Sale Agreement, with Jefferies, which superseded the 2022 Sale Agreement and provided for the sale of up to $450.0 million of our common stock from time to time.

In February 2024, we closed another underwritten offering of our common stock.

The net proceeds from the offering, after deducting the underwriting discounts and commissions and other offering expenses payable by us, were $197.4 million.

As of December 31, 2024, we had $330.1 million in cash, cash equivalents, investments, and restricted cash ($115.7 million of cash and cash equivalents, $208.1 million in short-term investments, and restricted cash of $6.4 million).

Accordingly, based on the funds we have available as of the date these consolidated financial statements are issued, which include estimated net proceeds (after deducting underwriting and other offering expenses) of approximately $197.1 million from the public offering of our common stock completed on February 22, 2024, we believe that we have sufficient capital to fund our anticipated operating expenses and capital expenditures as planned for at least the next twelve months following the issuance of our consolidated financial statements included in this Annual Report on Form 10-K.

However, in order to complete the development of our current product candidates, and in order to effect our business plan, including establishing our own manufacturing facility, we anticipate that we will have to spend more than the funds currently available to us.

Furthermore, changing circumstances may cause us to increase our spending significantly faster than we currently anticipate, and we may require additional capital for the further development of our product candidates and commercialization of our products and may need to raise additional funds sooner if we choose to expand more rapidly than we presently anticipate.

With the approval of the BLA, we began to generate revenue from the sale of our product Amtagvi ® in the second quarter of 2024.

Furthermore, following the Acquisition, we began to generate revenue from the sales of Proleukin ® .

There is no assurance that such funds will be sufficient to fund our operations during the 12 months from the date the consolidated financial statements are issued and this Form 10-K is filed.

However, based on the funds we have available as of the date these consolidated financial statements are issued, we believe that we have sufficient capital to fund our anticipated operating expenses and capital expenditures as planned for at least the next twelve months following the issuance of our consolidated financial statements included in this Form 10-K.

However, in order to complete the development of our current product candidates, and in order to affect our business plan, including expanding our own manufacturing facility, we anticipate that we will have to spend more than the funds currently available to us.

Furthermore, changing circumstances may cause us to increase our spending significantly faster than we currently anticipate.

We may require additional capital for the further development of our product candidates and commercialization of our products and may need to raise additional funds sooner if we choose to expand more rapidly than we presently anticipate.

Moreover, our fixed expenses such as rent, minimum payments to our contract manufacturers, and other contractual commitments, including those for our research collaborations, are substantial and are expected to increase in the future.

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● our ability to successfully commercialize our product candidates, if approved;

● our ability to have clinical and commercial product successfully manufactured consistent with FDA and European Medicines Agency, or EMA, regulations;

● our ability to have clinical and commercial product successfully manufactured consistent with FDA and foreign regulations, including those applicable in the EU;

● amount of sales and other revenues from product candidates that we may commercialize, if any, including the selling prices for such potential products and the availability of adequate third-party coverage and reimbursement for patients;

● sales and marketing costs associated with commercializing our products, if approved, including the cost and timing of building our marketing and sales capabilities;

● cost of building, staffing and validating our own manufacturing facility in the U.S.;

● cost of expanding, staffing and validating our own manufacturing facility in the U.S.;

● terms and timing of our current and any potential future collaborations, licensing or other arrangements that we have established or may establish;

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If we raise additional funds through strategic partnerships and alliances and licensing arrangements with third parties, we may have to relinquish valuable rights to our technologies or product candidates, or grant licenses on terms unfavorable to us.

Subject to various spending levels approved by our Board of Directors, our management will have broad discretion in the use of the net proceeds from our capital raises, including our July 2023, June 2020, October 2018 and January 2018 public offerings and the proceeds from sales pursuant to our “at-the-market” sale agreement with Jefferies LLC, and may not use them effectively.

Our management will have discretion in the application of the net proceeds from our capital raises, including our July 2023, June 2020, October 2018, and January 2018 public offerings, and the proceeds from sales pursuant to the 2023 Sale Agreement with Jefferies, which provides for the sale of up to $450.0 million of our common stock from time to time, and our stockholders will not have the opportunity as part of their investment decision to assess whether the net proceeds from our capital raises are being used appropriately.

Subject to various spending levels approved by our Board of Directors, our management will have broad discretion in the use of the net proceeds from our capital raises, including our February 2024, July 2023, June 2020, October 2018 and January 2018 public offerings and the proceeds from sales pursuant to our “at-the-market” sale agreement with Jefferies LLC, and may not use them effectively.

Our management will have discretion in the application of the net proceeds from our capital raises, including our February 2024, July 2023, June 2020, October 2018, and January 2018 public offerings, and the proceeds from sales pursuant to the 2023 Sale Agreement with Jefferies, which provides for the sale of up to $450.0 million of our common stock from time to time, and our stockholders will not have the opportunity as part of their investment decision to assess whether the net proceeds from our capital raises are being used appropriately.

You may not agree with our decisions, and our use of the proceeds from our capital raises may not yield any return to stockholders.

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Recently enacted tax reform legislation in the U.S., changes to existing tax laws, or challenges to our tax positions could adversely affect our business and financial condition.

The tax regimes to which we are subject or under which we operate are unsettled and may be subject to significant change.

Any such changes to existing federal and state tax laws could adversely impact our business, results of operations, and financial position as the impact of recent tax legislation is uncertain.

In recent years, various tax legislations were signed into law.

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On June 15, 2020, Assembly Bill 85 was passed in California, which suspended the use of net operating losses and limited the use of credits for certain corporations.

Changes to existing federal and state tax laws could adversely impact our business, results of operations and financial position as the impact of recent tax legislation is uncertain.

Following the change in U.S.

administration, there is uncertainty regarding future legislative and regulatory changes and policies related to matters such as taxation and importation, including tariffs, and any such proposed or enacted regulations, taxes, or tariffs by the current or a future U.S.

administration, Congress, or taxing and importation authorities in other jurisdictions could adversely impact the global economy and materially affect our tax obligations, tariff obligations, and operating results.

In addition, U.S.

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If we are unsuccessful in such a challenge, or if the site’s status as a KOZ is revoked, the relevant tax authorities may assess additional taxes, which could result in adjustments to, or impact the timing or amount of, taxable income, deductions or other tax allocations, which may adversely affect our results of operations and financial position.

In addition, given our current net loss and net loss carryforwards, we may not be able to realize the full benefit of these tax advantages before they expire.

Risks Related to the Manufacturing and Commercialization of Our Products and Product Candidates

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Such changes carry the risk that they will not achieve these intended objectives, and any of these changes could cause our product candidates to perform differently and affect the results of planned clinical trials or other future clinical trials or otherwise necessitate the conduct of additional studies.

Currently, our products and product candidates are manufactured using processes developed or modified by us or by our third-party research institution collaborators that we may not intend to use for more advanced clinical trials or commercialization.

Currently, our products and product candidates are manufactured at our internal facility, the i CTC, and by CMOs, using processes developed or modified by us or by our third-party research institution collaborators that we may not intend to use for more advanced clinical trials or commercialization.

Gen 2 is the FDA-approved, commercial manufacturing process for Amtagvi ® and has been selected for all ongoing and future company-sponsored clinical trials.

Although we believe Gen 2 is a commercially viable process, there are risks associated with scaling to the level required for advanced clinical trials or commercialization, including, among others, cost overruns, potential problems with process scale-up, process reproducibility, stability issues, lot consistency, and timely availability of raw materials.

overruns, potential problems with process scale-up, process reproducibility, stability issues, lot consistency, and timely availability of raw materials.

As a result of these challenges, we may experience delays in our clinical development and/or commercialization plans.

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In May 2019 we entered into a lease agreement to build a commercial-scale manufacturing facility, the i CTC, in Philadelphia, Pennsylvania for commercial and clinical production of autologous TIL products, including our product Amtagvi ® .

The i CTC is currently manufacturing TIL for our ongoing clinical trials and preparing to provide commercial supply upon potential BLA approval;

as of the end of 2021, we had completed the commissioning activities at the i CTC and successfully initiated manufacturing of clinical batches of lifileucel and LN-145, representing our first internally manufactured TIL product, as we continue our launch readiness activities to supply commercial TIL upon potential BLA approval.

The i CTC is currently manufacturing TIL for our ongoing clinical trials and Amtagvi ® for commercial supply.

Manufacturing performed by us is centralized at the i CTC, instead of manufacturing at various facilities.

As of the first quarter of 2024, the i CTC facility was approved by the FDA for commercial manufacturing of Amtagvi ® , and we successfully initiated commercial manufacturing and continue our capacity building and facility expansion activities to supply clinical and commercial TIL to meet demand.

We expect our manufacturing facility will provide us with enhanced control of material supply for both clinical trials and the commercial market, enable the more rapid implementation of process changes, and allow for better long-term margins.

We have built capacity to potentially treat thousands of cancer patients annually.

However, we may not be successful in finalizing the development of our own manufacturing facility or capability.

However, we may not be successful in finalizing the expansion of our own manufacturing facility or capability.

We may establish multiple manufacturing facilities as we expand our commercial footprint to multiple geographies, which may lead to regulatory delays or prove costly.

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The FDA may take a restrictive approach when regulating cell therapy manufacturing facilities that could result in delays, product release challenges, shortages, or capacity restraints.

Our current manufacturing strategy involves the use of CMOs in conjunction with the manufacturing capacity at the i CTC.

Currently our products and product candidates are also manufactured by WuXi and previously by Moffitt.

Additionally, we partner with American Red Cross, or ARC, to leverage their GMP approved facilities and operate our own facility to produce feeder cells for TIL manufacturing.

Our current manufacturing strategy involves the use of CMOs in conjunction with our internal manufacturing capacity at the i CTC.

Currently our products and product candidates are manufactured internally at the i CTC and externally by WuXi Advanced Therapies, Inc., or Wuxi, and previously by Moffitt.

Additionally, we partner with American Red Cross, or ARC, to operate our facility to produce feeder cells for TIL manufacturing.

The process for manufacturing TIL is heavily reliant on the supply of biological raw materials and maintaining a GMP facility capable of supplying our manufacturing facilities with quality cells to make the final product.

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The i CTC and our CMO are aseptic manufacturing facilities that operate clean rooms for the production of TIL cell therapies, which are subject to contamination, labor, occupational safety, regulatory, climate, and environmental risks that could interfere with production.

Any problems or delays we or our CMOs experience in preparing for commercial scale manufacturing of a product, product candidate, or component thereof may result, in the case of product candidates, a delay in the FDA approval thereof or, in the case of products, may impair our ability to manufacture commercial quantities or such quantities at an acceptable cost, which could result in the delay, prevention, or impairment of clinical development of our product candidates and commercialization of our products and could adversely affect our business.

Any problems or delays we or our CMOs experience in preparing for commercial scale manufacturing of a product, product candidate, or component thereof may result, in the case of product candidates, a delay in the approval thereof or, in the case of products, may impair our ability to manufacture commercial quantities or such quantities at an acceptable cost, which could result in the delay, prevention, or impairment of clinical development of our product candidates and commercialization of our products and could adversely affect our business.

Furthermore, if we or our commercial manufacturers fail to deliver the required commercial quantities of our product candidates on a timely basis and at reasonable costs, we would likely be unable to meet demand for our products and we would lose potential revenues.

Moreover, should we continue to use CMOs, we may not succeed in maintaining our relationships with our current CMO or establishing relationships with additional or alternative CMOs.

Moreover, while we are expanding our capabilities to enable more internal manufacturing, should we continue to use CMOs, we may not succeed in maintaining our relationships with our current CMO or establishing relationships with additional or alternative CMOs.

Our products and product candidates may compete with other products and product candidates for access to manufacturing facilities.

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The commercial terms of any new arrangement could be less favorable than our existing arrangements and the expenses relating to the transfer of necessary technology and processes could be significant.

Reliance on third-party manufacturers entails exposure to risks to which we would not be subject if we manufactured the product candidate ourselves, including:

Reliance on third-party manufacturers entails exposure to risks to which we would not be subject if we manufactured the products and product candidates exclusively by ourselves, including:

● inability to negotiate manufacturing and quality agreements with third parties under commercially reasonable terms;

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● our ability to synchronize operations and standards to ensure that all aspects of manufacturing are consistent without deviations across facilities.

In addition, the manufacturing process and facilities for any products that we may develop at the i CTC and or our CMOs is subject to FDA and foreign regulatory authority approval processes, and we or our CMOs will need to meet all applicable FDA and foreign regulatory authority requirements, including cGMP, on an ongoing basis.

In addition, the manufacturing process and facilities for any products and product candidates that we may develop at the i CTC and or our CMOs is subject to FDA and foreign regulatory authority approval processes, and we or our CMOs will need to meet all applicable FDA and foreign regulatory authority requirements, including cGMP, on an ongoing basis.

The cGMP requirements include quality control, quality assurance, and the maintenance of records and documentation.

The FDA and other regulatory authorities enforce these requirements through facility inspections.

Manufacturing facilities must submit to pre-approval inspections by the FDA that will be conducted after we submit our marketing applications, including our BLAs, to the FDA.

Manufacturing facilities must submit to pre-approval inspections by the FDA that will be conducted after we submit our marketing applications for our product candidates, including our BLAs, to the FDA.

Manufacturers are also subject to continuing regulatory oversight by FDA and other regulatory authorities, including inspections following marketing approval.

Further, we, in cooperation with our CMOs, must supply all necessary chemistry, manufacturing, and control documentation for a pre-approval inspection in support of a BLA on a timely basis.

There is no guarantee that we or our CMOs will be able to successfully pass all aspects of a pre-approval inspection by the FDA or other foreign regulatory authorities.

Our manufacturing facilities or our CMOs’ manufacturing facilities may be unable to comply with our specifications, cGMP, and with other FDA, state, and foreign regulatory requirements.

Although both the internal and external facilities were approved by the FDA for commercial manufacturing of Amtagvi ® , there is no guarantee that we or our CMOs will be able to successfully pass all aspects of surveillance or pre-approval inspections by the FDA or other foreign regulatory authorities for Amtagvi ® or future product candidates.

Our internal manufacturing facilities or our CMOs’ manufacturing facilities may be unable to comply with our specifications, cGMP, and with other FDA, state, and foreign regulatory requirements.

Poor control of production processes can lead to the introduction of adventitious agents or other contaminants, or to inadvertent changes in the properties or stability of product candidate that may not be detectable in final product testing.

If we or our CMOs are unable to reliably produce products to specifications acceptable to the FDA or other regulatory authorities, or in accordance with the strict regulatory requirements, we may not obtain or maintain the approvals we need to commercialize such products.

If we or our CMOs are unable to reliably produce products and/or product candidates to specifications acceptable to the FDA or other regulatory authorities, or in accordance with the strict regulatory requirements, we may not obtain or maintain the approvals we need to commercialize such products.

Even after obtaining regulatory approval, in the case of our products, and even if we obtain regulatory approval, in the case of our product candidates, there is no assurance that either we or our CMOs will be able to manufacture the approved product to specifications acceptable to the FDA or other regulatory authorities, to produce it in sufficient quantities to meet the requirements for the potential launch of the product, or to meet potential future demand.

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Even to the extent we use and continue to use CMOs, we are ultimately responsible for the manufacture of our products and product candidates.

injunctions, delay or denial of product approval or supplements to approved products, clinical holds or termination of clinical trials, warning or untitled letters, regulatory authority communications warning the public about safety issues with the biologic, refusal to permit the import or export of the products, product seizure, detention, or recall, operating restrictions, suits under the civil False Claims Act, corporate integrity agreements, consent decrees, or withdrawal of product approval.

A failure to comply with these requirements may result in regulatory enforcement actions against our manufacturers or us, including fines and civil and criminal penalties, which could result in imprisonment, suspension or restrictions of production, injunctions, delay or denial of product approval or supplements to approved products, clinical holds or termination of clinical trials, warning or untitled letters, regulatory authority communications warning the public about safety issues with the biologic, refusal to permit the import or export of the products, product seizure, detention, or recall, operating restrictions, suits under the civil False Claims Act, corporate integrity agreements, consent decrees, or withdrawal of product approval.

Any of these challenges could delay completion of clinical trials, require bridging clinical trials or the repetition of one or more clinical trials, increase clinical trial costs, delay approval of our product candidate, impair commercialization efforts, increase our cost of goods, and have an adverse effect on our business, financial condition, results of operations, and growth prospects.

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Because this is a relatively new and expanding area of novel therapeutic interventions, there are many uncertainties related to development, marketing, reimbursement, and the commercial potential for our product candidates.

There can be no assurance as to the length of the clinical trial period, the number of patients the FDA will require to be enrolled in the clinical trials in order to establish the safety, efficacy, purity and potency of immunotherapy products, or that the data generated in these clinical trials will be acceptable to the FDA to support marketing approval.

There can be no assurance as to the length of the clinical trial period, the number of patients the FDA and foreign regulatory authorities will require to be enrolled in the clinical trials in order to establish the safety, efficacy, purity and potency of immunotherapy products, or that the data generated in these clinical trials will be acceptable to the FDA and foreign regulatory authorities to support marketing approval.

The FDA may take longer than usual to come to a decision on any BLA that we submit and may ultimately determine that there is not enough data, information, or experience with our product candidates to support an approval decision.

The FDA may also require that we conduct additional post-marketing studies or implement risk management programs, such as REMS until more experience with our product candidates is obtained.

The FDA and foreign regulatory authorities may also require that we conduct additional post-marketing studies or implement risk management programs, such as Risk Evaluation and Mitigation Strategies, or REMS, until more experience with our product candidates is obtained.

Finally, after increased usage, we may find that our product candidates do not have the intended effect or have unanticipated side effects, potentially jeopardizing initial or continuing regulatory approval and commercial prospects.

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Should any of our contract manufacturers no longer produce our product candidates, it may take us significant time to find a replacement, if we are able to find a replacement at all.

There is no assurance that the approaches offered by our products will gain broad acceptance among doctors or patients or that governmental agencies or third-party medical insurers will be willing to provide reimbursement coverage for proposed product candidates.

There is no assurance that the approaches offered by our products will gain broad acceptance among doctors or patients or that governmental agencies, national healthcare systems, or third-party medical insurers will be willing to provide reimbursement coverage for proposed product candidates.

Moreover, we do not have verifiable internal marketing data regarding the potential size of the commercial market for our product candidates, nor have we obtained current independent marketing surveys to verify the potential size of the commercial markets for our current product candidates or any future product candidates.

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Accordingly, we may spend significant capital trying to obtain approval for product candidates that have an uncertain commercial market.

The market for any products that we successfully develop will also depend on the cost of the product.

Cell based therapies may take longer to attain insurance coverage, and although we may apply for special government programs and prepare the market for product approval, there is no way to ensure that healthcare providers, insurance companies, or other third parties will reimburse our product at an expeditious rate.

Even if we obtain insurance coverage for our product from payors, coverage at treatment centers will require payment for the total cost of care which involves surgery, conditioning chemotherapy, as well as other staffing and hospitalization needs.

This will require coordination between authorized treatment centers and other payors including government payors that may only cover a portion of charges.

If our treatment centers do not successfully obtain coverage in time, there may be a slow uptake or variable or limited access, if at all, to our therapies.

The market for any products that we successfully develop will also depend on the selling price of the product, which may be further impacted by future price increases for our products.

Cell based therapies may not be eligible for insurance coverage due to reluctance by third party payors to cover the costs associated with such therapies.

Payors may deny coverage or offer inadequate levels of reimbursement for these therapies if they determine that the product has not received appropriate clearances from the FDA or other government regulators or if they deem the therapies to be investigational or experimental, not medically necessary, or otherwise inappropriate.

Although we may apply for special government programs and prepare the market for product approval, there is no way to ensure that healthcare providers, insurance companies, or other third parties will reimburse our product at an expeditious rate.

Even if we obtain insurance coverage for our product from payors, there is no guarantee that third party payors will provide adequate coverage or reimbursement.

Coverage at treatment centers will require payment for the total cost of care, which includes the costs of not only our product but also the costs of surgery, conditioning chemotherapy, and other staffing and hospitalization needs.

Furthermore, coverage policies and reimbursement rates are subject to change.

With respect to any coverage or reimbursement that may be provided, payors may seek to impose restrictions on coverage, pricing, and reimbursement levels to contain these costs.

In some cases, we do not have long-term agreements with insurance companies but negotiate single-case agreements on a case-by-case basis to obtain prior authorization, coverage, and reimbursement for a particular case.

If coverage and reimbursement are not available or are inadequate, ATCs and clinics may decide not to recommend our product, and there may be a slow uptake or variable or limited access, if at all, to our therapies.

Likewise, in the absence of a long-term agreement with an insurance company, there is no guarantee that an insurance company will enter into a single-case agreement with us or otherwise provide prior authorization for a particular case, in which case there may be no or inadequate coverage and reimbursement for our products.

Seeking prior authorization and negotiating the single-case agreement may take anywhere from days to months to obtain, if at all, and may cause ATCs, clinics and patients to decline to use our products.

We do not yet have sufficient information to reliably estimate what it will cost to commercially manufacture our current product candidates, and the actual cost to manufacture these products could materially and adversely affect the commercial viability of these products.

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As a novel therapy, TIL manufacturing and product release is complex and must evolve with both industry-wide autologous cell therapy challenges and new regulatory requirements that may result in delays and unexpected denials.

We have never manufactured our adoptive cell therapy product candidate on a commercial scale, nor have our partners.

We have limited experience in manufacturing our adoptive cell therapy product candidate on a commercial scale, as do our partners.

As a result, we cannot give any assurance that the Gen 2 process or any future process that we select will be a manufacturing process that can produce our products in compliance with the applicable regulatory requirements, at a cost or in quantities necessary to make them commercially viable.

Moreover, we and our third-party manufacturers will have to continually adhere to current cGMP regulations enforced by the FDA through its facilities inspection program.

If our facilities or any of the facilities of these manufacturers cannot demonstrate adequate assurance of compliance with FDA standards during a pre-approval inspection, the FDA approval of our products will not be granted.

Moreover, we and our third-party manufacturers will have to continually adhere to current cGMP regulations enforced by the FDA and foreign regulatory authorities through facilities inspection programs.

If our facilities or any of the facilities of these manufacturers cannot demonstrate adequate assurance of compliance with applicable standards during a pre-approval inspection,

the approval of our products will not be granted.

In complying with cGMP and foreign regulatory requirements, we and any of our third-party manufacturers will be obligated to expend time, money and effort in production, record-keeping, and quality control to assure that our products meet applicable specifications and other requirements.

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Claims could also be asserted under state consumer protection acts.

Large judgements have also been awarded in class action lawsuits based on therapeutics that had unanticipated side effects.

Large judgments have also been awarded in class action lawsuits based on therapeutics that had unanticipated side effects.

If we cannot successfully defend ourselves against product liability claims, we may incur substantial liabilities or be required to limit or halt commercialization of our products and/or product candidates.

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● establish superior proprietary positions.

Due to the promising clinical therapeutic effect of competitor therapies in clinical exploratory trials, we anticipate substantial direct competition from other organizations developing advanced T-cell therapies targeting patients who have received prior anti-PD-1/PD-L1 therapies.

In particular, we expect to compete with other new therapies for our lead indications developed by companies such as Agenus, BeyondSpring, Bristol-Myers Squibb, Merck, Nektar Therapeutics, Checkmate Pharmaceuticals, Daiichi Sankyo, Eisai, Exelixis, Moderna, OncoSec Medical, Replimune, Regeneron Pharmaceuticals, Pfizer, and Genmab.

We also may compete with other TIL cell therapies in development by companies such as Instil Bio, Achilles Therapeutics, KSQ Therapeutics, Obsidian Therapeutics, Immatics, TILT Biotherapeutics, WindMIL Therapeutics, GRIT Biotechnology, Lyell Immunopharma, Cellular Biomedicine Group, and others.

We also may compete with therapies based on genetically engineered T-cell receptors rendered reactive against tumor-associated antigens prior to their administration to patients, as well as TIL cell therapies that are designed to be specific to neoantigens, including products developed by Adaptimmune Therapeutics, Alaunos Therapeutics, Intima Bioscience, Marker Therapeutics, Turnstone Biologics, Neogene, and others.

Due to the promising clinical therapeutic effect of competitor therapies in clinical trials, we anticipate substantial direct competition from other organizations developing therapies in our commercial and pipeline target indications.

In particular, we expect to compete with other new therapies for our lead indications developed by companies such as BioNtech, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Genmab, Immunocore, IO Biotech, Merck, Moderna, Pfizer, Regeneron Pharmaceuticals, and Replimune.

We also may compete with other T cell therapies in development, including therapies based on genetically engineered T cell receptors rendered reactive against tumor-associated antigens prior to their administration, other genetically engineered TIL products, and TIL products designed to be reactive to specific neoantigens, by companies such as AbelZeta Pharma, Achilles Therapeutics, Adaptimmune Therapeutics, Alaunos Therapeutics, Biosyngen, GRIT Biotechnology, Immatics, Immunocore, Intima Bioscience, KSQ Therapeutics, Lyell Immunopharma, Marker Therapeutics, Obsidian Therapeutics, TILT Biotherapeutics, and others.

To date, these technologies have been primarily applicable to hematologic malignancies, but their application in solid tumor indications may create competition with us.

We may also face competition from immunotherapy treatments offered by companies such as Amgen, AstraZeneca, Bristol-Myers Squibb, Merck, Pfizer, Regeneron Pharmaceuticals, Roche, and BioNTech.

We may also face competition from novel IL-2 treatments in development by Alkermes, Werewolf, Nektar Therapeutics, Merck, Sanofi, Neoleukin Therapeutics and others.

We may also face competition from immunotherapy treatments offered by companies such as Amgen, AstraZeneca, BioNTech, Bristol-Myers Squibb, Merck, Pfizer, Regeneron Pharmaceuticals, Roche, and others.

We may also face competition from novel IL-2 treatments in development by Alkermes, ILToo Pharma, Merck, Nektar Therapeutics, Sanofi, Werewolf Therapeutics, and others.

Many of these companies and our other current and potential competitors have substantially greater research and development capabilities and financial, scientific, regulatory, manufacturing, marketing, sales, human resources, and experience than we do.

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Our competitors may obtain regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in competitors establishing a strong market position before we are able to enter the market.

Universities and public and private research institutions in the U.S.

and Europe are also potential competitors.

Universities and public and private research institutions around the world are also potential competitors.

For example, a Phase 3 M14TIL clinical trial comparing TIL to standard ipilimumab in patients with metastatic melanoma is currently being conducted in Europe by the Netherlands Cancer Institute, the Copenhagen County Herlev University Hospital, and the University of Manchester.

Results from the M14TIL clinical trial were presented at the European Society for Medical Oncology Congress in September 2022.

While these universities and public and private research institutions primarily have educational objectives, they may develop proprietary technologies that lead to other FDA approved therapies or that secure patent protection that we may need for the development of our technologies and products.

While these universities and public and private research institutions primarily have educational objectives, they may develop proprietary technologies that lead to other approved therapies by the FDA, European Commission, or other regulatory agencies, or that secure patent protection that we may need for the development of our technologies and products.

Our lead product Amtagvi ® is an approved therapy for the treatment of metastatic melanoma and a candidate for the treatment of other cancers.

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The number of patients may turn out to be lower than expected.

Additionally, the potentially addressable patient population for our products and product candidates may be limited or may not be amenable to treatment with our products or product candidates and may also be limited by the cost of our treatments and the reimbursement of those treatment costs by third-party payors.

Additionally, the potentially addressable patient population for our products and product candidates may be limited or may not be amenable to treatment with our products or product candidates and may also be limited by the cost of our treatments for patients, any future increase to such costs, and the reimbursement of those treatment costs by third-party payors.

For instance, we expect Amtagvi ® to initially target a small patient population that suffers from metastatic melanoma.

Furthermore, we are also responsible for the manufacturing costs of products for patients that may have a tumor resection but ultimately do not receive an infusion, in which case we may incur manufacturing expenses without being able to recognize any revenue.

Even if we obtain significant market share for our products or product candidates, because the potential target populations are small, we may never achieve profitability without obtaining regulatory approval for additional indications.

We may be unable to establish effective marketing and sales capabilities or enter into agreements with third parties to market and sell our products and product candidates, if they are approved, and as a result, we may be unable to generate significant product revenues.

We currently have a small commercial team focused on our commercial strategy, but we do not have a large commercial infrastructure for the marketing, sale, and distribution of biopharmaceutical products.

In order to commercialize our products, we must build our marketing, sales, and distribution capabilities or make arrangements with third parties to perform these services, which will take time and require significant financial expenditures and we may not be successful in doing so.

Even if we are able to effectively establish a sales force and develop a marketing and sales infrastructure, our sales force and marketing teams may not be successful in commercializing our current or future product candidates.

We have limited commercial experience and may be unable to establish effective marketing and sales capabilities or enter into agreements with third parties to market and sell our products and product candidates, if they are approved, and as a result, we may be unable to generate significant product awareness, and the lack of awareness may limit the revenues that we generate.

We currently have a commercial team focused on our commercial strategy, but we do not have a large commercial infrastructure for the marketing, sale, and distribution of biopharmaceutical products.

In order to commercialize our products, we must continue to build our marketing, sales, and distribution capabilities or make arrangements with third parties to perform these services, which will take time and require significant financial expenditures, and we may not be successful in doing so.

In addition, we rely on one or more third-party distributors for the commercial sale of our products.

It may be difficult to pivot from our current distributors of biopharmaceutical products in the event that any agreements with such third-party distributors are terminated.

If we need to enter into alternative arrangements, this could adversely affect our business.

Furthermore, even if we are able to effectively establish a sales force and develop a marketing and sales infrastructure, our sales force and marketing teams may not be successful in commercializing our current or future product candidates.

To the extent we rely on third parties to commercialize any products for which we obtain regulatory approval, we would have less control over their sales efforts and could be held liable if they failed to comply with applicable legal or regulatory requirements.

In addition to marketing our product, we will need to establish authorized treatment centers that will be able to obtain patients from the broader community and provide access to our therapies.

Even if we are able to obtain approval for a product candidate, we may not be able to approve enough treatment centers for the provision of our product to a broad patient population.

In addition to marketing our product, we will need current and future ATCs both inside and outside the U.S.

that are prepared and have the capacity and experience to administer our therapies to patients.

Even if we are able to obtain approval for a product candidate in a country or region, we may not be able to approve enough treatment centers for the provision of our product to a broad patient population.

The number of ATCs we onboard to administer our product may fluctuate and affect our product launch, and even if we onboard a large number of ATCs, this does not ensure the uptake of our products.

Additionally, certain areas do not have hospitals with the facilities to safely administer our therapy.

Accordingly, we may only be able to launch our products with a limited number of treatment centers, which could ultimately reduce the uptake of our products.

Although we have a team allocated to authorize and monitor our treatment centers, substantial resources and investment from us and each treatment center may be required.

Accordingly, we may only be able to launch our products with a limited number of ATCs, which could ultimately reduce the uptake of our products.

Although we have a team allocated to authorize and monitor our ATCs, substantial resources and investment from us and each treatment center may be required.

Additionally, the treatment center onboarding process can be complicated and requires extensive training, technical equipment, and coordination of processes.

Once authorized, treatment centers will be required to ensure that their training, facilities, and treatment capabilities are adequately maintained.

Once authorized, ATCs will be required to ensure that their training, facilities, and treatment capabilities are adequately maintained.

We have limited prior experience in the marketing, sale, and distribution of biopharmaceutical products, and there are significant risks involved in the building and managing of a commercial infrastructure.

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We, or our collaborators, will have to compete with other pharmaceutical and biotechnology companies to recruit, hire, train, manage, and retain marketing, sales, and commercial support personnel.

In the event we are unable to develop a commercial infrastructure, we may not be able to commercialize our current or future product candidates, which would limit our ability to generate product revenues.

Although we have developed a commercial infrastructure, in the event we are

unable to continue to develop a successful commercial infrastructure, we may not be able to commercialize our current or future product candidates, which would limit our ability to generate product revenues.

Factors that may inhibit our efforts to commercialize our current or future products and product candidates and generate significant product revenues include:

● if the COVID-19 pandemic continues or reoccurs it may negatively impact our ability to establish commercial operations, educate and interact with healthcare professionals, and successfully launch our product on a timely basis;

● the inability of sales personnel to obtain access to physicians or persuade adequate numbers of physicians to prescribe our current or future product candidates;

● if a health epidemic or pandemic occurs it may negatively impact our ability to establish commercial operations, educate and interact with healthcare professionals, and successfully launch our product on a timely basis;

● the inability of sales personnel to obtain access to physicians or physicians do not prescribe our current or future product candidates;

● our inability to effectively oversee a geographically dispersed sales and marketing team;

● the costs and time associated with the initial and ongoing training of sales and marketing personnel on legal and regulatory compliance matters and monitoring their actions;

● an inability to secure adequate coverage and reimbursement by government and private health plans;

● an inability to secure adequate or any coverage and reimbursement by government and private health plans;

● the clinical indications for which the products are approved and the claims that we may make for the products;

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For example, physicians are often reluctant to switch their patients and patients may be reluctant to switch from existing therapies even when new and potentially more effective or safer treatments enter the market.

Physicians and their patients may likewise make decisions about therapies based on cost and insurance coverage and reimbursement.

Such reimbursement may be impacted by our ability to enter into single-case agreements (in the absence of a longer term agreement) with insurance companies, and the absence of any agreement or inadequate coverage or reimbursement may require patients to pay from their own funds, but the costs of our products may be prohibitive in such cases.

Efforts to educate the medical community and third-party payors on the benefits of our products and product candidates may require significant resources and may not be successful.

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● the safety, efficacy, and other potential advantages over, and availability of, alternative treatments already used or that may later be approved for any of our intended indications;

● distribution and use restrictions imposed by the FDA with respect to such products and product candidates or to which we agree as part of a mandatory risk evaluation and mitigation strategy or voluntary risk management plan;

● distribution and use restrictions imposed by the FDA with respect to such products and product candidates or to which we agree as part of a mandatory REMS or voluntary risk management plan;

● the timing of market introduction of such products and product candidates, as well as competitive products;

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Our efforts to educate the medical community and third-party payors on the benefits of our products and product candidates may require significant resources and may never be successful.

Even if the medical community accepts that our products and product candidates are safe and effective for their approved indications, physicians and patients may not immediately be receptive to such products or product candidates and may be slow to adopt them as an accepted treatment of the approved indications.

Even if the medical community accepts that our products and product candidates are safe and effective for their approved indications and third-party payors provide coverage and reimbursement for the same, physicians and patients may not immediately be receptive to such products or product candidates and may be slow to adopt them as an accepted treatment of the approved indications.

If our current or future products and product candidates are approved but do not achieve an adequate level of acceptance among physicians, patients, and third-party payors, we may not generate meaningful revenues from our product candidates, and we may not become profitable.

Our products and product candidates may face competition sooner than anticipated.

The enactment of the BPCIA created an abbreviated pathway for the approval of biosimilar and interchangeable biological products.

The enactment of the Biologics Price Competition and Innovation Act, or the BPCIA, created an abbreviated pathway for the approval of biosimilar and interchangeable biological products.

The abbreviated regulatory pathway establishes legal authority for the FDA to review and approve biosimilar biologics, including the possible designation of a biosimilar as “interchangeable” based on its similarity to an existing brand product.

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It is also possible that payors will give reimbursement preference to biosimilars even over reference biologics absent a determination of interchangeability.

We will need to obtain FDA approval of any proposed proprietary branded product names, and any failure or delay associated with such approval may adversely affect our business.

Any name we intend to use for our products and product candidates will require approval from the FDA regardless of whether we have secured a formal trademark registration from the U.S.

We will need to obtain approval of any proposed proprietary branded product names, and any failure or delay associated with such approval may adversely affect our business.

Any name we intend to use for our products and product candidates will require approval from the FDA and foreign regulatory authorities regardless of whether we have secured a formal trademark registration, including from the U.S.

Patent and Trademark Office, or USPTO.

The FDA typically conducts a review of proposed product names, including an evaluation of the potential for confusion with other product names.

The FDA may also object to a product name if it believes the name inappropriately implies medical claims or contributes to an overstatement of efficacy.

If the FDA objects to any of our proposed proprietary product names, we may be required to adopt alternative names for our products and/or product candidates.

If we adopt alternative names, we would lose the benefit of any existing trademark applications for such product and/or product candidate and may be required to expend significant additional resources in an effort to identify a suitable product name that would qualify under applicable trademark laws, not infringe the existing rights of third parties, and be acceptable to the FDA.

The FDA and foreign regulatory authorities typically conduct a review of proposed product names, including an evaluation of the potential for confusion with other product names.

The FDA and foreign regulatory authorities may also object to a product name if they believe the name inappropriately implies medical claims or contributes to an overstatement of efficacy.

If the FDA or a foreign regulatory authority objects to any of our proposed proprietary product names, we may be required to adopt alternative names for our products and/or product candidates.

the FDA and foreign regulatory authorities.

We may be unable to build a successful brand identity for a new trademark in a timely manner or at all, which would limit our ability to commercialize our products and product candidates.

As a condition of approval, the FDA may require that we implement various post-marketing requirements and conduct post-marketing studies, any of which would require a substantial investment of time, effort, and money, and which may limit our commercial prospects.

As a condition of biologic licensing, the FDA is authorized to require that sponsors of approved BLAs implement various post-market requirements, including REMS and Phase 4 studies.

For example, we reached an agreement with the FDA regarding a confirmatory trial to support full approval of lifileucel in post-anti-PD-1 advanced melanoma, which we refer to as TILVANCE-301.

We began startup activities for the randomized Phase 3 TILVANCE-301 trial in the fourth quarter of 2022.

If we receive approval of our product candidates, the FDA may determine that similar or additional post-approval requirements are necessary to ensure that our product candidates are safe, pure, and potent.

To the extent that we are required to establish and implement any post-approval

requirements, we will likely need to invest a significant amount of time, effort, and money.

As a condition of approval, the FDA and foreign regulatory authorities may require that we implement various post-marketing requirements and conduct post-marketing studies, any of which would require a substantial investment of time, effort, and money, and which may limit our commercial prospects.

As a condition of biologic licensing, the FDA and foreign regulatory authorities are authorized to require that sponsors of approved BLAs implement various post-market requirements, including REMS and Phase 4 studies.

For example, we reached an agreement with the FDA regarding a confirmatory trial to support the conversion from accelerated to full approval of Amtagvi ® in post-anti-PD-1 advanced melanoma, which we refer to as TILVANCE-301.

The randomized Phase 3 TILVANCE-301 trial has been ongoing since the fourth quarter of 2022.

If we receive approval of additional product candidates, the FDA and foreign regulatory authorities may determine that similar or additional post-approval requirements are necessary to ensure that our product candidates are safe, pure, and potent.

To the extent that we are required to establish and implement any post-approval requirements, we will likely need to invest a significant amount of time, effort, and money.

Such post-approval requirements may also limit the commercial prospects of our products and product candidates.

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If these third-party service providers fail to comply with applicable laws and regulations, fail to meet expected deadlines, or otherwise do not carry out their contractual duties to us, or encounter physical or natural damage at their facilities, our ability to deliver product to meet commercial demand would be significantly impaired and we may be subject to regulatory enforcement action.

Moreover, these agreements might terminate for a variety of reasons.

If we fail to enter into alternative arrangements, this could further delay the commercialization of our products and adversely affect our business.

In addition, we may engage third parties to perform various other services for us relating to adverse event reporting, safety database management, fulfillment of requests for medical information regarding our product candidates and related services.

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We may be unable to successfully or sufficiently expand our manufacturing capacity to meet demand for our products.

As noted above, we have never manufactured our adoptive cell therapy product candidates on a commercial scale, nor have our partners.

We anticipate expanding manufacturing capacity at our iCTC facility and/or at our contract manufacturer, WuXi.

Scale-up of manufacturing may require additional validation studies, including capacity demonstration and/or comparability studies, each of which are subject to FDA review, potential inspection, and approval.

Moreover, current geopolitical tensions with China may impact our ability to expand manufacturing capacity at our contract manufacturer, WuXi.

As noted above, we have limited experience in internal manufacturing our adoptive cell therapy product candidates on a commercial scale, as do our partners.

We anticipate expanding internal manufacturing capacity at our i CTC facility and potentially at our contract manufacturer, WuXi.

Scale-up of manufacturing may require additional validation studies, including capacity demonstration and/or comparability studies, each of which are subject to regulatory review, potential inspection, and approval.

Moreover, while we continue to expand our internal manufacturing capacity, the current geopolitical tensions with China may impact our ability to expand manufacturing capacity at our contract manufacturer, WuXi.

Recently, the Biden administration has signed multiple executive orders regarding China.

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domestic manufacturing of pharmaceutical products.

Additionally, there have been Congressional legislative proposals, such as the recent bill titled the Biosecure Act, to discourage contracting with Chinese companies on the development or manufacturing of pharmaceutical products.

Finally, in February 2024, the chair and ranking member of the House Select Committee on the Chinese Communist Party, Representatives Mike Gallagher and Raja Krishnamoorthi, respectively, along with Senators Gary Peters and Bill Haggerty sent a letter to the Biden administration requesting that both WuXi AppTec Co., Ltd., WuXi’s parent company, and the affiliated WuXi Biologics be added to the Department of Defense’s Chinese Military Companies List (1260H list), the Department of Commerce’s Bureau of Industry and Security Entity List, and the Department of Treasury’s Non-SDN Chinese Military-Industrial Complex Companies List.

While the Biden administration has yet to take action on this letter, adding either or both previously mentioned WuXi entities on any or all of the aforementioned lists could materially impact our MSA with WuXi.

Regardless, any expansion of our manufacturing capability will also require us to invest substantial additional funds to hire and retain the technical personnel who have the necessary manufacturing experience.

Additionally, in February 2024, the chair and ranking member of the House Select Committee on the Chinese Communist Party, Representatives Mike Gallagher and Raja Krishnamoorthi, respectively, along with Senators Gary Peters and Bill Hagerty, sent a letter to the Biden administration requesting that both WuXi AppTec Co., Ltd., WuXi’s parent company, and the affiliated WuXi Biologics be added to the Department of Defense’s Chinese Military Companies List (1260H list), the Department of Commerce’s Bureau of Industry and Security Entity List, and the Department of Treasury’s Non-SDN Chinese Military-Industrial Complex Companies List.

While the Biden administration did not take action on this letter, adding either or both previously mentioned WuXi entities on any or all of the aforementioned lists could materially impact our MSA with WuXi, and the current Trump administration could take action with regard to such letter.

The new administration may also enact regulations or policies that affect trade with China or otherwise impact the biopharmaceutical industry by enacting laws to restrict U.S.

biopharmaceutical companies from contracting with Chinese companies on the development, research or manufacturing of biopharmaceutical products.

Any additional executive orders, legislative action or potential sanctions on China could materially impact our current manufacturing partners.

Finally, there have been Congressional legislative proposals, such as a bill titled the BIOSECURE Act, to discourage contracting with certain Chinese companies, including two WuXi affiliates, on the development or manufacturing of pharmaceutical products.

The BIOSECURE Act passed the U.S.

House of Representatives on September 9, 2024.

The version of the BIOSECURE Act that passed the U.S.

House of Representatives included a grandfather clause that would allow contracts entered into with the Chinese companies named therein prior to the effective date of such legislation to survive until January 1, 2032.

The BIOSECURE Act did not pass the U.S.

Senate before expiring, thus not becoming law, but support for the legislation remains, and the current Trump administration has promised to take a hard line on Chinese entities.

While WuXi has recently entered into an agreement to be acquired by Altaris LLC, or Altaris, there is no guarantee that they will complete the transaction or that, after the transaction is completed, we will be able to continue to utilize their contract manufacturing services, as Altaris and its subsidiary Minaris Regenerative Medicine LLC, or Minaris, have limited resources and lack experience in supplying high volume commercial cell therapies for oncology

As a result, we may need to discontinue use of the WuXi manufacturing capacity and instead use the i CTC facility or other manufacturers to supply our therapies.

Regardless, any expansion of our internal and external manufacturing capability will also require us to invest substantial additional funds to hire and retain the technical personnel who have the necessary manufacturing experience.

As a result, we may not be able to successfully or sufficiently increase the manufacturing capacity for our product candidates or modify our manufacturing processes.

If we are unable to successfully increase the manufacturing capacity for a product candidate (as a result of lack of approval from, or capacity limitations imposed by, the FDA, or otherwise), the resulting capacity limitations could have a material adverse effect on our results of operations and financial condition.

In addition, if we are unable to successfully or sufficiently increase the manufacturing capacity at the iCTC facility to meet demand in a timely or economic manner, or at all, we may be dependent upon the performance and capacity of third-party manufacturers.

In addition, if we are unable to successfully or sufficiently increase the manufacturing capacity at the i CTC facility to meet demand in a timely or economic manner, or at all, we may be dependent upon the performance and capacity of third-party manufacturers.

Accordingly, we face risks of capacity limitations of, difficulties with, increased costs of, and interruptions in performance by third-party manufacturers, the occurrence of which could negatively impact the availability, launch, and/or sales of our products in the future, as well as on our results of operations and financial condition.

While we have agreements in place with such third-party manufacturers, we have limited influence over their actual performance and control only certain aspects of their activities.

The failure of these third parties to successfully carry out their contractual duties or meet expected deadlines or quality standards could substantially harm our business.

Moreover, these agreements might terminate for a variety of reasons.

If we fail to enter into alternative arrangements, this could further delay our product development and adversely affect our business.

For example, BI carries out the processing, manufacturing, and supply of Proleukin ® pursuant to a manufacturing and supply agreement, which includes a two-year notice of termination provision.

In the event that such notice of termination is given, it may be unlikely that we execute a new manufacturing and supply agreement with a manufacturer to run the processing, manufacturing, and supply of Proleukin ® within that time frame.

Risks Related to the Development of Our Product Candidates

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We currently have two products approved for commercial sale.

We have invested a significant portion of our efforts and financial resources in the development of our current product and/ or product candidates, including Amtagvi™, LN-145, IOV-4001, IOV-2001, and IOV-3001, and expect that we will continue to invest heavily in our current product candidates, as well as in any future product candidates we may develop.

We have invested a significant portion of our efforts and financial resources in the development of our current product and/or product candidates, including Amtagvi ® , lifileucel, and modified product candidates, IOV-4001, IOV-2001, IOV-3001, and IOV-5001, and expect that we will continue to invest heavily in our current product candidates, as well as in any future product candidates we may develop.

Our business depends on the successful development and commercialization of our product candidates.

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Our product candidates will require additional clinical and non-clinical development, regulatory approval, commercial manufacturing arrangements, establishment of a commercial organization, significant marketing efforts, and further investment before we generate any revenue from product sales.

We cannot assure you that we will meet our timelines for our current or future clinical trials, which may be delayed or not completed for a number of reasons, including the negative impact of the COVID-19 pandemic.

We cannot assure you that we will meet our timelines for our current or future clinical trials, which may be delayed or not completed for a number of reasons, including the continuing negative impact of the COVID-19 pandemic and any future pandemic or epidemic.

Additionally, the costs associated with development of cell therapy products may be significant due to the length of treatment and the supportive therapies provided to the patient during the treatment process.

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Our treatment centers may not be able to obtain necessary supplies, such as lymphodepleting chemotherapy agents, because of shortages.

If commercialized, our products will rely heavily on our ability to train centers and the centers’ ability to choose suitable patients and deliver a complex regimen.

Our commercial products and investigational therapies will rely heavily on our ability to train centers and the centers’ ability to choose suitable patients and deliver a

complex regimen.

We may be reliant on physicians with limited experience with TIL products and the associated regimens.

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Patients may progress in the course of their disease or may experience serious adverse events from our products or supportive regimens while undergoing or awaiting treatment with our therapies.

Prior to our completion of a rolling BLA submission for lifileucel in March 2023 and its acceptance by the FDA in May 2023, we had not previously submitted a BLA to the FDA, or a similar marketing application to comparable foreign authorities, for any product candidate, and we cannot be certain that our current or any future product candidates will be successful in clinical trials or receive regulatory approval.

Prior to our completion of a rolling BLA submission for lifileucel in March 2023 and its acceptance by the FDA in May 2023 and accelerated approval in February 2024, we had not previously submitted a BLA to the FDA, or a similar marketing application to comparable foreign authorities, for any product candidate, and we cannot be certain that our current or any future product candidates will be successful in clinical trials or receive regulatory approval.

Furthermore, although we have not submitted our BLA with comparisons to existing or more established therapies and likewise do not expect the FDA to base its determination with respect to product approval on such comparisons, the FDA may factor these comparisons into its decision whether to approve our TIL cell therapies.

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● price our product candidates competitively such that third-party and government reimbursement leads to broad product adoption;

● prepare a broad network of clinical sites for administration of our product;

● prepare a broad network of clinical sites ( e.g.

, ATCs) for administration of our product;

● train and monitor sites for product delivery and consistent flow of appropriate patients;

● create market demand for our product candidates through our own marketing and sales activities, and any other arrangements to promote these product candidates that we may otherwise establish;

● create market demand for our product candidates through our own marketing and sales activities, as well as through other arrangements with third parties marketing or selling on our behalf;

● receive regulatory approval for the targeted patient population(s) and claims that are necessary or desirable for successful marketing;

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● achieve market acceptance of our product candidates by patients, the medical community, and third-party payors;

● achieve appropriate reimbursement for our product candidates;

● obtain payor coverage at rates that will enable the market to adopt our product and enable sites to deliver the entire therapy to patients;

● obtain appropriate coverage and reimbursement for our product candidates, including at rates that will enable the market to adopt our products and enable sites to deliver the entire therapy to patients;

● partner with third party logistics providers that will successfully distribute our products;

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Development of a product candidate intended for use in combination with an already approved product may present more or different challenges than development of a product candidate for use as a single agent.

We are currently developing lifileucel as part of a regimen which uses IL-2.

We and our collaborators are also clinical trialing TIL cell therapy along with other products, such as pembrolizumab, ipilimumab and nivolumab.

Amtagvi ® received accelerated approval from the FDA, and we are currently developing lifileucel in clinical trials as part of a regimen which uses lymphodepletion and IL-2.

We and our collaborators are also developing TIL cell therapy along with other products, such as pembrolizumab, ipilimumab and nivolumab.

The development of product candidates for use in combination with another product may present challenges.

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Such developments may include changes to the approved product’s safety or efficacy profile, changes to the availability of the approved product, and changes to the standard of care.

A Fast Track product designation, BTD, or other designation to facilitate product candidate development may not lead to faster development or a faster regulatory review or approval process, and it does not increase the likelihood that our product candidates will receive marketing approval.

A Fast Track, breakthrough therapy, or regenerative medicines advanced therapy product designations, or other designation to facilitate product candidate development may not lead to faster development or a faster regulatory review or approval process, and it does not increase the likelihood that our product candidates will receive marketing approval.

We were granted Fast Track designation by the FDA for lifileucel in metastatic melanoma and metastatic cervical cancer, as well as for lifileucel in combination with pembrolizumab in advanced melanoma.

We were granted BTD for lifileucel for metastatic cervical cancer and RMAT designation for lifileucel in advanced melanoma.

We were granted breakthrough therapy designation, or BTD, for lifileucel for metastatic cervical cancer and RMAT designation for lifileucel in advanced melanoma.

We may seek Fast Track or Breakthrough designation for other of our current or future product candidates.

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In addition, the FDA may later decide that the products no longer meet the designation conditions.

While lifileucel has received ODD for melanoma stages IIB-IV and for cervical cancer patients with tumors greater than 2 cm, there is no guarantee that we will be able to maintain this designation, receive these designations for any of our other product candidates, or receive or maintain any corresponding benefits, including periods of exclusivity.

We received ODD in the U.S.

While lifileucel has received orphan drug designation for melanoma stages IIB-IV and for cervical cancer patients with tumors greater than 2 cm, there is no guarantee that we will be able to maintain this designation, receive these designations for any of our other product candidates, or receive or maintain any corresponding benefits, including periods of exclusivity.

We received orphan drug designation, or ODD, in the U.S.

for lifileucel to treat malignant melanoma stages IIB-IV and cervical cancer patients with tumors greater than 2 cm.

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Even if we obtain orphan exclusivity, that exclusivity may not effectively protect the product from competition because different products can be approved for the same condition and the same product can be approved for different conditions.

Even after an orphan product is approved, the FDA can subsequently approve a product containing the same principal molecular features for the same

condition if the FDA concludes that the later product is clinically superior in that it is shown to be safer or more effective or makes a major contribution to patient care.

Even after an orphan product is approved, the FDA can subsequently approve a product containing the same principal molecular features for the same condition if the FDA concludes that the later product is clinically superior in that it is shown to be safer or more effective or makes a major contribution to patient care.

Moreover, the FDA may grant ODDs to multiple of the same products for the same indication.

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We are heavily reliant on third parties to conduct our clinical trials.

We have a limited history of conducting clinical trials and have no experience as a company in filing and supporting the applications necessary to gain marketing approvals.

We have a limited history of conducting clinical trials and as a company in filing and supporting the applications necessary to gain marketing approvals.

Securing marketing approval requires the submission of extensive preclinical and clinical data and supporting information to regulatory authorities for each therapeutic indication to establish the product candidate’s safety, purity, and potency for that indication.

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Failure can occur at any time during the clinical trial process.

As a result of the COVID-19 pandemic, institutions and research sites that currently conduct clinical trials may not be able to return to normal clinical trial operations for some time or may no longer choose to participate in studies in the future.

As a result of the continuing impact of the COVID-19 pandemic, institutions and research sites that currently conduct clinical trials may not be able to return to normal clinical trial operations for some time or may no longer choose to participate in studies in the future.

Furthermore, clinical trials may be delayed or otherwise may be more difficult to execute in the future.

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however, we as a company have limited experience completing pivotal clinical trials for cell therapy products or developing preclinical immunotherapy products.

In part because of this lack of experience, we cannot be certain that our ongoing pivotal clinical trials will be completed on time, if at all, will progress according to our plans or expectations, or that our planned clinical trials will be initiated or initiated in a timely manner, progress according to our plans or expectations, or be completed on time, if they are completed at all.

In part because of this lack of experience, we cannot be certain that our ongoing pivotal clinical trials will be completed on time, if at all, that they will progress according to our plans or expectations, or that our planned clinical trials will be initiated or initiated in a timely manner, progress according to our plans or expectations, or be completed on time, if they are completed at all.

Large-scale clinical trials require significant financial and management resources, and reliance on third-party clinical investigators, CROs, CMOs, or consultants.

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Nevertheless, we are responsible for ensuring that each of our studies is conducted in accordance with the applicable protocol, legal, regulatory, and scientific standards and our reliance on the CROs, clinical trial sites, and other third parties do not relieve us of these oversight responsibilities.

For example, we will remain responsible for ensuring that each of our clinical trials is conducted in accordance with the general

investigational plan and protocols for the clinical trial and for ensuring that our preclinical studies are conducted in accordance with Good Laboratory Practices, or GLPs, as appropriate.

For example, we will remain responsible for ensuring that each of our clinical trials is conducted in accordance with the general investigational plan and protocols for the clinical trial and for ensuring that our preclinical studies are conducted in accordance with Good Laboratory Practices, or GLPs, as appropriate.

Moreover, the FDA and comparable foreign regulatory authorities require us to comply with Good Clinical Practices, or GCPs, for conducting, recording, and reporting the results of clinical trials to assure that data and reported results are credible and accurate and that the rights, integrity, and confidentiality of clinical trial participants are protected.

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Failure to do so could result in enforcement actions and adverse publicity.

In addition, our clinical trials must be conducted with product candidates that were produced under cGMP.

Our failure to comply or our CMOs’ failure to comply with these regulations may require us to repeat clinical trials, which would delay the regulatory approval process.

We also are required to register certain clinical trials and post the results of certain completed clinical trials on a government sponsored database, ClinicalTrials.gov, within specified timeframes.

Failure to do so could result in enforcement actions and adverse publicity.

In the EU, revised transparency rules for clinical trials became applicable with the launch of the new Clinical Trials Information System, or CTIS.

The CTIS is the online system for the regulatory submission, authorization, and supervision of clinical trials conducted in the EU/European Economic Area, or EEA, under Regulation (EU) 536/2014.

Data of all clinical trials conducted in the EU/EEA – including their results – must be submitted to the CTIS and are made publicly available, unless a specific exemption applies.

Our CROs, clinical trial sites, and other third parties may also have relationships with other entities, some of which may be our competitors, for whom they may also be conducting clinical trials or other therapeutic development activities that could harm our competitive position.

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Any performance failure on the part of these third parties could delay clinical development or marketing approval of our product candidates or commercialization of our product candidates, if approved, producing additional losses and depriving us of potential product revenue.

We may encounter substantial delays in our clinical trials or may not be able to conduct our clinical trials on the timelines we expect, and we may be required to conduct additional clinical trials or modify current or future clinical trials based on feedback we receive from the FDA.

We may encounter substantial delays in our clinical trials, not be able to conduct our clinical trials on the timelines we expect, and be required to conduct additional clinical trials or modify current or future clinical trials based on feedback we receive from the FDA and foreign regulatory authorities.

Clinical testing is expensive, time consuming, and subject to uncertainty.

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Additionally, temporary or permanent clinical holds could be placed on our clinical trials for a variety of reasons.

For instance, on December 22, 2023, the FDA placed a clinical hold on the IOV-LUN-202 trial in response to a recently reported Grade 5 (fatal) serious adverse event potentially related to the non-myeloablative lymphodepletion pre-conditioning regimen, and we have paused enrollment and the LN-145 treatment regimen for new patients in IOV-LUN-202 during the clinical hold.

A failure of one or more clinical trials can occur at any stage of testing, and our future clinical studies may not be successful.

For instance, on December 22, 2023, the FDA placed a clinical hold on the IOV-LUN-202 trial in response to a reported Grade 5 (fatal) serious adverse event potentially related to the non-myeloablative lymphodepletion pre-conditioning regimen, and we paused enrollment and the lifileucel treatment regimen for new patients in IOV-LUN-202 during the clinical hold.

On March 4, 2024, the FDA lifted the partial clinical hold on the IOV-LUN-202 trial, permitting us to resume patient enrollment.

A failure of one or more clinical trials can occur at any stage of testing, and our future

clinical studies may not be successful.

Events that may prevent successful or timely initiation or completion of clinical development, or product approval include:

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● clinical trials of our product candidates producing negative or inconclusive results may fail to provide sufficient data and information to support product approval, or our studies may fail to reach the necessary level of statistical or clinical significance, which may result in our deciding, or regulators requiring us, to conduct additional clinical trials studies, or preclinical studies, or abandon product development programs;

● early results from our clinical trials of our product candidates may be negatively affected by changes in efficacy measures such as overall response rate and duration of response as more patients are enrolled in our clinical trials or as new cohorts of our clinical trials are tested, and overall response rate and duration of response may be negatively affected by the inclusion of unconfirmed responses in preliminary results that we report if such responses are not later confirmed;

our clinical trials are tested, and overall response rate and duration of response may be negatively affected by the inclusion of unconfirmed responses in preliminary results that we report if such responses are not later confirmed;

● we may not be able to demonstrate that a product candidate provides an advantage over current standards of care or current or future competitive therapies in development;

● there may be changes to the therapeutics or their regulatory status which we are administering in combination with our product candidates;

● delays in patient enrollment due to the ongoing COVID-19 pandemic;

● delays in patient enrollment due to potential health epidemics, such as the COVID-19 pandemic;

● the FDA or comparable foreign regulatory authorities may fail to approve or subsequently find fault with the manufacturing processes or our manufacturing facilities for clinical and future commercial supplies;

● the FDA or comparable regulatory authorities may take longer than we anticipate making a decision on our product candidates;

● the FDA or comparable regulatory authorities may take longer than we anticipate when making a decision on our product candidates and prolonged government shutdowns, inadequate funding, loss of employees, changes in regulations or policies by the new U.S.

administration or other disruptions may occur at the FDA, and thus, final FDA approval of our product candidates may be further delayed;

● transfer of our manufacturing processes to our CMOs or other larger-scale facilities operated by a CMO or by us and delays or failures by our CMOs or us to make any necessary changes to such manufacturing process;

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● delays in manufacturing, testing, releasing, validating, or importing/exporting sufficient stable quantities of our product candidates for use in clinical trials or the inability to do any of the foregoing, including as a result of any quality issues associated with the contract manufacturer.

If prolonged government shutdowns, inadequate funding, loss of employees, changes in regulations or policies by the new U.S.

administration or other disruptions were to occur at the FDA, final FDA approval of our product candidates may be delayed.

The ability of the FDA and other government agencies to review and approve new or modified products can be affected by a variety of factors, including government budget and funding levels, statutory, regulatory and policy changes, a government agency’s ability to hire and retain key personnel and accept the payment of user fees, and other events that may otherwise affect the government agency’s ability to perform routine functions.

Average review times at the FDA and other government agencies have fluctuated in recent years as a result.

For example, over the last several years, the U.S.

government has shut down several times and certain regulatory agencies, such as the FDA and SEC, have had to furlough critical employees and stop critical activities.

In addition, government funding of agencies on which our operations may rely, including those that fund research and development activities, is subject to the political process, which is inherently fluid and unpredictable.

Such disruptions at the FDA and other agencies may also increase the time necessary for new drugs or modifications to approved drugs to be reviewed and/or approved by necessary government agencies, which would adversely affect our business.

We also may conduct clinical and preclinical research in collaboration with other academic, pharmaceutical, biotechnology and biologics entities in which we combine our technologies with those of our collaborators.

Such collaborations may be subject to additional delays because of the management of the clinical trials, contract negotiations, the need to obtain agreement from multiple parties, and the necessity of obtaining additional approvals for therapeutics used in the combination clinical trials.

These combination therapies will require additional testing and clinical trials will require additional FDA regulatory approval and will increase our future cost of expenses.

These combination therapies will require additional testing and clinical trials will require additional regulatory approval and will increase our future cost of expenses.

Any inability to successfully complete preclinical and clinical development could result in additional costs to us or impair our ability to generate revenue.

In addition, if we make manufacturing changes to our product candidates, we may be required to, or we may elect to, conduct additional studies to bridge our modified product candidates to earlier versions.

These changes may require FDA approval or notification, may not have their desired effect, or the FDA may not accept data from prior versions of the product to support an application, delaying our clinical trials or programs or necessitating additional clinical trials or preclinical studies.

These changes may require regulatory approval or notification, may not have their desired effect, or the FDA or foreign regulatory authorities may not accept data from prior versions of the product to support an application, delaying our clinical trials or programs or necessitating additional clinical trials or preclinical studies.

For example, while our first BLA submission includes our Gen 2 manufacturing process, in the future we may seek to commercialize other manufacturing processes, such as our Gen 3 manufacturing process or our PD-1 selected TIL manufacturing process.

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For budgeting and planning purposes, we have projected the date for the commencement of future clinical trials, and continuation and completion of our ongoing clinical trials.

However, a number of factors, including scheduling conflicts with participating clinicians and clinical institutions, difficulties in identifying and enrolling patients who meet clinical trial eligibility criteria, and the ongoing COVID-19 pandemic, may cause significant delays.

However, a number of factors, including scheduling conflicts with participating clinicians and clinical institutions, and difficulties in identifying and enrolling patients who meet clinical trial eligibility criteria, may cause significant delays.

We may not commence or complete clinical trials involving any of our products as projected or may not conduct them successfully.

We are currently enrolling seven company-sponsored clinical trials to assess the overall safety and efficacy of Iovance TIL monotherapy and TIL combinations in patients with melanoma, cervical, head and neck and lung cancers across late-line and early treatment settings, as well as our genetically modified TIL cell therapy IOV-4001 and our peripheral blood lymphocyte, or PBL, technology for hematological malignancies.

We are currently conducting eight company-sponsored clinical trials to assess the overall safety and efficacy of Iovance TIL monotherapy and TIL combinations in patients with melanoma, cervical, endometrial, head and neck, and lung cancers across late-line and early treatment settings, as well as our genetically modified TIL cell therapy IOV-4001 and our peripheral blood lymphocyte, or PBL, technology for hematological malignancies.

However, we may experience difficulties in patient enrollment in our clinical trials for a variety of reasons.

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This opportunity for investigator selection bias in our clinical trials as a result of open-label design may not be adequately handled and may cause a decline in or distortion of clinical trial data from our preliminary results.

Depending on the outcome of our open-label studies, we may need to conduct one or more follow-up or supporting studies in order to successfully develop our products for FDA approval.

Depending on the outcome of our open-label studies, we may need to conduct one or more follow-up or supporting studies in order to successfully develop our products for regulatory approval.

Many companies in the biotechnology, pharmaceutical, and medical device industries have suffered significant setbacks in late-stage clinical trials after achieving positive results in earlier development, and we cannot be certain that we will not face such setbacks.

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Accordingly, we cannot guarantee that the clinical trial will progress as planned or as scheduled.

Delays in patient enrollment may result in increased costs or may affect the timing or

outcome of our ongoing clinical trial and planned clinical trials, which could prevent completion of these clinical trials and adversely affect our ability to advance the development of our product candidates.

Delays in patient enrollment may result in increased costs or may affect the timing or outcome of our ongoing clinical trial and planned clinical trials, which could prevent completion of these clinical trials and adversely affect our ability to advance the development of our product candidates.

We expect to rely on medical institutions, academic institutions, or CROs to conduct, supervise or monitor some or all aspects of clinical trials involving our products.

We will have less control over the timing and other aspects of these clinical trials than if we conducted them entirely on our own.

We will have less control over the timing and other aspects of these clinical trials than if we

conducted them entirely on our own.

If we fail to commence or complete, or experience delays in, any of our planned clinical trials, our stock price and our ability to conduct our business as currently planned could be harmed.

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Our clinical trials may fail to demonstrate adequately the safety and efficacy of our product candidates, which would prevent or delay regulatory approval and commercialization.

The clinical trials of our product candidates are, and the manufacturing and marketing of our products will be, subject to extensive and rigorous review and regulation by numerous government authorities in the U.S.

The clinical trials of our product candidates are, and the manufacturing and marketing of our products is, subject to extensive and rigorous review and regulation by numerous government authorities in the U.S.

and in other countries where we intend to test and market our product candidates.

Before obtaining regulatory approvals for the commercial sale of any of our product candidates, we must demonstrate through lengthy, complex and expensive preclinical testing and clinical trials that our product candidates are both safe and effective for use in each target indication.

Before obtaining additional regulatory approvals for the commercial sale of any of our product candidates, we must demonstrate through lengthy, complex and expensive preclinical testing and clinical trials that our product candidates are both safe and effective for use in each target indication.

Because our product candidates are subject to regulation as biological drug products, we will need to demonstrate that they are safe, pure, and potent for use in their target indications.

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There is typically an extremely high rate of attrition from the failure of product candidates proceeding through clinical trials.

Product candidates in later stages of clinical trials

may fail to show the desired safety and efficacy profile despite having progressed through preclinical studies and initial clinical trials.

Product candidates in later stages of clinical trials may fail to show the desired safety and efficacy profile despite having progressed through preclinical studies and initial clinical trials.

Many companies in the biopharmaceutical industry have suffered significant setbacks in advanced clinical trials due to lack of efficacy or unacceptable safety issues, notwithstanding promising results in earlier clinical trials.

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To the extent that the results of the clinical trials are not satisfactory to the FDA or foreign regulatory authorities for support of a marketing application, we may be required to expend significant resources, which may not be available to us, to conduct additional clinical trials in support of potential approval of our product candidates.

We have reported preliminary results for clinical trials of our product candidates, including TIL for the treatment of metastatic melanoma, non-small cell lung cancer, cervical cancer, and head and neck cancers.

We have reported preliminary results for clinical trials of our product candidates, including TIL cell therapy for the treatment of metastatic melanoma, non-small cell lung cancer, cervical cancer, and head and neck cancers.

These preliminary results, which include assessments of efficacy such as ORR, are subject to substantial risk of change due to small sample sizes and may change as patients are evaluated or as additional patients are enrolled in these clinical trials.

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● clinical investigators enrolling patients who do not meet the enrollment criteria, requiring the inclusion of additional patients in the clinical trial;

● the ongoing COVID-19 pandemic limiting our access to patients who would otherwise be eligible for enrollment, including treatment-naïve patients who may be more likely to seek standard of care therapies available at local treatment centers rather than enroll in a clinical trial at a larger hospital;

● health epidemics, such as the COVID-19 pandemic, limiting our access to patients who would otherwise be eligible for enrollment, including treatment-naïve patients who may be more likely to seek standard of care therapies available at local treatment centers rather than enroll in a clinical trial at a larger hospital;

● approval of new indications for existing therapies or approval of new therapies in general;

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Even if we are able to enroll a sufficient number of patients in our clinical trials, delays in patient enrollment or small population size may result in increased costs or may affect the timing or outcome of the planned clinical trials, which could prevent completion of these clinical trials and adversely affect our ability to advance the development of our product candidates.

Our product candidates may cause undesirable side effects or have other properties that could halt their clinical development, prevent their regulatory approval, limit their commercial potential, or result in significant negative consequences.

Our commercial product and product candidates may cause undesirable side effects or have other properties that could halt their clinical development, prevent their regulatory approval, limit their commercial potential, or result in significant negative consequences.

Results of our clinical trials could reveal a high and unacceptable severity and prevalence of side effects or unexpected characteristics.

Undesirable side effects caused by our product candidates could cause us, IRBs, DSMBs, or regulatory authorities to interrupt, delay or halt clinical trials and could result in a more restrictive label or the delay or denial of regulatory approval by the FDA or other comparable foreign regulatory authorities.

Even if we were to receive product approval, such approval could be contingent on inclusion of unfavorable information in our product labeling, such as limitations on the indications for use for which the products may be marketed or distributed, a label with significant safety warnings, including boxed warnings, contraindications, and precautions, a label without statements necessary or desirable for successful commercialization, or requirements for costly post marketing testing and surveillance, or other requirements, including a Risk Evaluation and Mitigations Strategy or REMS, to monitor the safety or efficacy of the products, and in turn prevent us from commercializing and generating revenues from the sale of our current or future product candidates.

Even if we were to receive product approval, such approval could be contingent on inclusion of unfavorable information in our product labeling, such as limitations on the indications for use for which the products may be marketed or distributed, a label with significant safety warnings, including boxed warnings, contraindications, and precautions, a label without statements necessary or desirable for successful commercialization, or requirements for costly post marketing testing and surveillance, or other requirements, including a REMS, to monitor the safety or efficacy of the products, and in turn prevent us from commercializing and generating revenues from the sale of our current or future product candidates.

If unacceptable toxicities or side effects arise in the development of our product candidates, we, an IRB, DSMB, or the FDA or comparable foreign regulatory authorities could order us to cease clinical trials, order our clinical trials to be placed on clinical hold, or deny approval of our product candidates for any or all targeted indications.

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In addition, failure to manage toxicities, adverse events or side effects and to take recommended or other precautions may result in deaths or harm to patients.

Furthermore, harm to patients may not be appropriately recognized or managed by the treating medical

staff, because treatments related to personalized cell therapy are not normally encountered in the general patient population and by medical personnel.

Furthermore, harm to patients may not be appropriately recognized or managed by the treating medical staff, because treatments related to personalized cell therapy are not normally encountered in the general patient population and by medical personnel.

Any of these occurrences may harm our business, financial condition and prospects significantly.

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It could take as much as 12 months or more before we learn the results from any clinical trial using our adoptive cell therapy with TIL.

The data collected from our clinical trials may not be sufficient to support approval by the FDA of our TIL-based product candidates for the treatment of solid tumors.

The clinical trials for our products under development may not be completed on schedule and the FDA may not ultimately approve any of our product candidates for commercial sale.

The data collected from our clinical trials may not be sufficient to support approval by the FDA and foreign regulatory authorities of our TIL-based product candidates for the treatment of solid tumors.

The clinical trials for our products under development may not be completed on schedule and the FDA and foreign regulatory authorities may not ultimately approve any of our product candidates for commercial sale.

If we fail to adequately demonstrate the safety and efficacy of any product candidate under development, we may not receive regulatory approval for those products, which would prevent us from generating revenues or achieving profitability.

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Failure to obtain additional rights and licenses may detrimentally affect our planned development of additional product candidates and could increase the cost, and extend the timelines associated with our development of such other products.

We are required to pay substantial royalties and lump sum benchmark payments under our license or acquisition agreements with the NIH, Moffitt, Novartis, Clinigen and Cellectis, and we must meet certain milestones to maintain our license rights.

Under our license or acquisition agreements with the NIH, Moffitt, Novartis, Clinigen and Cellectis for our adoptive cell therapy and immunotherapy technologies, we are currently required to pay both substantial benchmark payments and royalties to each entity based on our revenues from sales of our products utilizing the licensed or acquired technologies.

We are required to pay substantial royalties and lump sum benchmark payments under our license or acquisition agreements with the NIH, Novartis, Clinigen, and Cellectis, and we must meet certain milestones to maintain our license rights.

Under our license or acquisition agreements with the NIH, Novartis, Clinigen, and Cellectis for our adoptive cell therapy and immunotherapy technologies, we are currently required to pay both substantial benchmark payments and royalties to each entity based on our revenues from sales of our products utilizing the licensed or acquired technologies.

These payments could adversely affect the overall profitability for us of any products that we may seek to commercialize under these license agreements.

In order to maintain our license rights under the NIH, Moffitt, Novartis, and Cellectis license agreements, we will need to meet certain specified milestones, subject to certain cure provisions, in the development of our product candidates, and a milestone payment is required to Clinigen upon the approval of lifileucel in melanoma.

In order to maintain our license rights under the NIH, Novartis, and Cellectis license agreements, we will need to meet certain specified milestones, subject to certain cure provisions, in the development of our product candidates, and a milestone payment is required to Clinigen upon the approval of lifileucel in melanoma.

There is no assurance that we will be successful in meeting these milestones on a timely basis, or at all.

We are dependent on third parties to support our research, development, and manufacturing activities and, therefore, are subject to the efforts of these parties and our ability to successfully collaborate with these third parties.

As a result of our current strategy to outsource most of our manufacturing, we rely very heavily on third parties to perform for us the manufacturing of our products and/or product candidates.

We are dependent on third parties to support our research, development, and supplement our internal manufacturing activities and, therefore, are subject to the efforts of these parties and our ability to successfully collaborate with these third parties.

As a result of our current strategy to supplement our internal manufacturing by outsourcing, we rely very heavily on third parties to perform for us the manufacturing of our products and/or product candidates.

We also license a portion of our technology from others.

We intend to rely upon our contract manufacturers to produce large quantities of materials needed for clinical trials and product commercialization.

We intend to rely upon both our internal facility, the i CTC, as well as our CMOs to produce large quantities of materials needed for clinical trials and product commercialization.

Third party manufacturers may not be able to meet our needs with respect to timing, quantity, or quality.

If we are unable to contract for a sufficient supply of needed materials on acceptable terms, or if we should encounter delays or difficulties in our relationships with manufacturers, our clinical testing and/or commercialization efforts may be delayed, thereby delaying the submission of products for regulatory approval or the market introduction and subsequent sales of our products.

Any such delay may lower our revenues and potential profitability.

In addition, in order to supplement our own efforts to improve TIL manufacturing and develop TIL cell therapies in new indications in clinical trials, we currently work and collaborate with government and academic research institutions, medical institutions, and corporate partners such as the NCI, Moffitt, Cellectis, Yale University, and Novartis.

We also intend to continue to enter into additional third-party collaborative agreements in the future.

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● a collaborator with marketing and distribution rights to one or more of our product candidates that achieve regulatory approval may not commit sufficient resources to the marketing and distribution of such product candidate or product;

● disagreements with collaborators, including disagreements over proprietary rights, contract interpretation, or the preferred course of development, might cause delays or termination of the research, development, or commercialization of products and/or product candidates, might lead to additional responsibilities for us with respect to products and/or product candidates, or might result in litigation or arbitration, any of which would be time consuming and expensive;

and/or product candidates, might lead to additional responsibilities for us with respect to products and/or product candidates, or might result in litigation or arbitration, any of which would be time consuming and expensive;

● collaborators may not properly maintain or defend our intellectual property rights or may use our proprietary information in such a way as to invite litigation that could jeopardize or invalidate our intellectual property or proprietary information or expose us to potential litigation;

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However, because the majority of our collaborations are conducted at outside laboratories and we do not have complete control over how the studies are conducted or reported or over the manufacturing methods used to manufacture TIL product, the results of such studies, which we may use as the basis for our conclusions, projections or decisions with respect to our current or future products and product candidates, may be incorrect or unreliable, or may have a negative impact on us if the results of such studies are imputed to our products or proposed indications, even if such imputation is improper.

For example, we have entered into collaborations with Moffitt, and MDACC to perform clinical trials using TIL products that differ from our products, but the results of these clinical trials, if negative, may adversely impact our stock price and our development plans for our products.

Additionally, we may use third party data to analyze, reach conclusions or make predictions or decisions with respect to our product candidates that may be incomplete, inaccurate or

otherwise unreliable.

For example, we have entered into collaborations with academic partners to perform clinical trials using TIL products that differ from our products, but the results of these clinical trials, if negative, may adversely impact our stock price and our development plans for our products.

Additionally, we may use third party data to analyze, reach conclusions or make predictions or decisions with respect to our product candidates that may be incomplete, inaccurate or otherwise unreliable.

There may also be delays or other limitations on our activities as a result of the inability of these entities to expedite our priorities in the product, facility, or regulatory approval process.

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There can be no assurance that we will be successful in developing our business.

Our internal computer systems, or those used by our contract research organizations or other contractors or consultants, may fail or suffer security breaches.

Despite the implementation of security measures, our internal computer systems and those of our contract research organizations and other contractors and consultants are vulnerable to damage from computer viruses, unauthorized and authorized access, natural disasters, terrorism, war and telecommunication and electrical failures.

Our internal computer systems, or those used by our CROs or other contractors or consultants, may fail or suffer security breaches.

Despite the implementation of security measures, our internal computer systems and those of our CROs and other contractors and consultants are vulnerable to damage from computer viruses, unauthorized and authorized access, natural disasters, terrorism, war and telecommunication and electrical failures.

If such an event was to occur and cause interruptions in our operations, it could result in a disruption of our drug development programs.

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While we have invested, and continue to invest, in the protection of our data and information technology infrastructure, there can be no assurance that our efforts, or the efforts of our partners and vendors, will prevent service interruptions, or identify breaches in our systems, that could adversely affect our business and operations and/or result in the loss of critical or sensitive information, which could result in financial, legal, business or reputational harm to us.

In addition, our liability

insurance may not be sufficient in type or amount to cover us against claims related to security breaches, cyberattacks and other cybersecurity related breaches.

In addition, our liability insurance may not be sufficient in type or amount to cover us against claims related to security breaches, cyberattacks and other cybersecurity related breaches.

Our business could be adversely affected by the effects of health epidemics, including the COVID-19 pandemic, in regions where we or third parties on which we rely have significant manufacturing facilities, concentrations of clinical trial sites or other business operations.

The COVID-19 pandemic could materially affect our operations, including at our headquarters in San Carlos, California, at our manufacturing facility in Philadelphia, Pennsylvania, which have previously been subject to state executive orders and shelter-in-place orders, and at our clinical trial sites, as well as the business or operations of our other manufacturers, contract research organizations, or CROs, or other third parties with whom we conduct business.

The COVID-19 pandemic could materially affect our operations, including at our headquarters in San Carlos, California, at our manufacturing facility in Philadelphia, Pennsylvania, which have previously been subject to state executive orders and shelter-in-place orders, and at our clinical trial sites, as well as the business or operations of our other manufacturers, CROs, or other third parties with whom we conduct business.

Our business could be adversely affected by health epidemics in regions where we have offices, manufacturing facilities, concentrations of clinical trial sites or other business operations, and could cause significant disruption in the operations of clinical trial sites, third party manufacturers and CROs upon whom we rely.

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Throughout 2020 and 2021, similar executive orders were issued by state and local governments, and states of emergency had been declared at the state and local level in most jurisdictions throughout the U.S.

As recently as April 2022, ports and airports in Shanghai, China have been closed due to another outbreak of COVID-19, resulting in a lockdown of the city and disruption to export and import activities.

In the U.S., many of these executive orders have been rescinded, however, the Company remains vigilant and continues to monitor the ongoing COVID-19 pandemic closely to determine if additional actions are required.

As recently as April 2022, ports and airports in Shanghai, China closed due to another outbreak of COVID-19, resulting in a lockdown of the city and disruption to export and import activities.

In the U.S., many of these executive orders have been rescinded, however, we remain vigilant and continue to monitor any ongoing effects of the COVID-19 pandemic closely to determine if additional actions are required.

Quarantines, shelter-in-place, and similar government orders, or the perception that such orders, shutdowns or other restrictions on the conduct of business operations could occur, related to the COVID-19 pandemic or other infectious diseases could impact personnel at third-party manufacturing facilities in the U.S.

and other countries, or the availability or cost of materials, which would disrupt our supply chain.

In addition, our clinical trials may be affected by the COVID-19 pandemic.

Clinical site initiation, patient enrollment and patient monitoring may be delayed due to prioritization of hospital resources toward the COVID-19 pandemic.

In addition, our clinical trials may be affected by health epidemics, such as the COVID-19 pandemic.

Clinical site initiation, patient enrollment and patient monitoring may be delayed due to prioritization of hospital resources toward health epidemics, such as the COVID-19 pandemic.

Some sites may no longer be available to see patients for clinical trials.

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Patients may also miss follow-up visits after receiving our therapies during our clinical trials, which may or may not be rectified by future patient visits and which may result in the exclusion of data from such patients from the clinical trial data.

Similarly, our ability to recruit and retain patients and principal investigators and site staff who, as healthcare providers, may have heightened exposure to the virus that causes the COVID-19 pandemic and adversely impact our clinical trial operations.

The COVID-19 pandemic may also affect our ability to recruit treatment-naïve patients into our clinical trials, because those patients may be more likely to seek standard of care therapies available at local treatment centers rather than enroll in a clinical trial at a larger hospital.

We continue to monitor the impact, if any, of the COVID-19 pandemic on our current and future operations, including our regulatory filing timelines and strategy as well as our preparation for commercial launch.

Despite the wide-spread availability of COVID-19 vaccines, it is unclear the extent to which the COVID-19 pandemic (including future variants) will impact our business, results of operations, financial condition and our future strategic plans as future developments of the outbreak are highly uncertain and cannot be predicted.

New information is constantly emerging concerning the severity of COVID-19 and the actions to contain COVID-19 or treat its impact, among others.

As the COVID-19 pandemic continues for an extended period of time, any restrictions regarding travel and face to face interactions or constraints on resources, either by us or our contractors, including our CMOs, may negatively impact our regulatory strategy or commercial launch preparations.

The COVID-19 pandemic may also impact the FDA and their ability to timely review our regulatory filings and conduct the pre-approval inspections necessary for ultimate approval of BLA.

Similarly, our ability to recruit and retain patients and principal investigators and site staff who, as healthcare providers, may have heightened exposure to viruses that cause pandemic and epidemics, such as the virus that causes the COVID-19 pandemic, and such exposure may adversely impact our clinical trial operations.

Health epidemics, such as the COVID-19 pandemic, may also affect our ability to recruit treatment-naïve patients into our clinical trials, because those patients may be more likely to seek standard of care therapies available at local treatment centers rather than enroll in a clinical trial at a larger hospital.

We continue to monitor the impact, if any, of health epidemics, including the COVID-19 pandemic, on our current and future operations, including our regulatory filing timelines and strategy, as well as our preparation for commercial launch.

As with the COVID-19 pandemic, any restrictions regarding travel and face to face interactions or constraints on resources, either by us or our contractors, including our CMOs, may negatively impact our regulatory strategy or commercial launch preparations.

Health epidemics may also impact the FDA and their ability to timely review our regulatory filings and conduct the pre-approval inspections necessary for ultimate approval of BLA.

We cannot predict at this time whether and how FDA operations may be impacted at relevant times for our planned regulatory submissions.

Our failure to comply with international data protection laws and regulations could lead to government enforcement actions and significant penalties against us, and adversely impact our operating results.

European Union, or EU, member states and other foreign jurisdictions, including Switzerland, the United Kingdom and Canada, have adopted data protection laws and regulations which impose significant compliance obligations on us.

EU member states and other foreign jurisdictions, including Switzerland, the UK, and Canada, have adopted data protection laws and regulations which impose significant compliance obligations on us.

Moreover, the collection and use of personal health data in the EU, which was formerly governed by the provisions of the EU Data Protection Directive, was replaced with the EU General Data Protection Regulation, or the GDPR, in May 2018.

The GDPR, which is wide-ranging in scope, imposes several requirements relating to the consent of the individuals to whom the personal data relates, the information provided to the individuals, the security and confidentiality of the personal data, data breach notification and the use of third-party processors in connection with the processing of personal data.

confidentiality of the personal data, data breach notification and the use of third-party processors in connection with the processing of personal data.

The GDPR also imposes strict rules on the transfer of personal data out of the EU to the U.S., provides an enforcement authority and imposes large penalties for noncompliance, including the potential for fines of up to €20 million or 4% of the annual global revenues of the noncompliant company, whichever is greater.

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Our failure to comply with state and/or national data protection laws and regulations could lead to government enforcement actions and significant penalties against us, and adversely impact our operating results.

There are numerous other laws and legislative and regulatory initiatives at the federal and state levels addressing privacy and security concerns, and some state privacy laws apply more broadly than the Health Insurance Portability and Accountability Act, or HIPAA, and associated regulations.

For example, California recently enacted legislation, the California Consumer Privacy Act, or CCPA, which went into effect January 1, 2020, and was recently amended and expanded by the California Privacy Rights Act, or CPRA, which will take effect on January 1, 2023.

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In addition, even if we are able to pursue certain strategic acquisition opportunities, we cannot guarantee that such acquisitions may completed in a timely manner, if at all, or that all conditions necessary to consummate such transactions will be satisfied, including the receipt of all required regulatory approvals.

We are currently operating in a period of economic uncertainty and capital markets disruption, which has been significantly impacted by geopolitical instability, ongoing military conflicts between Russia and Ukraine and Israel and Hamas and record inflation .

Our business, financial condition and results of operations could be materially adversely affected by any negative impact on the global economy and capital markets resulting from the conflicts in Ukraine and the Middle East, geopolitical tensions or record inflation.

and global markets are experiencing volatility and disruption following the escalation of geopolitical tensions and the start of the military conflict between Russia and Ukraine.

We have global operations, which expose us to additional risks, and any adverse event could have a material adverse effect on our results of operations and financial condition.

Our operations outside the U.S.

have recently expanded.

Risks inherent in conducting a global business include:

● changes in medical reimbursement policies and programs and pricing restrictions in key markets;

● multiple regulatory requirements that could restrict our ability to manufacture and sell our products in key markets;

● trade protection measures, tariffs, and import or export licensing requirements, including the imposition of trade sanctions or similar restrictions by the U.S.

or other governments;

● foreign exchange fluctuations;

● diminished protection of intellectual property in some countries;

● possible nationalization and expropriation.

In addition, there may be changes to our business if there is instability, disruption, or destruction in a significant geographic region, regardless of cause, including war, terrorism, riot, civil insurrection or social unrest;

and natural or man-made disasters, including famine, flood, fire, earthquake, storm, or disease.

Events like these, such as the ongoing war between Russia and Ukraine and rising conflict in the Middle East, could result in material adverse effects on macroeconomic conditions, currency exchange rates and financial markets, and may adversely affect our business, results of operations, and financial condition.

Furthermore, changes in regulations and policies by the new U.S.

administration, including increases in tariffs, and the resulting political and economic uncertainty in the U.S.

may also impact our operations as well as the financial markets and the global economy.

Our business, financial condition and results of operations could be materially adversely affected by any negative impact on the global economy and capital markets resulting from the conflicts in Ukraine and the Middle East, geopolitical tensions, or inflation.

and global markets are experiencing volatility and disruption following the escalation of geopolitical tensions and the continuation of the military conflict between Russia and Ukraine.

On February 24, 2022, a full-scale military invasion of Ukraine by Russian troops was reported.

Although the length and impact of the ongoing military conflict is highly unpredictable, the conflict in Ukraine could lead to market disruptions, including significant volatility in commodity prices, credit and capital markets, as well as supply chain interruptions, which has led to record inflation globally.

We are continuing to monitor inflation, the situation in Ukraine, and global capital markets, and assessing the potential impacts on our business.

The global economy has been, and may continue to be, negatively impacted by Russia’s invasion of Ukraine.

As a result of Russia’s invasion of Ukraine, the U.S., the European Union, the United Kingdom, and other G7 countries, among other countries, have imposed substantial financial and economic sanctions on certain industry sectors and parties in Russia.

As a result of Russia’s invasion of Ukraine, the U.S., the EU, the UK, and other G7 countries, among other countries, have imposed substantial financial and economic sanctions on certain industry sectors and parties in Russia.

Broad restrictions on exports to Russia have also been imposed.

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(iii) designations of individuals and entities involved in Russian military activities;

and (iv) enhanced export controls and trade sanctions limiting Russia’s ability to import various goods.

and (iv) enhanced export controls and trade sanctions limiting Russia’s ability to import various

Russian military actions and the resulting sanctions could continue to adversely affect the global economy and financial markets and lead to instability and lack of liquidity in capital markets, potentially making it more difficult for us to obtain additional funds.

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Shortly following the attack, Israel’s security cabinet declared war against Hamas and launched an aerial bombardment of various targets within the Gaza Strip.

The Israeli government subsequently called for the evacuation of over one million residents of the northern part of the Gaza Strip and began a ground invasion of the Gaza Strip.

It is possible that other terrorist and/or regional organizations will join the hostilities as well, including Hezbollah in Lebanon, and Palestinian military organizations in the West Bank, resulting in a widening of the conflict.

The intensity and duration of Israel’s current war against Hamas is difficult to predict as are such war’s economic implications on the global economy.

The Israeli government subsequently called for the evacuation of over one million residents of the northern part of the Gaza Strip and began a ground invasion of the Gaza Strip that remains ongoing.

Other terrorist and/or regional organizations have joined the hostilities as well, including Hezbollah in Lebanon, and the Houthis in Yemen, and it is possible that Palestinian military organizations in the West Bank will also join, resulting in a further widening of the conflict.

The intensity and duration of Israel’s current wars are difficult to predict as are such wars’ economic implications on the global economy.

There are also current geopolitical tensions with China.

Recently, the Biden administration has signed multiple executive orders regarding China.

One particular executive order titled Advancing Biotechnology and Biomanufacturing Innovation for a Sustainable,

Safe, and Secure American Bioeconomy signed on September 12, 2022 will likely impact the pharmaceutical industry to encourage U.S.

One particular executive order titled Advancing Biotechnology and Biomanufacturing Innovation for a Sustainable, Safe, and Secure American Bioeconomy, signed on September 12, 2022, will likely impact the pharmaceutical industry to encourage U.S.

domestic manufacturing of pharmaceutical products.

Moreover, there have been Congressional legislative proposals, such as the recent bill titled the Biosecure Act, to discourage contracting with Chinese companies on the development or manufacturing of pharmaceutical products.

Any additional executive action, legislative action or potential sanctions with China could materially impact our current manufacturing partners and our agreements with them, including our MSA with WuXi.

For example, in February 2024, the chair and ranking member of the House Select Committee on the Chinese Communist Party, Representatives Mike Gallagher and Raja Krishnamoorthi, respectively, along with Senators Gary Peters and Bill Haggerty sent a letter to the Biden administration requesting that both WuXi AppTec Co., Ltd., WuXi’s parent company, and the affiliated WuXi Biologics be added to the Department of Defense’s Chinese Military Companies List (1260H list), the Department of Commerce’s Bureau of Industry and Security Entity List, and the Department of Treasury’s Non-SDN Chinese Military-Industrial Complex Companies List.

Although our business has not been materially impacted by the ongoing military conflicts between Russia and Ukraine or Israel and Hamas, geopolitical tensions, or record inflation to date, it is impossible to predict the extent to which our operations, or those of our suppliers and manufacturers, will be impacted in the short and long term, or the ways in which the conflict may impact our business.

The extent and duration of the conflicts in Ukraine and the Middle East, geopolitical tensions, record inflation, sanctions and resulting market disruptions are impossible to predict, but could be substantial.

Additionally, on February 28, 2024, President Biden signed Executive Order 14117 (“Preventing Access to Americans’ Bulk Sensitive Personal Data and United States Government-Related Data by Countries of Concern”) which implements a new framework to protect the privacy of personal data shared between the U.S.

and Europe, which may, in effect, impact privacy laws with “countries of concern” such as China or Russia.

Moreover, there have been Congressional legislative proposals, such as the bill titled the BIOSECURE Act, to discourage contracting with Chinese companies, including two WuXi affiliates, on the development or manufacturing of pharmaceutical products.

The BIOSECURE Act did not pass in 2024, but support for the policies contained therein remains broad in Congress, and the bill could be reintroduced in 2025.

Any additional executive action, legislative action, or potential sanctions with respect to China could materially impact our current manufacturing partners and our agreements with them, including our MSA with WuXi.

For example, in February 2024, the chair and ranking member of the House Select Committee on the Chinese Communist Party, Representatives Mike Gallagher and Raja Krishnamoorthi, respectively, along with Senators Gary Peters and Bill Hagerty sent a letter to the Biden administration requesting that both WuXi AppTec Co., Ltd., WuXi’s parent company, and the affiliated WuXi Biologics be added to the Department of Defense’s Chinese Military Companies List (1260H list), the Department of Commerce’s Bureau of Industry and Security Entity List, and the Department of Treasury’s Non-SDN Chinese Military-Industrial Complex Companies List.

The new administration may also enact new regulations or policies that affect trade with China or otherwise impact the biopharmaceutical industry by enacting laws to restrict U.S.

biopharmaceutical companies from contracting with Chinese companies on the development, research or manufacturing of biopharmaceutical products.

Any additional executive orders, legislative action or potential sanctions on China could materially impact our current manufacturing partners.

Although our business has not been materially impacted by the ongoing military conflicts between Russia and Ukraine or Israel and Hamas, Hezbollah, and the Houthis, geopolitical tensions, tariffs, or inflation to date, it is impossible to predict the extent to which our operations, or those of our suppliers and manufacturers, will be impacted in the short and long term, or the ways in which the conflict may impact our business.

The extent and duration of the conflicts in Ukraine and the Middle East, geopolitical tensions, inflation, sanctions and resulting market disruptions are impossible to predict, but could be substantial.

Any such disruptions may also magnify the impact of other risks described herein.

We are exposed to fluctuations in currency exchange rates that could negatively impact our financial results and cash flows.

With the acquisition of Proleukin ® in May 2023, a portion of our business will be conducted outside the United States.

Furthermore, we are required to make certain future payments under the Proleukin ® acquisition agreement that are denominated in non-US dollars, including a milestone payment to Clinigen upon the approval of lifileucel in melanoma as well as future deferred consideration and earnout payments based on Proleukin ® sales.

With the acquisition of Proleukin ® in May 2023 and with the future commercialization of Amtagvi ® in other markets, a portion of our business will be conducted outside the U.S.

Furthermore, we are required to make certain future payments under the Proleukin ® acquisition agreement that are denominated in non-U.S.

dollars, including future deferred consideration and earnout payments based on Proleukin ® sales.

As such, we face exposure to adverse movements in foreign currency exchange rates, including movements in foreign currency for the future milestone payment.

These exposures may change over time as business practices evolve, and they could have a material adverse impact on our results of operations, financial position, and cash flows.

These exposures may change over time as business practices evolve, and they could have a material adverse impact on our business, cash flow, results of operations, financial condition, and prospects.

Our primary exposure to movements in foreign currency exchange rates currently relates to non-U.S.

dollar denominated sales in Europe, the United Kingdom, and Asia, and non-U.S.

dollar denominated sales in Europe, the UK, and Asia, and non-U.S.

dollar denominated operating expenses and certain assets and liabilities in our operating subsidiaries.

Additionally, we have entered and may enter into business development transactions, borrowings, or other financial transactions that may give rise to currency and interest rate exposure.

Since we cannot, with certainty, foresee and mitigate against such adverse changes, fluctuations in currency exchange rates, interest rates, and inflation could negatively affect our business, cash flow, results of operations, financial condition, and prospects.

In order to mitigate against the adverse impact of these market fluctuations, we may from time to time enter into hedging agreements.

While hedging agreements, such as currency options and forwards and interest rate swaps, may limit some of the exposure to exchange rate and interest rate fluctuations, such attempts to mitigate these risks may be costly and not always successful.

Climate change or legal, regulatory, or market measures to address climate change may negatively affect our business, results of operations, cash flows and prospects.

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Our ability to compete could also be affected by changing customer preferences and requirements, such as growing demand for more environmentally friendly products, packaging or supplier practices, or by failure to meet such customer expectations or demand.

Changes in regulations and policies of the new U.S.

administration may have the effect of scaling back or halting the progress of proposed or enacted ESG-related regulations, which may also have an effect on requirements and preferences of various government agencies and external stakeholders.

While we strive to improve our ESG performance, we risk negative stockholder reaction, including from proxy advisory services, as well as damage to our brand and reputation, if we do not act responsibly, or if we are perceived to not be acting responsibly in key ESG areas, including equitable access to medicines and vaccines, product quality and safety, diversity and inclusion, environmental stewardship, support for local communities, corporate governance and transparency, and addressing human capital factors in our operations.

If we do not meet the ESG expectations of our investors, customers, and other stakeholders, we could experience reduced demand for our products, loss of customers, and other negative impacts on our business and results of operations.

In addition, this emphasis on environmental, social, and other sustainability matters has resulted and may result in the adoption of new laws and regulations, including new reporting requirements.

If we fail to comply with new laws, regulations, or reporting requirements, our reputation and business could be adversely impacted.

Risks Related to Government Regulation

We are subject to extensive regulation, which can be costly, time consuming and can subject us to unanticipated delays;

even after obtaining regulatory approval for some of our products and/or product candidates, those products and/or product candidates may still face regulatory difficulties.

Our products, potential products, cell processing and manufacturing activities, are subject to comprehensive regulation by the FDA in the U.S.

We are subject to extensive regulation, which can be costly and time consuming and can subject us to unanticipated delays in obtaining regulatory approvals for our products and/or product candidates, and even after obtaining regulatory approval for some of our products and/or product candidates, those products and/or product candidates may still face regulatory difficulties.

Our products, potential products, and cell processing and manufacturing activities are subject to comprehensive regulation by the FDA in the U.S.

and by comparable authorities in other countries.

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In addition, regulatory agencies may lack experience with our technologies and products, which may lengthen the regulatory review process, increase our development costs and delay or prevent their commercialization.

Prior to Amtagvi™, no adoptive cell therapy using TIL had been approved for marketing by the FDA.

Prior to Amtagvi ® , no adoptive cell therapy using a TIL product had been approved for marketing by the FDA.

Consequently, there is no precedent for the successful commercialization of products based on our technologies.

In addition, we have had only limited experience in filing and pursuing applications necessary to gain regulatory approvals, which may impede our ability to obtain timely FDA approvals, if at all.

In addition, we have had only limited experience in filing and pursuing applications necessary to gain regulatory approvals, which may impede our ability to obtain timely FDA or foreign regulatory approvals, if at all.

We have completed the process for FDA approval for one adoptive cell therapy product.

We will not be able to commercialize any of our potential products until we obtain FDA approval, and so any delay in obtaining, or inability to obtain, FDA approval would harm our business.

We will not be able to commercialize any of our potential products until we obtain FDA or foreign regulatory approvals, and so any delay in obtaining, or inability to obtain, FDA or foreign regulatory approvals would harm our business.

If we fail to comply with regulatory requirements at any stage, whether before or after marketing approval is obtained, we may face a number of regulatory consequences, including refusal to approve pending applications, license suspension or revocation, withdrawal of an approval, imposition of a clinical hold or termination of clinical trials, warning letters, untitled letters, modification of promotional materials or labeling, provision of corrective information, imposition of post-market requirements, including the need for additional testing, imposition of distribution or other restrictions under a REMS, product recalls, product seizures or detentions, refusal to allow imports or exports, total or partial suspension of production or distribution, FDA debarment, injunctions, fines, consent decrees, corporate integrity agreements, debarment from receiving government contracts and new orders under existing contracts, exclusion from participation in federal and state healthcare programs, restitution, disgorgement, or civil or criminal penalties, including fines and imprisonment, and adverse publicity, among other adverse consequences.

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In addition, if we or others identify side effects after any of our adoptive cell therapies are on the market, or if manufacturing problems occur, regulatory approval may be withdrawn and reformulation of our products may be required.

The FDA regulatory approval process is lengthy and time-consuming, and we may experience significant delays in the clinical development and regulatory approval of our product candidates.

The FDA and foreign regulatory approval process is lengthy and time-consuming, and we may experience significant delays in the clinical development and regulatory approval of our product candidates.

We completed our first submission of a rolling BLA to the FDA for lifileucel in March 2023.

The FDA accepted our BLA for Amtagvi TM for patients with advanced melanoma in May 2023 and granted lifileucel Priority Review.

The FDA originally assigned November 25, 2023 as the target action date for a decision under PDUFA, however, the FDA recently reassigned February 24, 2024 as the revised target action date.

The FDA accepted our BLA for Amtagvi ® for patients with advanced melanoma in May 2023 and granted lifileucel Priority Review.

The FDA originally assigned November 25, 2023 as the target action date for a decision under PDUFA, however, the FDA then reassigned February 24, 2024 as the revised target action date before approving the BLA on February 16, 2024.

A BLA must include extensive preclinical and clinical data and supporting information to establish the product candidate’s safety and effectiveness for each desired indication.

Our BLA submissions and expected timelines for our product candidates are based on our interpretation of communications received from the FDA to date regarding each product candidate and are

subject to revision if additional communications are received from the FDA.

Our BLA submissions and expected timelines for our product candidates are based on our interpretation of communications received from the FDA to date regarding each product candidate and are subject to revision if additional communications are received from the FDA.

As such, we may experience delays with FDA approval of additional BLAs.

We have announced our intention to conduct registrational trials for both advanced NSCLC and cervical cancer with our LN-145 and lifileucel product candidates, respectively.

These trials, which we refer to as IOV-LUN-202 Cohorts 1 and 2 in the case of advanced NSCLC and C-145-04 Cohort 2 in the case of cervical cancer, are currently underway and have been the subject of formal FDA meetings and communications.

Our current beliefs regarding the registration pathway for the lifileucel and LN-145 product candidates in these indications are based on our interpretation of communications with the FDA to date and our efforts to address such communications, which may be incorrect.

We are conducting registrational trials for advanced NSCLC and frontline advanced melanoma cancer with our lifileucel product candidate.

These trials, which we refer to as IOV-LUN-202 Cohorts 1 and 2 in the case of advanced NSCLC and TILVANCE-301 in the case of advanced melanoma, are currently underway and have been the subject of formal FDA meetings and communications.

On March 4, 2024, the FDA lifted the partial clinical hold on the IOV-LUN-202 trial, permitting us to resume patient enrollment.

Our current beliefs regarding the registration pathway for lifileucel in these indications are based on our interpretation of communications with the FDA to date and our efforts to address such communications, which may be incorrect.

Our statements that the clinical trial may support a BLA submission also assume that our as-adjusted clinical trial has addressed the additional requests and feedback by the FDA.

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Protocol revisions may have an adverse effect on the results reported to date.

Changes to implement an independent review committee and assay validation and implementation, and the data within these clinical trials may not ultimately be supportive of product approval, all of which could result in significant delays to our currently anticipated timeline for development and approval of lifileucel and LN-145 product candidates or prevent their approval.

Changes to implement an

independent review committee and assay validation and implementation, and the data within these clinical trials may not ultimately be supportive of product approval, all of which could result in significant delays to our currently anticipated timeline for development and approval of the lifileucel product candidate or prevent their approval.

A BLA must also include significant information regarding the chemistry, manufacturing and controls for the product.

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For example, the FDA has limited experience with commercial development of cell therapies for cancer.

We may also not be able to successfully utilize the BTD designation we have received for metastatic cervical cancer to successfully complete the development and commercialization of Amtagvi TM for such indication.

We may not be able to reach agreement with the FDA on an interpretation of outcomes from our meetings, including meetings we have held with the FDA in relation to our C-145-04 clinical trial and future meetings.

In addition, as previously disclosed, Iovance began startup activities for a confirmatory Phase 3 clinical trial, TILVANCE-301, of lifileucel in combination with pembrolizumab in frontline metastatic melanoma in late 2022.

In addition, as previously disclosed, Iovance began a confirmatory Phase 3 clinical trial, TILVANCE-301, of lifileucel in combination with pembrolizumab in frontline metastatic melanoma in late 2022.

The FDA previously granted Fast Track Designation for lifileucel in combination with pembrolizumab for the treatment of immune checkpoint inhibitor naïve metastatic melanoma.

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Further, a clinical trial may be suspended or terminated by us, the IRBs for the institutions in which such clinical trials are being conducted by the FDA or other regulatory authorities, or recommended for suspension or termination by DSMBs due to a number of factors, including failure to conduct the clinical trial in accordance with regulatory requirements or our clinical protocols, inspection of the clinical trial operations or clinical trial site by the FDA or other regulatory authorities resulting in the imposition of a clinical hold, including as a result of genetic editing methods, unforeseen safety issues or adverse side effects, failure to demonstrate a benefit from using a product candidate, changes in governmental regulations or administrative actions or lack of adequate funding to continue the clinical trial.

If we experience

termination of, or delays in the completion of, any clinical trial of our product candidates, the commercial prospects for our product candidates will be harmed, and our ability to generate product revenue will be delayed.

If we experience termination of, or delays in the completion of, any clinical trial of our product candidates, the commercial prospects for our product candidates will be harmed, and our ability to generate product revenue will be delayed.

In addition, any delays in completing our clinical trials will increase our costs, slow down our product development and approval process and jeopardize our ability to commence product sales and generate revenue.

Obtaining and maintaining regulatory approval of our product candidates in one jurisdiction does not mean that we will be successful in obtaining regulatory approval of our product candidates in other jurisdictions.

Obtaining and maintaining regulatory approval of our product candidates in one jurisdiction does not mean that we will be successful in obtaining or maintaining regulatory approval of our product candidates in other jurisdictions.

In order to market and sell our products outside the U.S., we or our third-party collaborators may be required to obtain or maintain separate marketing approvals and comply with numerous and varying regulatory requirements.

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For example, even if the FDA grants marketing approval of a product candidate, comparable regulatory authorities in foreign jurisdictions must also approve the manufacturing, marketing and promotion of the product candidate in those countries.

Approval procedures vary among jurisdictions and can involve requirements and administrative review periods different from, and greater than, those in the U.S., including additional preclinical studies or clinical trials as clinical studies conducted in one jurisdiction may not be accepted by regulatory authorities in other jurisdictions.

other jurisdictions.

In many jurisdictions outside the U.S., a product candidate must be approved for reimbursement before it can be approved for sale in that jurisdiction.

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Any regulatory approvals that we receive for our product candidates will require ongoing surveillance to monitor the safety and efficacy of the product candidate.

The FDA may also require a REMS to approve our product candidates, which could entail requirements for a medication guide, physician communication plans or additional elements to ensure safe use, such as restricted distribution methods, patient registries and other risk minimization tools.

Although not required for Amtagvi ® or Proleukin ® , it is possible in the future that the FDA may also require a REMS to approve our product candidates, which could entail requirements for a medication guide, physician communication plans or additional elements to ensure safe use, such as restricted distribution methods, patient registries and other risk minimization tools.

The FDA may also require post-approval Phase 4 studies.

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If we are slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies, or if we are not able to maintain regulatory compliance, we may lose any marketing approval that we may have obtained, be subject to other regulatory enforcement action, and we may not achieve or sustain profitability.

If we fail to comply with federal and state healthcare and promotional laws, including fraud and abuse and information privacy and security laws, we could face substantial penalties and our business, financial condition, results of operations, and prospects could be adversely affected.

As a biopharmaceutical company, we are subject to many federal and state healthcare laws, including the federal AKS, the federal civil and criminal FCA, the civil monetary penalties statute, the Medicaid Drug Rebate statute and other price reporting requirements, the Veterans Health Care Act of 1992, the federal Health Insurance Portability and Accountability Act of 1996 (as amended by the Health Information Technology for Economics and Clinical Health Act), the Foreign Corrupt Practices Act of 1977, the Patient Protection and Affordable Care Act of 2010, and similar state laws.

Even though we do not and will not control referrals of healthcare services or bill directly to Medicare, Medicaid, or other third-party payors, certain federal and state healthcare laws and regulations pertaining to fraud and abuse and patients’ rights are and will be applicable to our business.

If we do not comply with all applicable fraud and abuse laws, we may be subject to enforcement by both the federal government and the states in which we conduct our business.

If we fail to comply with applicable healthcare and promotional laws, including fraud and abuse and information privacy and security laws, we could face substantial penalties and our business, financial condition, results of operations, and prospects could be adversely affected.

As a biopharmaceutical company, we are subject to many federal and state healthcare laws, including the federal Anti-Kickback Statute, or the AKS, the federal civil and criminal False Claims Act, or the FCA, the civil monetary penalties statute, or the CMP Law, the Medicaid Drug Rebate statute and other price reporting requirements, the Veterans Health Care Act of 1992, or the VHCA, HIPAA, the Foreign Corrupt Practices Act of 1977, or FCPA, the Patient Protection and Affordable Care Act of 2010, or the ACA, and similar state laws.

Even though we do not and will not control referrals of healthcare services or bill directly to Medicare, Medicaid, or other third-party payors, certain federal and state healthcare laws and regulations pertaining to fraud and abuse, disclosures, and patients’ rights are and will be applicable to our business.

If we do not comply with all applicable laws, we may be subject to enforcement by both the federal government and the states in which we conduct our business as well as by other third parties, such as patients.

We do not currently participate in the Medicaid Drug Rebate Program.

If we fail to comply with the reporting and payment obligations under the Medicaid Drug Rebate Program or other governmental pricing programs because we incorrectly determined participating was not required, we could be subject to certain reimbursement requirements, penalties, sanctions, and fines, which could adversely impact our business, financial condition, results of operations, and prospects.

In the event that we begin to participate in such a program, in certain circumstances, our products would be subject to ceiling prices set by such programs, which could reduce the revenue we may generate from any such products.

Participation in such programs would also expose us to the risk of significant civil monetary penalties, sanctions, and fines should we be found to be in violation of any applicable obligations thereunder.

Laws and regulations require calculation and reporting of complex pricing information for prescription drugs, and compliance will require us to invest in significant resources and develop a price reporting infrastructure or depend on third parties to compute and report our drug pricing.

Pricing reported to CMS must be certified.

Pricing reported to the Centers for Medicare & Medicaid Services, or CMS, must be certified.

Non-compliant activities expose us to FCA risk if they result in overcharging agencies, underpaying rebates to agencies, or causing agencies to overpay providers.

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If any of the physicians or other healthcare providers or entities with whom we expect to do business, including our collaborators, is found not to be in compliance with applicable laws, they may be subject to criminal, civil, or administrative sanctions, including but not limited to, exclusions from participation in government healthcare programs, which could also materially affect our business.

In order to obtain additional clarification on the AKS or the CMP Law, a written interpretative advisory opinion can be requested from the Department of Health and Human Services’ Office of Inspector General, or OIG, regarding existing or contemplated arrangements.

Advisory opinions are binding as to the OIG, but only with respect to the requesting party or parties.

The advisory opinions are not binding as to other governmental agencies (e.g., the Department of Justice) and certain matters (e.g., whether certain payments made in conjunction with conduct seeking to meet certain safe harbor protections are at fair market value) are not within the purview of an advisory opinion.

In 2024, the OIG issued to us a favorable advisory opinion concluding that a proposed arrangement, providing travel and lodging for certain patients and caregivers in connection with a patient’s receipt of our cell therapy product, presented a sufficient low risk of fraud and abuse under the AKS and did not generate prohibited remuneration under the CMP Law.

We offer travel and lodging support for patients and caregivers who meet our criteria and have structured our program in line with the OIG advisory opinion.

While we believe we have properly structured our support in compliance with the AKS and the CMP Law, we cannot guarantee that the OIG or other regulators will not be able to successfully challenge our arrangements.

In particular, if we are found to have impermissibly promoted any of our product candidates, we may become subject to significant liability and government fines.

We, and any of our collaborators, must comply with requirements concerning advertising and promotion for any of our product candidates for which we or they obtain marketing approval.

Promotional communications with respect to therapeutics are subject to a variety of legal and regulatory restrictions and continuing review by the FDA, Department of Justice, Department of Health and Human Services’ Office of Inspector General, state attorneys general, members of Congress, and the public.

Additionally, advertising and promotional activities may be scrutinized and challenged by members of Congress, competitors, healthcare professionals, and the public.

When the FDA or comparable foreign regulatory authorities issue regulatory approval for a product candidate, the regulatory approval is limited to those specific uses and indications for which a product is approved.

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In the U.S., engaging in the impermissible promotion of our products, following approval, for off-label uses can also subject us to false claims and other litigation under federal and state statutes, including fraud and abuse and consumer protection laws, which can lead to civil and criminal penalties and fines, agreements with governmental authorities that materially restrict the manner in which we promote or distribute therapeutic products and do business through, for example, corporate integrity agreements, suspension or exclusion from participation in federal and state healthcare programs, and debarment from government contracts and refusal of future orders under existing contracts.

These false claims statutes include the federal civil False Claims Act, which allows any individual to bring a lawsuit against a biopharmaceutical company on behalf of the federal government alleging submission of false or fraudulent claims or causing others to present such false or fraudulent claims, for payment by a federal program such as Medicare or Medicaid.

These false claims statutes include the federal civil FCA, which allows any individual to bring a lawsuit against a biopharmaceutical company on behalf of the federal government alleging submission of false or fraudulent claims or causing others to present such false or fraudulent claims, for payment by a federal program such as Medicare or Medicaid.

If the government decides to intervene and prevails in the lawsuit, the individual will share in the proceeds from any fines or settlement funds.

If the government declines to intervene, the individual may pursue the case alone.

These False Claims Act lawsuits against manufacturers of drugs and biologics have increased significantly in volume and breadth, leading to several substantial civil and criminal settlements, up to $3.0 billion, pertaining to certain sales practices and promoting off-label uses.

In addition, False Claims Act lawsuits may expose manufacturers to follow-on claims by private payors based on fraudulent marketing practices.

These FCA lawsuits against manufacturers of drugs and biologics have increased significantly in volume and breadth, leading to several substantial civil and criminal settlements, up to $3.0 billion, pertaining to certain sales practices and promoting off-label uses.

In addition, FCA lawsuits may expose manufacturers to follow-on claims by private payors based on fraudulent marketing practices.

This growth in litigation has increased the risk that a biopharmaceutical company will have to defend a false claim action, pay settlement fines or restitution, as well as criminal and civil penalties, agree to comply with burdensome reporting and compliance obligations, and be excluded from Medicare, Medicaid, or other federal and state healthcare programs.

If we or our future collaborators do not lawfully promote our approved products, if any, we may become subject to such litigation and, if we do not successfully defend against such actions, those actions may have a material adverse effect on our business, financial condition, results of operations and prospects.

If we or our future collaborators do not lawfully promote our approved products, if any, we may become subject to such

litigation and, if we do not successfully defend against such actions, those actions may have a material adverse effect on our business, financial condition, results of operations and prospects.

Although an effective compliance program can mitigate the risk of investigation and prosecution for violations of these laws, the risks cannot be entirely eliminated.

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Any action against us for violation of these laws, even if we successfully defend against it, could cause us to incur significant legal expenses and divert our management’s attention from the operation of our business.

In the EU, companies may not promote unauthorized products or therapeutic indications.

Therefore, it is generally prohibited to disseminate information regarding off-label uses of medicinal products.

Exceptionally, companies may provide information on unauthorized products or indications in response to a written unsolicited request by an HCP ( i.e ., on a reactive basis only), as that is excluded from the definition of advertising under EU law.

This should be done through the medical team/Medical Science Liaisons, or MSLs, and not the marketing/sales representatives.

Moreover, specific rules may apply in each EU member state as regards the interactions between MSLs and HCPs.

Coverage and reimbursement may be limited or unavailable in certain market segments for our product candidates, which could make it difficult for us to sell our product candidates profitably.

In both domestic and foreign markets, sales of our product candidates, if approved, depend on the availability of coverage and adequate reimbursement from third-party payors.

Such third-party payors include government health programs such as Medicare and Medicaid, managed care providers, private health insurers, and other organizations.

In addition, because our product candidates represent new approaches to the treatment of cancer, we cannot accurately estimate the potential revenue from our product candidates.

Patients who are provided medical treatment for their conditions generally rely on third-party payors to reimburse all or part of the costs associated with their treatment.

Obtaining coverage and adequate reimbursement from governmental healthcare programs, such as Medicare and Medicaid, and commercial payors is critical to new product acceptance.

Government authorities and third-party payors decide which drugs and treatments they will cover and the amount of reimbursement.

Such third-party payors include government health programs such as Medicare and Medicaid, managed care entities, private health insurers, self-insured employers, and other organizations.

In addition, because our product candidates represent new approaches to the treatment of cancer for which no reimbursement rates may currently or definitively apply, we cannot accurately estimate the potential revenue from our product candidates.

Patients who are provided medical treatment for their conditions often rely on third-party payors to reimburse all or part of the costs associated with their treatment.

Obtaining coverage and adequate reimbursement from payors is critical to new product acceptance.

Third-party payors, including government health care programs, decide which drugs and treatments they will cover and the amount of reimbursement.

Coverage decisions may depend upon clinical and economic standards that disfavor new drug products when more established or lower cost therapeutic alternatives are already available or subsequently become available.

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● neither experimental nor investigational.

Federal and state legislatures and agencies continue to promulgate laws and regulations impacting coverage and reimbursement of drugs and treatments.

For example, on September 26, 2024, the CMS issued a final rule titled “Medicaid Program;

Misclassification of Drugs, Program Administration and Program Integrity Updates Under the Medicaid Drug Rebate Program,” which may impact our reimbursement and rebate strategy.

Obtaining coverage and reimbursement approval of a product from a government or other third-party payor is a time-consuming and costly process that could require us to provide to the payor supporting scientific, clinical, and cost-effectiveness data for the use of our products.

Even if we obtain coverage for a given product, the resulting reimbursement payment rates might not be adequate for us to achieve or sustain profitability or may require co-payments that patients find unacceptably high.

Payors may refuse to provide coverage for or may deny reimbursement for a product, depending on how they view such data.

Even if we obtain coverage for a given product, the resulting reimbursement payment rates might not be adequate for us to achieve or sustain profitability.

If payors subject our product candidates to maximum payment amounts or impose limitations that make it difficult to obtain reimbursement, providers may choose to use therapies which are less expensive when compared to our product candidates.

Payors may require co-payments that patients find unacceptably high.

Moreover, the factors noted above have continued to be the focus of policy and regulatory debate that has, thus far, shown the potential for movement towards permanent policy changes;

this trend is apt to continue, and may result in more or less favorable impacts on pricing.

Patients are unlikely to use our product candidates unless coverage is provided, and reimbursement is adequate to cover a significant portion of the cost of our product candidates.

Seeking prior authorization and negotiating the single-case agreement may take anywhere from days to months to obtain, if at all, and may cause ATCs, clinics, and patients to decline to use our products.

Providers may be unlikely to prescribe, and patients may be unlikely to use our product candidates unless coverage is provided, and reimbursement is adequate to cover a significant portion of the cost of our product candidates.

This effort may include post-marketing studies in order to demonstrate the cost-effectiveness of any future products to the satisfaction of hospitals and other target customers and their third-party payors.

Such studies might require us to commit a significant amount of management time and financial and other resources.

Our future products might not ultimately be considered cost-effective.

Adequate third-party coverage and reimbursement might not be available to enable us to maintain price levels sufficient to realize an appropriate return on investment in product development.

In the U.S., no uniform policy of coverage and reimbursement for products exists among third-party payors.

Therefore, coverage and reimbursement for products can differ significantly from payor to payor.

As a result, the coverage determination process is often a time-consuming and costly process that will require us to provide scientific and clinical support for the use of our product candidates to each payor separately, with no assurance that coverage and adequate reimbursement will be obtained.

Therefore, coverage and reimbursement for products can differ significantly from payor to payor and from jurisdiction to jurisdiction.

As a result, the coverage determination process is often a time-consuming and costly process that will require us to provide scientific, clinical, and cost-effectiveness data to support the use of our product candidates to each payor separately, with no assurance that coverage and adequate reimbursement will be obtained.

In the EU, each member state is responsible for establishing the price and reimbursement conditions of medicinal products placed in its market.

Prices paid for a drug also vary depending on the class of trade.

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Cost control initiatives could cause us, or our collaborators, to decrease, discount, or rebate a portion of the price we, or they, might establish for products, which could result in lower than anticipated product revenues.

If the realized prices for our products, if any, decrease or if governmental and other third-party payors do not provide adequate coverage or reimbursement, our prospects for revenue and profitability will suffer.

Moreover, the recent and ongoing series of congressional hearings relating to drug pricing has presented heightened attention to the biopharmaceutical industry, creating the potential for political and public pressure, while the potential for resulting legislative or policy changes presents uncertainty.

If the realized prices for our products, if any, decrease or if governmental and other third-party payors do not provide adequate coverage or reimbursement, our prospects to generate revenue and achieve profitability will decline.

Moreover, recent and ongoing series of congressional hearings relating to drug pricing has presented heightened attention to the biopharmaceutical industry, creating the potential for political and public pressure.

The potential for resulting legislative or policy changes presents uncertainty.

Assuming coverage is approved, the resulting reimbursement payment rates might not be adequate.

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In addition, third-party payors are requiring higher levels of evidence of the benefits and clinical outcomes of new technologies and are challenging the prices charged.

We, and our collaborators, cannot be sure that coverage will be available for any product candidate that we, or they, commercialize and, if available, that the reimbursement rates will be adequate.

We, and our collaborators, cannot be sure that coverage will be

available for any product candidate that we, or they, commercialize and, if available, that the reimbursement rates will be adequate.

Further, the net reimbursement for drug products may be subject to additional reductions if there are changes to laws that presently restrict imports of drugs from countries where they may be sold at lower prices than in the U.S.

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We expect that current laws, as well as other healthcare reform measures that may be adopted in the future, may result in more rigorous coverage criteria and in additional downward pressure on the price that we, or our collaborators, may receive for any approved products.

Since enactment of the Patient Protection and Affordable Care Act, as amended, or the ACA, in 2010, in both the U.S.

and certain foreign jurisdictions, there have been a number of legislative and regulatory changes to the health care system that could impact our ability to sell our products profitably.

In August 2011, the Budget Control Act of 2011, among other things, created measures for spending reductions by Congress.

A Joint Select Committee on Deficit Reduction, tasked with recommending a targeted deficit reduction of at least $1.2 trillion for the years 2013 through 2021, was unable to reach required goals, thereby triggering the legislation’s automatic reduction to several government programs.

This includes aggregate reductions of Medicare payments to providers up to 2% per fiscal year, which went into effect on April 1, 2013, and were to remain in effect until 2024.

The Bipartisan Budget Act of 2015 extended the 2% sequestration to 2025.

In January 2013, the American Taxpayer Relief Act of 2012, or ATRA, was approved which, among other things, reduced Medicare payments to several providers, with primary focus on the hospital outpatient setting and ancillary services, including hospitals, imaging centers and cancer treatment centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

On January 20, 2017, the Trump administration signed an Executive Order directing federal agencies with authorities and responsibilities under the ACA to waive, defer, grant exemptions from, or delay the implementation of any provision of the ACA that would impose a fiscal or regulatory burden on states, individuals, healthcare providers, health insurers, or manufacturers of pharmaceuticals or medical devices, and, for that reason, some final regulations have yet to take effect.

In December 2017, Congress repealed the individual mandate for health insurance required by the ACA and could consider further legislation to repeal other elements of the ACA.

At the end of 2017, CMS promulgated regulations that reduce the amount paid to hospitals for outpatient drugs purchased under the 340B program, and some states have enacted transparency laws requiring manufacturers to report information on drug prices and price increases.

In June 2021, the Supreme Court issued its opinion in California v.

Texas, upholding the constitutionality of the ACA.

Additional federal and state healthcare reform measures may be adopted in the future that may result in more rigorous coverage criteria, increased regulatory burdens and operating costs, decreased net revenue from our pharmaceutical products, decreased potential returns from our development efforts, and additional downward pressure on the price that we receive for any approved drug.

In the EU, several pieces of legislation recently approved—or still in the process of being approved—will impact regulatory procedures applicable to medicinal products, including those based on genes, tissues, or cells, or Advanced Therapy Medicinal Products.

These include, among others, the new Regulation (EU) 2024/1938 on standards of quality and safety for substances of human origin intended for human application and the new Regulation (EU) 2021/2282 on health technology assessment, which went into effect on January 12, 2025.

Moreover, on April 10, 2024, the European Parliament adopted its position on the European Commission proposal to reform EU pharmaceutical legislation, consisting of a new directive replacing Directive 2001/83/EC and a new regulation replacing Regulation (EC) 726/2004.

If approved, this will represent the most significant review of EU pharmaceutical legislation since 2004.

The changes proposed are far reaching, including a change in the period of standard regulatory exclusivity, a package of incentives aimed at addressing unmet medical needs, and an extension of the so-called Bolar exemption.

Moreover, it is unclear how regulations and sub-regulatory policy, which fluctuate continually, may affect interpretation and further implementation of the existing law and its practical effects on our business.

We are unable to predict the future course of federal or state healthcare legislation in the U.S.

directed at broadening the availability of healthcare and containing or lowering the cost of healthcare, including drugs and biologics.

Any further changes in the law or regulatory framework that reduce our revenue or increase our costs could also have a material and adverse effect on our business, financial condition and results of operations.

In addition, there is a great degree of uncertainty regarding how recent U.S.

Supreme Court decisions, including Loper Bright Enterprises v.

Raimondo, 603 U.S.

369 (2024) and Corner Post, Inc.

Board of Governors of the Federal Reserve System, 603 U.S.

799 (2024), will impact the FDA’s enforcement and decision-making authority.

Loper Bright explicitly overturned Chevron deference, which previously gave

judicial deference to administrative action by agencies in the executive branch.

Furthermore, the Supreme Court’s decision in Corner Post may result in challenges to FDA decisions by new litigants long into the future.

New federal and state healthcare reform measures may be adopted in the future that may result in more rigorous coverage criteria, increased regulatory burdens and operating costs, decreased net revenue from our pharmaceutical products, decreased potential returns from our development efforts, and additional downward pressure on the price that we receive for any approved drug.

There is also an increasing focus on the price of drugs, both at the state and federal levels, and it is likely that additional pricing controls will be enacted and could harm our business, financial condition and results of operations.

For instance, states such as California have begun enacting transparency laws aimed at curbing drug price increases and with the change in administration it is possible that President Biden may issue executive orders with the potential to change a number of prior executive branch actions on drug pricing.

For instance, states such as California have begun enacting transparency laws aimed at curbing drug price increases and with the change in administration it is possible that President Trump may issue executive orders with the potential to change a number of prior executive branch actions on drug pricing.

We continue to monitor the potential impact of proposals and recently enacted legislation to lower prescription drug costs at the federal and state level.

For example, the Inflation Reduction Act, or the IRA, was signed into law in August 2022 by President Biden, which makes significant changes to how drugs are covered and paid for under the Medicare program, including the creation of financial penalties for drugs whose prices rise faster than the rate of inflation, redesign of the Medicare Part D program to require manufacturers to bear more of the liability for certain drug benefits, and government price-setting for certain Medicare Part D drugs, starting in 2026, and Medicare Part B drugs starting in 2028.

We are evaluating what effect, if any, the IRA may have on our business.

As an example, of changes enacted by a new administration, the Inflation Reduction Act, or the IRA, was signed into law in August 2022 by President Biden, which makes significant changes to how drugs are covered and paid for under the Medicare program, including the creation of financial penalties for drugs whose prices rise faster than the rate of inflation, redesign of the Medicare Part D program to require manufacturers to bear more of the liability for certain drug benefits, and government price-setting for certain Medicare Part D drugs, starting in 2026, and Medicare Part B drugs starting in 2028.

We continue to evaluate what effect, if any, the IRA may have on our business.

Any reduction in reimbursement from Medicare or other government healthcare programs may result in a similar reduction in payments from private payors.

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In addition, there have been a number of other policy, legislative and regulatory proposals aimed at changing the pharmaceutical industry.

government, state legislatures and foreign governmental entities have shown significant interest in implementing cost containment programs to limit the growth of government-paid healthcare costs, including price controls, restrictions on reimbursement

and coverage and requirements for substitution of generic products for branded prescription drugs.

Adoption of government controls and measures and tightening of restrictive policies in jurisdictions with existing controls and measures, could exclude or limit our product candidates from coverage and limit payments for pharmaceuticals.

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directed at broadening the availability of healthcare and containing or lowering the cost of healthcare.

The ACA and any further changes in the law or regulatory framework that reduce our revenue or increase our costs could also have a material and adverse effect on our business, financial condition and results of operations.

Any changes in the law or regulatory framework that reduce our revenue or increase our costs could also have a material and adverse effect on our business, financial condition and results of operations.

Political uncertainty may have an adverse impact on our operating performance and results of operations, and uncertainty surrounding the potential legal, regulatory, and policy changes by a new U.S.

presidential administration may directly affect us and the global economy.

General political uncertainty may have an adverse impact on our operating performance and results of operations.

Changing regulatory policies resulting from the changing political environment could impact our regulatory and compliance costs and future revenues, all of which could materially and adversely affect our business, financial condition, and operating results.

Failure to adapt to or comply with evolving regulatory requirements or investor or stakeholder expectations and standards could negatively impact our reputation, ability to do business with certain partners, access to capital, and our stock price.

In particular, the U.S.

continues to experience significant political events that cast uncertainty on global financial and economic markets, especially following the recent election.

administration and recent congressional seat turnover may result in increased regulatory and economic uncertainty.

Changes in federal policy by the executive branch and regulatory agencies may occur over time through the new presidential

administration’s and/or Congress’s policy and personnel changes, which could lead to changes involving the level of oversight and focus on the biopharmaceutical industry.

However, the nature, timing, and economic and political effects of such potential changes remain highly uncertain.

It is presently unclear exactly what actions the new presidential administration in the U.S.

will implement, and if implemented, how these actions may impact the biopharmaceutical industry in the U.S.

Any actions taken by the new presidential administration may have a negative impact on the U.S.

economy and on our business, financial condition, and results of operations.

We are subject to a variety of U.S.

and international laws and regulations.

We are currently subject to a number of government laws and regulations, and, in the future, could become subject to new government laws and regulations.

The costs of compliance with such laws and regulations, or the negative results of non-compliance, could adversely affect our business, cash flow, results of operations, financial condition, and prospects;

these laws and regulations include (i) additional health care reform initiatives in the U.S.

or in other countries, including additional mandatory discounts or fees;

(ii) the FCPA, FCA or other anti-bribery and corruption laws across all of the jurisdictions that we operate in;

(iii) new laws, regulations, and judicial or other governmental decisions affecting pricing, drug reimbursement, and access or marketing within or across jurisdictions;

(iv) changes in intellectual property laws;

(v) changes in accounting standards;

(vi) new and increasing data privacy regulations and enforcement, particularly in the EU, the U.S., and China;

(vii) legislative mandates or preferences for local manufacturing of pharmaceutical products;

(viii) emerging and new global regulatory requirements for reporting payments and other value transfers to HCPs;

(ix) environmental regulations, such as the EU’s Corporate Sustainability Reporting Directive;

and (x) the potential impact of importation restrictions, embargoes, trade sanctions, and legislative and/or other regulatory changes.

Governments outside the U.S.

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In international markets, reimbursement and health care payment systems vary significantly by country, and many countries have instituted price ceilings on specific products and therapies.

In some countries, particularly the countries of the EU and the United Kingdom, the pricing of prescription pharmaceuticals is subject to governmental control.

In some countries, particularly the countries of the EU and the UK, the pricing of prescription pharmaceuticals is subject to governmental control.

In these countries, pricing negotiations with governmental authorities can take considerable time after the receipt of marketing approval for a product.

To obtain coverage and reimbursement or pricing approval in some countries, we may be required to conduct a clinical trial that compares the cost-effectiveness of our product candidate to other available therapies.

To obtain coverage and reimbursement or pricing approval in some countries, we may be required to undergo a health technology assessment or conduct a clinical trial that compares the cost-effectiveness of our product candidate to other available therapies.

There can be no assurance that our products will be considered cost-effective by third-party payors, that an adequate level of reimbursement will be available, or that the third-party payors’ reimbursement policies will not adversely affect our ability to sell our products profitably.

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Efforts to ensure that our business arrangements will comply with applicable healthcare laws may involve substantial costs.

It is possible that governmental and enforcement authorities will conclude that our, or our employees’, consultants’, collaborators’, contractors’, or vendors’ business practices may not comply with current or future statutes, regulations or case law interpreting applicable fraud and abuse or other healthcare laws and regulations.

If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could have a significant impact on our business, including the imposition of civil, criminal and administrative penalties, damages, disgorgement, monetary fines, possible exclusion from participation in Medicare, Medicaid and other federal healthcare programs, contractual damages, reputational harm, diminished profits and future earnings, compliance agreements, withdrawal of product approvals, and curtailment of our operations, among other things, any of which could

adversely affect our ability to operate our business and our results of operations.

fraud and abuse or other healthcare laws and regulations.

In addition, the approval and commercialization of any of our product candidates outside the U.S.

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In the event of a successful claim of infringement against us, we may be enjoined from manufacturing, use, and marketing our products, or may have to pay substantial damages, including treble damages and attorneys’ fees for willful infringement, obtain one or more licenses from third parties, pay royalties or redesign our infringing products, which may be impossible or require substantial time and monetary expenditure.

Periodic maintenance fees on any issued patent are due to be paid to the U.S.

Patent and Trademark Office, or USPTO, and foreign patent agencies in several stages over the lifetime of the patent.

Periodic maintenance fees on any issued patent are due to be paid to the USPTO, and foreign patent agencies in several stages over the lifetime of the patent.

The USPTO and various foreign governmental patent agencies require compliance with several procedural, documentary, fee payment and other similar provisions during the patent application process.

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With respect to the validity question, for example, we cannot be certain that there is no invalidating prior art, of which we, our patent counsel and the patent examiner were unaware during prosecution.

If a defendant or third

party were to prevail on a legal assertion of invalidity and/or unenforceability, we would lose at least part, and perhaps all, of the patent protection on our product candidates.

If a defendant or third party were to prevail on a legal assertion of invalidity and/or unenforceability, we would lose at least part, and perhaps all, of the patent protection on our product candidates.

Such a loss of patent protection could have a material adverse impact on our business.

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No consistent policy regarding the breadth of claims allowed in biotechnology patents has emerged to date.

The issuance of a patent is not conclusive as to its validity or enforceability and it is uncertain how much protection, if any, will be given to the patents we have licensed from the NIH, Moffitt, or MDACC if any of these parties, or we, attempt to enforce the patents and/or if they are challenged in court or in other proceedings, such as oppositions, which may be brought in foreign jurisdictions to challenge the validity of a patent.

The issuance of a patent is not conclusive as to its validity or enforceability and it is uncertain how much protection, if any, will be given to the patents we own or have licensed from the NIH, Cellectis or Novartis if any of these parties, or we, attempt to enforce the patents and/or if they are challenged in court or in other proceedings, such as oppositions, which may be brought in foreign jurisdictions to challenge the validity of a patent.

A third party may challenge the validity or enforceability of a patent after its issuance by the Patent Office.

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Co-ownership of these intellectual properties will create issues with respect to our ability to enforce the intellectual property rights in courts and will create issues with respect to the accountability of one entity with respect to the other.

Since the NCI, Moffitt, MDACC, and others already use TIL cell therapy for the treatment of metastatic melanoma and other indications, their methods and data are also available to third parties, who may want to enter into our line of business and compete against us.

Other than the Gen 2 manufacturing process, we currently do not own any exclusive rights on our entire product portfolio that could be used to prevent third parties from duplicating our business plan or from otherwise directly competing against us.

While additional technologies that may be developed under our CRADA may be licensed to us on an exclusive basis, no assurance can be given that our existing exclusive rights and will be sufficient to prevent others from competing with us and developing substantially similar products.

Since the NCI and numerous other academic institutions already use TIL cell therapy for the treatment of metastatic melanoma and other indications, their methods and data are also available to third parties, who may want to enter into our line of business and compete against us.

Other than the Gen 2 manufacturing process, our licensed rights, and our method of use rights in certain indications,

we currently do not own any exclusive rights on our entire product portfolio that could be used to fully prevent third parties from duplicating our business plan or from otherwise directly competing against us.

While additional technologies that may be developed under our CRADA may be licensed to us on an exclusive basis, no assurance can be given that our existing exclusive rights will be sufficient to prevent others from competing with us and developing substantially similar products.

The use of our technologies could potentially conflict with the rights of others.

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The legal systems of certain countries, particularly certain developing countries, do not favor the enforcement of patents, trade secrets and other intellectual property protection, particularly those relating to biopharmaceutical products, which could make it difficult for us to stop the infringement of our patents or marketing of competing products in violation of our proprietary rights generally.

Proceedings to enforce our patent rights in foreign jurisdictions could result in substantial costs and divert our efforts and attention from other aspects of our business, could put our patents at risk of being invalidated or interpreted narrowly and our patent applications at risk of not issuing and could provoke third parties to assert claims against us.

risk of not issuing and could provoke third parties to assert claims against us.

We may not prevail in any lawsuits that we initiate, and the damages or other remedies awarded, if any, may not be commercially meaningful.

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To raise additional capital, we may in the future offer additional shares of our common stock or other securities convertible into or exchangeable for our common stock at prices that may be lower than the current price per share of our common stock.

In addition, investors purchasing shares or other securities in the future could have rights superior to existing stockholders.

In addition, investors purchasing shares or other securities in the future could have rights superior

to existing stockholders.

The price per share at which we sell additional shares of our common stock, or securities convertible or exchangeable into common stock, in future transactions may be higher or lower than the price per share paid by investors in prior offerings.

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In addition, in the future, we may issue additional shares of common stock or other equity or debt securities convertible into common stock in connection with a financing, acquisition, litigation settlement, employee arrangements or otherwise.

For example, in July 2023, we issued 23,000,000 shares of common stock in connection with an underwritten public offering, and we may offer additional shares under our automatic shelf registration statement in the future.

For example, in February 2024, we issued 23,014,000 shares of common stock in connection with an underwritten public offering, and we may offer additional shares under our automatic shelf registration statement in the future.

Future issuances may result in substantial dilution to our existing stockholders and could cause our stock price to decline.

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The complaint alleges breach of fiduciary duty and a claim for unjust enrichment in connection with alleged excessive compensation of certain of our non-executive directors and seeks unspecified damages on behalf of our company.

The parties have agreed to a proposed

settlement, which was submitted to the Court on June 15, 2022.

The parties continue to work toward settlement after a hearing on November 17, 2022, where the Court required additional steps to be taken by the parties before it will determine whether final approval will be given to the settlement.

The parties agreed to proposed settlements in 2022 and 2024, which the Court declined to approve.

The Company continues to vigorously defend against the complaint.

The outcome of this and other future litigation is uncertain.

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Our certificate of incorporation, as amended, designates the Court of Chancery of the State of Delaware as the sole and exclusive forum for certain types of actions and proceedings that may be initiated by our stockholders, which could limit our stockholders’ ability to obtain a favorable judicial forum for disputes with us or our directors, officers or employees.

Our certificate of incorporation, as amended, provides that, subject to limited exceptions, the Court of Chancery of the State of Delaware shall, to the fullest extent permitted by law, be the sole and exclusive forum for (1) any derivative action or proceeding brought on our behalf, (2) any action asserting a claim of breach of a fiduciary duty owed by any of our directors, officers, employees or agents to us or our stockholders, creditors or other constituents, (3) any action asserting a claim against us arising pursuant to any provision of the Delaware General Corporation Law, our certificate of incorporation, as amended, or our amended bylaws, or (4) any other action asserting a claim against us that is governed by the internal affairs doctrine.

Any person or entity purchasing or otherwise acquiring any interest in shares of our capital stock shall be deemed to have notice of and to have consented to the provisions of our certificate of incorporation described above.

Our certificate of incorporation, as amended, provides that, subject to limited exceptions, the Court of Chancery of the State of Delaware shall, to the fullest extent permitted by law, be the sole and exclusive forum for (1) any derivative action or proceeding brought on our behalf, (2) any action asserting a claim of breach of a fiduciary duty owed by any of our directors, officers, employees or agents to us or our stockholders, creditors or other constituents, (3) any action asserting a claim against us arising pursuant to any provision of the Delaware General Corporation Law, our certificate of incorporation, as amended, or our amended and restated bylaws, or (4) any other action asserting a claim against us that is governed by the internal affairs doctrine.

Any person or entity purchasing or otherwise acquiring any interest in shares of our capital stock shall be deemed to have notice of and to have consented to the provisions of our

certificate of incorporation described above.

This choice of forum provision may limit a stockholder’s ability to bring a claim in a judicial forum that it finds favorable for disputes with us or our directors, officers, or other employees, which may discourage such lawsuits against us and our directors, officers, and employees.

Further, this choice of forum provision does not preclude or contract the scope of exclusive

federal or concurrent jurisdiction for any actions brought under the Securities Act or the Exchange Act.

Further, this choice of forum provision does not preclude or contract the scope of exclusive federal or concurrent jurisdiction for any actions brought under the Securities Act or the Exchange Act.

Section 27 of the Exchange Act creates exclusive federal jurisdiction over all suits brought to enforce any duty or liability created by the Exchange Act or the rules and regulations thereunder.

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federal courts, which ultimately may disadvantage our shareholders or be cost prohibitive.

Notwithstanding the foregoing, there is uncertainty as to whether a court (other than state courts in the State of Delaware, which have recently upheld the validity of such a provision) would enforce such a provision and whether investors can waive compliance with the federal securities laws and the rules and regulations thereunder.

Notwithstanding the foregoing, there is uncertainty as to whether a court (other than those states which have upheld the validity of such a provision) would enforce such a provision and whether investors can waive compliance with the federal securities laws and the rules and regulations thereunder.

Furthermore, the exclusive forum provision only applies to claims brought under the Securities Act and does not apply to actions arising under the Exchange Act, which is already subject to federal courts as the exclusive forum.

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1A. Risk Factors