What changed in this filing

/stocks — the workspaceLOADING

Item 1. Business

2024-02-28 compared with 2023-02-28 · 416 added, 456 removed, 463 unchanged (65% of the section changed)

We are a clinical-stage biopharmaceutical company pioneering a transformational approach to treating cancer by harnessing the human immune system’s ability to recognize and destroy diverse cancer cells using therapies personalized for each patient.

We are preparing for potential U.S.

regulatory approval and commercialization of the first autologous T-cell therapy to address a solid tumor cancer.

Our mission is to be the global leader in innovating, developing and delivering tumor infiltrating lymphocyte, or TIL, therapies for patients with solid tumor cancers.

Our autologous TIL therapy platform uses a centralized, scalable and proprietary 22-day manufacturing process to grow polyclonal T-cells unique to each patient and yields a cryopreserved, individualized therapy.

We have applied multiple TIL therapy modalities in clinical trials in solid tumors, including TIL monotherapies for patients with later stage disease who have progressed on or after standard of care, as well as TIL combinations with standard of care therapies in patients who are earlier in their disease, to potentially improve outcomes compared to current standard(s) of care.

Our lead product candidate, lifileucel, is being developed in advanced, or metastatic or unresectable, melanoma as well as in other indications.

Lifileucel was investigated in two consecutive cohorts in a clinical trial of advanced melanoma patients post-anti-PD-1 therapy, including in a prospectively defined pivotal cohort.

These patients had progressed on or after standard of care therapy, which is immune checkpoint inhibitors, or ICIs, and, targeted BRAF/MEK inhibitor therapy where appropriate.

Based on the positive results of these cohorts, we initiated a rolling Biologics License Application, or BLA, submission to the U.S.

Food and Drug Administration, or FDA, for lifileucel in August 2022.

We expect to complete this rolling BLA submission in the first quarter of 2023.

Our Phase 3 clinical trial of lifileucel in combination with pembrolizumab, TILVANCE-301, is intended to be registrational in frontline advanced melanoma and serve as a confirmatory clinical trial to support full approval of lifileucel monotherapy in post-anti-PD-1 melanoma.

We are also pursuing registrational strategies for lifileucel in advanced cervical cancer and for our TIL therapy, LN-145, in metastatic non-small cell lung cancer, or NSCLC.

To continuously innovate and maintain our global leadership within the field, we are investigating next generation approaches to optimize TIL products, manufacturing processes and treatment regimens, including a first-in-human clinical trial of our lead genetically modified TIL therapy, IOV-4001.

We are also exploring a 16-day manufacturing

process, tumor tissue procurement via core biopsy, additional genetically modified TIL therapies including multiple immune checkpoint gene edits and cytokine-tethered TIL therapies, and a novel interleukin-2, or IL-2, analog, designated IOV-3001, as potential avenues to improve manufacturing timelines, sample collection and supportive treatments involved in the overall TIL therapy process and treatment regimen.

Highlights of our current development pipeline are presented in the figure below:

Platform Technologies and Manufacturing

Our T-cell-based immunotherapy technology platforms are potentially applicable to many solid tumor types and blood cancers.

Each platform is focused on leveraging patient-specific cells to recognize and attack diverse cancer cells that are unique to each patient.

Unlike cell therapies that act on a single or small number of shared antigen targets common to certain tumors, our polyclonal T-cells are personalized therapies designed to target a variety of neoantigens that are unique to the patient or tumor.

The majority of solid tumor immune targets are patient-specific, with fewer than 1% shared among patients.

TIL therapy is our lead T-cell-based immunotherapy platform in multiple advanced solid tumor cancers.

For blood cancers, our peripheral blood lymphocyte, or PBL, therapy platform is based on polyclonal T-cells that are collected from a patient’s blood sample, and then amplified and reinvigorated.

TIL Clinical Development in Advanced, Metastatic or Unresectable Solid Tumor Cancers

Building on the prior TIL therapy clinical trials conducted at single academic centers, including the National Cancer Institute, or NCI, we have investigated TIL therapy in global, multi-center Phase 2 clinical trials in advanced melanoma, cervical cancer, NSCLC, and head and neck squamous cell carcinoma, or HNSCC.

Additional information about our clinical trials is summarized below.

In post-anti-PD-1 advanced melanoma, we are investigating lifileucel in our C-144-01 clinical trial that supports our BLA submission and potential approval of lifileucel in advanced post-anti-PD-1 melanoma.

In frontline advanced melanoma patients who are naïve to anti-PD-1 therapy, we are investigating lifileucel in combination with pembrolizumab in the IOV-COM-202 clinical trial and the Phase 3 TILVANCE-301 clinical trial.

TILVANCE-301 is a randomized Phase 3 clinical trial intended to support registration in advanced frontline melanoma as well as to serve as a confirmatory trial for full approval in advanced post-anti-PD-1 melanoma.

We are also executing a registrational strategy for lifileucel in advanced cervical cancer.

C-145-04 is a multicenter Phase 2 clinical trial that is currently enrolling a pivotal cohort to support a BLA in cervical cancer following progression on or after chemotherapy and pembrolizumab.

In NSCLC, we are investigating our TIL therapy, LN-145, in two clinical trials in several NSCLC patient populations with significant unmet need.

IOV-LUN-202 is a clinical trial of LN-145 in advanced NSCLC patients who have progressed following chemotherapy and anti-PD-1 therapy.

IOV-COM-202 also includes cohorts of NSCLC patients treated with LN-145 monotherapy and combination therapy.

Our first genetically modified, PD-1 inactivated TIL therapy, IOV-4001, entered a first-in-human Phase 1/2 clinical trial, IOV-GM1-201, in 2022 in patients with previously treated advanced melanoma and NSCLC.

IOV-4001 utilizes the gene-editing TALEN® technology, licensed from Cellectis S.A., or Cellectis, to inactivate the gene coding for the programmed cell death protein-1, or PD-1.

Beyond our Iovance-sponsored clinical trials, we have academic collaborations with leading cancer research centers to investigate TIL therapy, including next-generation processes and technologies, in other cancers and treatment settings.

Next-Generation Therapeutic and Manufacturing Approaches

Our current next-generation technology platforms are designed to optimize TIL therapy across four key initiatives:

genetic modification, potency, manufacturing process and treatment regimens.

More information on our next-generation approaches is included in the Next-Generation Product Candidates section of this Annual Report on Form 10-K.

Intellectual Property

We have established a leading intellectual property portfolio developed internally and licensed from third parties.

We currently own more than 60 U.S.

patents related to TIL therapy, including patents directed to compositions and methods of treatment and manufacturing in a broad range of cancers.

Pending patent applications and granted patents cover the fields of TIL therapy, marrow infiltrating lymphocytes, or MIL therapy, and PBL therapy.

We also license rights to a broad range of technologies related to our platforms.

More details on our intellectual property portfolio are included within this Annual Report on Form 10-K.

We are a commercial-stage biopharmaceutical company pioneering a transformational approach to treating cancer by harnessing the human immune system’s ability to recognize and destroy diverse cancer cells using therapies personalized for each patient.

Our mission is to be the global leader in innovating, developing and delivering tumor infiltrating lymphocyte, or TIL, cell therapies for patients with solid tumor cancers.

With the recent approval of our biologics license application, or BLA, we are executing the U.S.

launch of Amtagvi™ (lifileucel), the first product within our autologous TIL cell therapy platform, while also marketing Proleukin ® (aldesleukin), an interleukin-2, or IL-2, product used in the Amtagvi™ treatment regimen.

Amtagvi™ is a tumor-derived autologous T cell immunotherapy indicated for the treatment of adult patients with unresectable or metastatic melanoma previously treated with a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor.

This indication is approved under accelerated approval based on an endpoint of overall response rate, or ORR.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in future confirmatory trials.

Amtagvi™ is the first and the only one-time, individualized T cell therapy to receive FDA approval for a solid tumor cancer.

Amtagvi™ and Proleukin ® are part of a treatment regimen that also includes lymphodepletion.

Iovance was founded to build upon the promise of TIL cell therapy that was previously demonstrated in single-center clinical trials at academic centers, including the National Cancer Institute, or the NCI.

Our multi-center trials, novel TIL products, manufacturing processes, facilities, and bioanalytical platforms have transformed TIL cell therapy into a commercially viable treatment, which many more patients with cancer can access.

We manufacture Amtagvi™ and our investigational TIL cell therapies using a centralized, scalable, and proprietary 22-day manufacturing process which rejuvenates and multiplies polyclonal T cells unique to each patient into the billions and yields a cryopreserved, individualized therapy.

Our development pipeline includes multicenter trials of TIL cell therapies in additional treatment settings for solid tumor cancers.

We are investigating TIL monotherapies for patients with later stage disease who were previously treated with standard of care therapies and TIL combinations with standard of care therapies to potentially improve outcomes in patients who are earlier in their disease.

These trials include two ongoing registrational trials to support a supplementary BLA, or sBLA, of our TIL cell therapies in frontline advanced

melanoma and in advanced non-small cell lung cancer following standard of care chemo-immunotherapy.

We are also developing next generation therapies using TIL, such as genetically modified TIL cell therapy.

Corporate Strategy

Be the global leader in innovating, developing and delivering TIL therapy

Our mission is to be the global leader in innovating, developing and delivering TIL therapy for patients with cancer.

Be the global leader in innovating, developing and delivering TIL cell therapy

Our mission is to be the global leader in innovating, developing and delivering TIL cell therapy for patients with solid tumor cancers.

We are pioneering this transformational approach to cure cancer by harnessing the human immune system’s ability to recognize and destroy diverse cancer cells in each patient.

We are committed to continuous innovation in developing TIL cell therapy and optimizing the TIL treatment regimen that may extend and improve life for patients with cancer.

Obtain regulatory approval and successfully commercialize our lead product candidate lifileucel for the treatment of post-anti-PD-1 advanced melanoma

Our top priority is to expedite the regulatory approval and commercialization of our lead product candidate, lifileucel, for the treatment of patients with post-anti-PD-1 advanced melanoma.

We initiated a rolling BLA for lifileucel in post-anti-PD-1 advanced melanoma in August 2022 and plan to complete the BLA submission in the first quarter of 2023.

Our medical affairs team is in the field educating key opinion leaders, or KOLs, and presenting and publishing our clinical results.

commercial leadership team is preparing to launch lifileucel in 2023, if approved.

We have experienced marketing, payer access and distribution teams, and we are building a specialty oncology sales force for launch.

More than half the team has prior cell therapy experience.

The five primary areas of our pre-launch efforts include:

● onboarding of authorized treatment centers, or ATCs, with the goal of 40 ATCs for commercial launch;

● collaboration with healthcare professionals, or HCPs, who will be handling or administering our product;

Through the U.S.

launch of Amtagvi™ and the advancement of our pipeline, we are committed to continuous innovation in developing TIL cell therapy and optimizing TIL treatment regimens that may extend and improve life for patients with cancer.

Successfully commercialize our lead product Amtagvi™ for the treatment of post-anti-PD-1 advanced melanoma

Our top priority is commercialization of Amtagvi TM in the U.S.

for the treatment of patients with post-anti-PD-1 advanced melanoma, for which we received FDA approval on February 16, 2024.

We have experienced marketing, payer access and distribution teams as well as a sales force with extensive experience in oncology and cell therapy.

Our medical affairs team is also in the field educating key opinion leaders, or KOLs, about Amtagvi™ and TIL cell therapy as well as presenting and publishing our clinical results.

More than half of the members of our field teams have prior cell therapy experience.

The four primary areas of our Amtagvi™ launch efforts include:

● onboarding of authorized treatment centers, or ATCs, for commercial launch, with the goal of activating 50 ATCs within 90 days of the BLA Prescription Drug User Fee Act, or PDUFA, date of February 24, 2024;

● collaboration with healthcare professionals, or HCPs, who will be administering our product;

● operational excellence in launch execution, commercial manufacturing and delivery of therapy;

● communication with payors about the value of lifileucel;

● establishment of a cross-functional, patient-centric organization.

● ongoing and continuous communication with payors about the value of Amtagvi™.

Prepare for commercial manufacturing to meet forecasted demand

We are the first company to obtain FDA approval for a TIL cell therapy product.

We believe that we are the only company in the U.S.

to have a centralized, demonstrated, and commercially viable TIL manufacturing process.

To date more than 600 patients have been treated with Iovance TIL therapy manufactured using our proprietary processes, by contract manufacturing organizations, or CMOs, and by us at our own manufacturing facility, the Iovance Cell Therapy Center, or i CTC.

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

We began construction of the i CTC in 2019, in Philadelphia, Pennsylvania, in order to control manufacturing capacity, product quality, manage logistics around supply and delivery, implement process improvement and realize potential cost efficiencies for TIL therapies that we may develop or commercialize.

We intend to carefully manage our cost structure, and reduce the long-term cost of manufacturing our products, although there can be no assurance that we will be able to reduce our manufacturing costs to commercially attractive levels.

We are building capacity to treat thousands of cancer patients annually, with flexibility to expand within existing shell space and an option to build on an adjacent lot to support future growth.

We expect i CTC to supply most of our commercial TIL therapies at launch, with CMOs to supplement our internal manufacturing capacity under various manufacturing services agreements, or MSAs.

Details of related agreements are provided in the Research, Development, Manufacturing and License agreements section of this Annual Report on Form 10-K.

Continue to improve our TIL manufacturing processes and technology

In 2018, we first utilized our TIL manufacturing process known as Gen 2, which reduced TIL manufacturing time from 5-6 weeks to 22 days while producing a cryopreserved TIL product for ease of administration and handling.

We intend to establish Gen 2 as a viable commercial manufacturing process for our initial TIL therapies.

Gen 2 was utilized in all patients in both Cohorts 2 and 4 of our C-144-01 clinical trial and is the manufacturing process for registration and the BLA submission for lifileucel.

Gen 2 is also being utilized in most of our ongoing TIL clinical development programs.

We also continue to develop and evaluate potential future TIL manufacturing processes, including our 16-day Gen 3 process, as well as processes for genetically modified and other next generation TIL products.

Advance and expand our pipeline of polyclonal T-cell therapies

We seek to collaborate with government, academic research institutions, and corporate partners to improve TIL manufacturing, and to develop and explore next generation approaches as well as TIL therapies for new indications.

We have a Cooperative Research and Development Agreement, or CRADA, with the National Institutes of Health, or NIH, and the National Cancer Institute, or NCI.

We also have ongoing licensing agreements and collaborations with H.

Lee Moffitt Cancer Center, or Moffitt, The University of Texas M.D.

Anderson Cancer Center, or MDACC, Yale University, The Ohio State University, Cellectis, Novartis Pharma AG, or Novartis, Melanoma Institute Australia, or MIA, and Beth-Israel Deaconess Medical Center, or BIDMC.

A description of some of these collaborations and related agreements is provided in the Collaborations for New Tumor Types and Treatment Settings section of this Annual Report on Form 10-K.

to have a centralized, scalable and commercially viable TIL manufacturing process.

To date, more than 700 patients have been treated with Iovance TIL cell therapy products manufactured using our proprietary processes across multiple indications.

Iovance TIL cell therapies are manufactured for commercial use and clinical trials at our manufacturing facility, the Iovance Cell Therapy Center, or the i CTC, and by a contract manufacturing organization, or CMO.

We are building capacity to treat several thousands of cancer patients annually at the i CTC, which is the first centralized and scalable current Good Manufacturing Practice, or cGMP, manufacturing facility dedicated to producing TIL.

Located in Philadelphia, Pennsylvania, the 136,000 square feet i CTC is also among the largest cell therapy manufacturing facilities in existence.

Additional expansion at the i CTC is under way which will significantly increase this capacity.

The proximity of the i CTC to multiple airports facilitates delivery of TIL cell therapies to treatment centers, with the i CTC expected to cover logistics and delivery of TIL cell therapies in both North America and Europe.

Owning our own facility allows us to control manufacturing capacity and product quality, manage logistics around supply and delivery, implement process improvement and realize potential cost efficiencies for TIL cell therapies that we may develop and commercialize.

We are also exploring future TIL manufacturing processes, as well as next-generation treatments and technologies, which may further streamline development timelines and costs.

The i CTC has a flexible design that allows future expansion within existing shell space and an option to build on an adjacent lot to support future growth and capacity needs.

In 2018, we began using our Gen 2 TIL manufacturing process, which reduced TIL manufacturing time to 22 days while producing a cryopreserved TIL product.

The Gen 2 process was used to manufacture Amtagvi TM for the clinical trial that supported FDA approval, and most of our ongoing clinical trials use the Gen 2 process.

Amtagvi TM is approved for commercial manufacturing at the i CTC.

In addition, our CMO is approved for additional capacity to supplement our internal manufacturing.

We plan to carefully manage our cost structure and reduce the long-term cost of manufacturing our products.

Details of related agreements are provided in the Research, Development, Manufacturing and License Agreements for TIL Cell Therapy section of this Annual Report on Form 10-K.

Commercial Launch of the First TIL Cell Therapy in Advanced Melanoma

Amtagvi™ (lifileucel) was approved by the FDA on February 16, 2024 for the treatment of adult patients with unresectable or metastatic melanoma previously treated with a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF inhibitor with or without MEK inhibitor.

The approval is based on safety and efficacy results from the C-144-01 clinical trial, a global, multicenter trial investigating Amtagvi™ in patients with advanced melanoma previously treated with anti-PD-1 therapy and targeted therapy, where applicable.

Amtagvi™ demonstrated deep and durable responses.

The primary efficacy analysis set included 73 patients from Cohort 4 who received the recommended Amtagvi™ dose from an approved manufacturing facility.

Among the 73 patients, 31.5% achieved an objective response by Response Evaluation Criteria in Solid Tumors, or RECIST 1.1, with a median duration of response not reached at 18.6 months follow-up;

43.5% of responses had a duration greater than 12 months.

Additionally, the supporting pooled efficacy set included a total of 153 patients from Cohort 4 and Cohort 2.

Among the 153 patients, 31.4% achieved an objective response by RECIST 1.1 with a median duration of response not reached at 21.5 months follow-up;

54.2% of responses had a duration greater than 12 months.

We completed the BLA submission in March 2023, which the FDA accepted in May 2023 for Priority Review.

Based on the unmet need in post-anti-PD-1 advanced melanoma, as well as initial clinical data, Amtagvi™ previously received a Regenerative Medicine Advanced Therapy, or RMAT, designation from the FDA in 2018.

Amtagvi™ has a boxed warning for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment.

Warnings and precautions include treatment-related mortality, prolonged severe cytopenia, internal organ hemorrhage, severe infection, cardiac disorder, respiratory failure, acute renal failure, and hypersensitivity reactions.

Amtagvi™ is manufactured using a proprietary process to collect and multiply a patient’s unique T cells from a portion of their tumor.

Amtagvi™ returns billions of the patient’s T cells back to the body to fight cancer.

ATCs will administer Amtagvi™ to patients as part of a treatment regimen that includes lymphodepletion and a short course of high-dose Proleukin ® (aldesleukin).

There are three key steps in the Amtagvi™ treatment process.

Sample Collection.

At an ATC, a tumor tissue sample of at least 1.5 cm in diameter is removed and collected during a surgical resection and shipped to an approved, centralized manufacturing facility.

Manufacturing.

Patient-specific TIL are manufactured using our commercial Gen 2 manufacturing process.

Upon arrival at the facility, TIL are separated from other cells within the patient’s tumor tissue sample.

Over the next 22 days, the cells are multiplied into the billions, so they can be returned to the patient to fight cancer cells.

Upon completion of manufacturing, Amtagvi™ is quality tested to meet specific product release criteria.

The final product is cryopreserved and sent back to the ATC for administration to the patient.

Additional details on the Gen 2 manufacturing process are provided in the Manufacturing Process section of our Annual Report on Form 10-K.

Treatment Regimen .

The patient’s cell therapy treatment begins with a preparative regimen of non-myeloablative lymphodepletion, or NMA-LD, to suppress the immunosuppressive tumor microenvironment, which we believe will enhance the efficacy of TIL cell therapy.

After NMA-LD, the patient is treated at the ATC with Amtagvi™, followed by a short course of up to six doses of Proleukin ® to promote T cell activity in the body after TIL infusion.

Until now, there were no FDA approved therapies in this treatment setting for advanced melanoma after anti-PD-1 therapy.

In May 2023, we acquired the worldwide rights to Proleukin ® (aldesleukin) as well as the manufacturing, supply, and commercialization income generated from such rights and associated operations from Clinigen Holdings Limited, Clinigen Healthcare Limited, and Clinigen, Inc, which we refer to collectively as Clinigen.

Ownership of Proleukin ® provides an additional revenue source,

allows Iovance to secure its supply chain and logistics surrounding TIL cell therapy administration, and lowers cost of goods and clinical trial expenses for Proleukin ® used with TIL cell therapies.

Proleukin ® is an IL-2 product used in the Amtagvi™ treatment regimen.

Proleukin ® has also received regulatory approvals for treatment of adults with metastatic melanoma and metastatic renal cell carcinoma in the United States.

Proleukin ® is also licensed in multiple countries around the world for treatment of patients with metastatic renal cell carcinoma and/or metastatic melanoma.

TIL Cell Therapy Clinical Development in Advanced, Metastatic or Unresectable Solid Tumor Cancers

TIL cell therapy is a T cell-based immunotherapy technology platform that leverages patient-specific cells to recognize and attack diverse cancer cells that are unique to each patient.

Unlike other cell therapies that act on a single or small number of shared antigen targets common to certain tumors, our individualized T cell therapy are polyclonal or designed to target a variety of neoantigens that are unique to the patient or tumor.

We believe this polyclonal cell therapy is potentially applicable to many solid tumor cancers, where the majority of immune targets are patient-specific.

Our TIL cell therapy platform and manufacturing process have been initially validated through the FDA approval of Amtagvi™.

We have investigated TIL cell therapy in global, multicenter clinical trials in advanced melanoma, cervical cancer, non-small cell lung cancer, or NSCLC, and head and neck squamous cell carcinoma, or HNSCC.

Through ongoing academic collaborations, as well as government and other partners, we are investigating the next frontier for TIL cell therapy in other tumor types and treatment settings.

● Frontline Advanced Melanoma:

In frontline advanced melanoma patients who are naïve to anti-PD-1 therapy, we are investigating lifileucel in combination with pembrolizumab in the Phase 3 TILVANCE-301 clinical trial.

TILVANCE-301 is expected to enroll approximately 670 patients and features dual primary endpoints of ORR and progression free survival, or PFS, by a blinded independent review committee.

● Non-Small Cell Lung Cancer:

In NSCLC, we are investigating LN-145 TIL cell therapy in two clinical trials in NSCLC patient populations with significant unmet need.

IOV-LUN-202 is a registrational clinical trial of LN-145 in advanced NSCLC patients who have progressed following chemotherapy and anti-PD-1 therapy.

The IOV-COM-202 trial in solid tumors also includes cohorts of NSCLC patients treated with LN-145 monotherapy and combination therapy.

● Gynecological Cancers:

We are planning to initiate a clinical trial for lifileucel TIL cell therapy in endometrial cancer to potentially address the unmet need for patients previously treated with anti-PD-1 therapy.

We also are exploring lifileucel in advanced cervical cancer in the C-145-04 multicenter Phase 2 clinical trial.

● Next Generation TIL Cell Therapy:

Our first genetically modified, PD-1 inactivated TIL cell therapy, IOV-4001, entered a first-in-human Phase 1/2 clinical trial, IOV-GM1-201, in 2022 in patients with previously treated advanced melanoma and NSCLC.

IOV-4001 utilizes the gene-editing TALEN ® technology, licensed from Cellectis S.A., or Cellectis, to inactivate the gene coding for the programmed cell death protein-1, or PD-1.

● Additional Solid Tumor Cancers:

Iovance TIL cell therapy has been investigated in additional solid tumor cancers in Iovance-and-investigator-sponsored clinical trials.

LN-145 was evaluated as a monotherapy and in combination with pembrolizumab in the Phase 2 C-145-03 and IOV-COM-202 clinical trials in multiple patient cohorts with metastatic HNSCC.

Indications studied in investigator sponsored clinical trials supported by Iovance include soft tissue sarcoma, osteosarcoma, pancreatic and colorectal cancer, platinum resistant ovarian cancer, anaplastic thyroid cancer and triple negative breast cancer.

Additional information is included in the Iovance-Sponsored Clinical Trials section of this Annual Report on Form 10-K.

Intellectual Property

We established leadership within the field of TIL cell therapy by building and augmenting a leading intellectual property portfolio developed internally and licensed from third parties.

We currently own more than 60 U.S.

patents related to TIL cell therapy, including patents directed to compositions and methods of treatment in a broad range of cancers.

Pending patent applications and granted patents cover the fields of TIL cell therapy, genetically edited TIL cell therapy, selected TIL cell therapy, small core or biopsy TIL cell therapy,

fresh or frozen tumor digest-derived TIL cell therapy, TIL and ICI combination therapy, marrow infiltrating lymphocytes, or MIL therapy, and PBL therapy.

We also license rights to a broad range of technologies related to our platforms.

More details on our intellectual property portfolio are included within this Annual Report on Form 10-K.

Iovance-Sponsored Clinical Trials

TIL Therapy in Advanced Solid Tumor Cancers

Lifileucel for Advanced Melanoma

Frontline Advanced Melanoma

Melanoma is a common type of skin cancer, accounting for an estimated 99,780 patients diagnosed and 7,650 deaths in 2023 in the U.S.

according to the Surveillance, Epidemiology and End Results program, or SEER, program.

We are developing lifileucel to treat advanced melanoma.

Our Phase 2 clinical trial, C-144-01, is a prospective, clinical trial evaluating lifileucel in advanced melanoma patients who have progressed on or after prior anti-PD-1 therapy and if BRAF mutant, after BRAF or BRAF/MEK inhibitor therapy.

There are no FDA approved therapies in this treatment setting for advanced melanoma after anti-PD-1 therapy.

Based on the unmet need in post-anti-PD-1 advanced melanoma, as well as initial clinical data, lifileucel received a Regenerative Medicine Advanced Therapy, or RMAT, designation from the FDA in 2018.

In the C-144-01 trial, our Generation 1, or Gen 1, manufacturing process with non-cryopreserved product was used in Cohort 1, which was closed to enrollment in 2017.

Our Gen 2 process with cryopreserved product was used in subsequent patients enrolled in both Cohorts 2 and 4.

Cohort 2 was closed to enrollment in late 2018.

Cohort 3 is an optional retreatment cohort.

Cohort 4, a pivotal cohort, was added in 2019, following an end of Phase 2, or EOP2, meeting held with the FDA in the third quarter of 2018 and completed dosing in January 2020.

Cohort 4 built on the Cohort 2 results in the same patient population and used the same eligibility criteria, treatment and manufacturing process.

Cohort 4 was designed to evaluate objective response rate, or ORR, read by an independent review committee, or IRC, using RECIST v1.1 as the prospectively defined primary endpoint.

The results from Cohort 2, including ORR as assessed by investigator, were presented at several medical meetings since 2018 and published in the Journal of Clinical Oncology in May 2021.

We reported durable responses across a wide age range of metastatic melanoma patients, among those who have received prior anti-CTLA-4 and BRAF targeted treatments, regardless of BRAF mutation status, and in patients with PD-L1 high and low status.

In May 2022, we announced topline IRC read data from the C-144-01 clinical trial from Cohort 4, which met the primary endpoint, ORR, of the clinical trial.

In addition, we reported updated data from Cohort 2 and pooled Cohorts 2 and 4.

We presented additional data from C-144-01 Cohorts 2 and 4 at the Society for Immunotherapy of Cancer, or SITC, Annual Meeting in November 2022.

The SITC 2022 presentation included pooled efficacy data read by IRC and safety data from 153 patients with advanced melanoma, including 66 patients enrolled in Cohort 2 and 87 patients enrolled in Cohort 4, with a median study follow up of 36.5 months and a data cutoff date of July 15, 2022.

Across both cohorts, patients had received a median of 3 lines of prior therapy, including anti-PD-1 therapy in 100% of patients and anti-CTLA-4 therapy in 81.7% of patients, with prior combination anti-PD-1 and anti-CTLA-4 therapy received in 53.6% of patients.

Baseline disease characteristics were generally similar between Cohorts 2 and 4.

However, Cohort 4 patients showed both a higher disease burden and a higher proportion of patients with elevated lactate dehydrogenase, or LDH, a well-known negative prognostic factor in melanoma.

The ORR assessed by an IRC using RECIST v1.1 was 31.4%, with 9 complete responses and 39 partial responses.

The median time from lifileucel infusion to best response was 1.5 months, and responses deepened over time.

Median duration of response, or mDOR, was not reached as estimated by Kaplan-Meier, or KM, method.

Responses lasted for 24 months or greater in 41.7% of responders, including 47.8% of responders in Cohort 2 and 36.0% of responders in Cohort 4.

Median overall survival, or mOS, had not been reached in patients who achieved a response at first assessment at 6 weeks, and mOS in all patients was 13.9 months.

The treatment-related adverse event, or TEAE, profile was generally consistent with the underlying advanced disease and the safety profile of the lymphodepletion and IL-2 regimens.

In December 2022, we published additional detail from C-144-01 in the Journal for Immuno Therapy of Cancer, or JITC.

Based on results from the C-144-01 clinical trial, we held a pre-BLA meeting with the FDA in July 2022 and initiated a rolling BLA for lifileucel in metastatic melanoma in August 2022.

The BLA submission includes C-144-01 data from pivotal Cohort 4 and supportive Cohort 2.

We plan to complete the rolling BLA submission in the first quarter of 2023.

We are also pursuing a registrational path for lifileucel in combination with pembrolizumab in frontline advanced melanoma.

Our strategy is based on clinical results from Cohort 1A of the IOV-COM-202 clinical trial that support the combination, as well as prior published NCI data for TIL monotherapy in anti-PD-1 naïve melanoma patients.

We reported initial results and updates from ongoing Cohort 1A of the IOV-COM-202 clinical trial at the American Society of Clinical Oncology, or ASCO, annual meeting in June 2021, SITC in November 2021.

The Cohort 1A results to date have demonstrated that lifileucel can be safely combined with pembrolizumab.

At our most recent medical meeting oral presentation at SITC, in November 2021, updated results from 10 patients demonstrated ORR of 60%.

Six out of the 10 patients had a confirmed objective response, including three complete responses and three partial responses.

The TEAE profile was consistent with the underlying advanced disease and the known adverse event profiles of pembrolizumab, lymphodepletion, and IL-2 regimens.

In an April 2022 corporate announcement, we provided updated data that demonstrated a 67% ORR in 12 patients in Cohort 1A.

Eight patients had a confirmed objective response per RECIST v1.1, including three complete responses and five partial responses.

Six of the eight responders had ongoing response at the time of the last data cut, and five responders had a duration of response of more than one year.

In a January 2023 corporate press release, we disclosed that updated efficacy and safety results from nearly 20 patients treated in Cohort 1A remain consistent with previously reported Cohort 1A data and continue to support our strategy in frontline advanced melanoma.

During the fourth quarter of 2022, we reached agreement with the FDA and began start up activities for a Phase 3 multicenter, open-label, randomized, parallel group, treatment clinical trial, TILVANCE-301, in frontline advanced melanoma.

The TILVANCE-301 trial, or NCT05727904, will randomize 670 patients to investigate lifileucel in combination with pembrolizumab in the experimental arm compared with pembrolizumab monotherapy in the control arm.

The clinical trial will enroll participants with unresectable or metastatic melanoma who have had no prior therapy for metastatic disease.

Previous adjuvant/neoadjuvant therapy with a single line of BRAF-targeted therapy, PD-1 inhibitor, or CTLA-4 inhibitor is allowed, if completed at least 6 months before progression to metastatic disease.

In the experimental arm, a tumor sample is resected from each patient for lifileucel manufacturing.

Patients receive pembrolizumab prior to and after the lifileucel regimen, every 6 weeks until disease progression.

In the control arm, pembrolizumab monotherapy is given every 6 weeks until disease progression, with an optional crossover period to lifileucel monotherapy upon confirmed progressive disease verified by a blinded independent review committee, or BIRC, and if patients meet eligibility criteria.

The FDA agreed to dual primary endpoints of ORR to support accelerated approval and progression free survival, or PFS, to support full approval of lifileucel in frontline advanced melanoma.

TILVANCE-301 is also designed to serve as a confirmatory clinical trial to support full approval of lifileucel in post-anti-PD-1 advanced melanoma.

The dual primary endpoints will be verified by BIRC using RECIST v1.1.

Lifileucel for Cervical Cancer

According to estimates from the SEER program, in 2022 approximately 14,100 women would be diagnosed with cervical cancer and approximately 4,280 cervical cancer-related deaths would occur in the U.S.

We are developing lifileucel alone and in combination with pembrolizumab for the treatment of advanced, unresectable or metastatic, cervical cancer.

Lifileucel for advanced cervical cancer was formerly known as LN-145.

C-145-04 is an ongoing Phase 2, multicenter pivotal clinical trial.

In March 2019, the protocol for this clinical trial was amended to modify the primary endpoint of from ORR by investigator to ORR based on IRC assessment.

Initial results from the C-145-04 clinical trial were reported at ASCO in June 2019.

In anticipation of a changing landscape, we amended the protocol for the C-145-04 clinical trial in November 2019 from a single cohort design into a multicohort study.

Cohort 1 was defined to include patients who had progressed during or after systemic chemotherapy excluding ICI.

Cohort 2 was newly added to include patients who have progressed during or after treatment with anti-PD-1/-L1 checkpoint inhibitor in addition to systemic chemotherapy.

Cohort 3 was added to enroll patients who had not received prior systemic therapy to investigate lifileucel in combination with pembrolizumab.

Cohort 3 results from 14 initial patients were included as part of an oral presentation at SITC in November 2021.

The ORR was 57.1 % with eight out of 14 patients achieving an objective response, including one complete response, six partial responses and one unconfirmed partial response.

The TEAE profile was consistent with the underlying advanced disease and the known adverse event profiles of pembrolizumab, lymphodepletion, and IL-2 regimens.

In the C-145-04 trial, we completed enrollment of Cohort 1 in 2020, Cohort 2 in 2021 and Cohort 3 in 2022.

During 2022, following the FDA discussions and feedback on a registration strategy to address the shift in standard of care following the FDA approval of pembrolizumab in the frontline cervical cancer setting, we reopened Cohort 2 to enroll additional patients and to be a pivotal cohort to support a BLA for cervical cancer following progression on chemotherapy and pembrolizumab.

We expect to continue enrollment in Cohort 2 in 2023.

Following the accelerated approval of Amtagvi™, our confirmatory trial is designed to support a registrational path for lifileucel in combination with pembrolizumab in frontline advanced melanoma as well as full U.S.

approval for Amtagvi™, which has received an accelerated U.S.

approval in its initial indication in post-anti-PD-1 advanced melanoma.

During the second quarter of 2023, the first patient was randomized in TILVANCE-301 in patients with unresectable or metastatic melanoma who have had no prior therapy for metastatic or unresectable disease.

TILVANCE-301 is a Phase 3 multicenter, open-label, randomized, parallel group, treatment clinical trial that will randomize approximately 670 patients to investigate lifileucel in combination with pembrolizumab in the experimental arm compared with pembrolizumab monotherapy in the control arm.

In the experimental arm, a tumor sample is procured from each patient for lifileucel manufacturing using the Gen 2 process.

Patients receive pembrolizumab prior to and after the lifileucel regimen until disease progression.

In the control arm, pembrolizumab monotherapy is given every six weeks until disease progression, with an optional crossover to lifileucel monotherapy upon confirmed progressive disease verified by a blinded independent review committee, or BIRC, and if patients meet eligibility criteria.

In 2022, we reached agreement with the FDA on the TILVANCE-301 clinical trial design, including dual primary endpoints of ORR to support accelerated approval and PFS to support full approval of lifileucel in frontline advanced melanoma.

The dual primary endpoints will be assessed by a BIRC using RECIST 1.1.

Our strategy in frontline melanoma is supported by clinical results from the ongoing Cohort 1A of our IOV-COM-202 clinical trial as well as prior published NCI data for TIL monotherapy in anti-PD-1 naïve melanoma patients.

As of the most recent detailed update from April 2022 in Cohort 1A, we observed a 67% ORR in twelve patients per RECIST 1.1.

Eight patients had a confirmed objective response, including three complete responses and five partial responses.

Six responders had ongoing response, and five responders had a duration of response of more than one year at the time of the data cut.

The treatment-emergent adverse event, or TEAE, profile was consistent with the underlying advanced disease and the known adverse event profiles of pembrolizumab, lymphodepletion and IL-2 regimens.

In January 2023, we disclosed that updated efficacy and safety results from nearly 20 patients treated in Cohort 1A remain consistent with previously reported Cohort 1A data and continue to support our strategy in frontline advanced melanoma.

Our strategy is also supported by several NCI trials of TIL cell therapy that were conducted prior to anti-PD-1 approval.

In anti-PD-1 naïve melanoma patients, ORR was over 50% and approximately 22-24% of patients had a complete response per RECIST 1.1.

Most complete responses remained ongoing in three to seven years of follow up.

LN-145 for Advanced, or Metastatic or Unresectable NSCLC

According to SEER program estimates, approximately 236,740 people would be diagnosed with lung and bronchus cancers, and approximately 130,180 deaths would occur related to these cancers in the U.S.

We are developing our TIL therapy LN-145 alone and in combination with approved therapies to treat advanced NSCLC in the IOV-LUN-202 and IOV-COM-202 clinical trials.

IOV-LUN-202 is investigating LN-145 monotherapy in patients with metastatic NSCLC who previously received approved systemic therapy of combined or sequential ICI and chemotherapy in three cohorts.

According to the SEER program estimates, approximately 238,340 people were diagnosed with lung and bronchus cancers, and approximately 127,070 deaths occurred related to these cancers in the U.S.

Patients previously treated with standard of care chemo-immunotherapy have a poor prognosis, limited treatment options and a real-world overall survival of less than six months.

We are developing our TIL cell therapy, LN-145, alone and in combination with approved therapies to treat advanced NSCLC in the IOV-LUN-202 and IOV-COM-202 clinical trials.

IOV-LUN-202 Registrational Trial

IOV-LUN-202 is a single-arm, registrational trial investigating LN-145 in patients who have progressed on or after chemotherapy and anti-PD-1 therapy for advanced (unresectable or metastatic) NSCLC without epidermal growth factor receptor, or EGFR, ROS proto-oncogene receptor tyrosine kinase, or ROS, anaplastic lymphoma kinase, or ALK, genomic mutations and had received at least one line of an FDA-approved targeted therapy if indicated by other actionable tumor mutations.

IOV-LUN-202 includes two

registrational patient cohorts (Cohorts 1 and 2) and two exploratory patient cohorts (Cohort 3 and 4).

The programmed death-ligand 1, or PD-L1, tumor proportion score, or TPS, in patients at the time they started frontline therapy was less than one percent or unknown in patients in Cohort 1 and greater than or equal to one percent in patients in Cohort 2.

In Cohort 3, we are exploring treatment with TIL that is extracted from core biopsy and manufactured using our Gen 3 process.

In June 2021, the first patient was treated in the IOV-LUN-202 clinical trial.

In a poster on IOV-LUN-202 at the American Association for Cancer Research, or AACR, Annual Meeting in April 2022, we featured protocol updates including changes to eligibility criteria, and the option for pre-progression tumor harvest, to broaden enrollment in reflection of the unmet need in NSCLC.

We enrolled patients during 2022 and intend to continue enrollment in 2023.

IOV-COM-202 is a clinical trial that includes 2 active cohorts and one previously completed cohort in patients with recurrent or metastatic NSCLC as follows:

● Cohort 3A is evaluating LN-145 in combination with pembrolizumab in patients who have not received prior immunotherapy, including ICIs.

Cohort 3B was previously completed and investigated LN-145 monotherapy in patients who had progressed on or after prior ICI therapy, including patients with oncogene-driven tumors who received prior tyrosine kinase inhibitor, or TKI, therapy.

● Cohort 3C is investigating LN-145 in combination with ipilimumab or nivolumab in patients who previously received only a prior line of approved systemic ICI monotherapy.

We have reported full results from Cohort 3B and initial results from Cohort 3A in the IOV-COM-202 study.

Cohort 3B results were reported in June 2021 and presented at SITC in November 2021.

For the completed Cohort of 28 patients in the analysis population, the ORR was 21.4%, including one complete response and five partial responses.

All patients had received prior anti-PD-1/-L1 therapy, and all six responding patients had also received prior chemotherapy.

In Cohort 3, TIL is extracted from core biopsy and manufactured using our Gen 3 process.

In Cohort 4, patients undergo surgical resection for TIL manufacturing prior to disease progression.

Based on the regulatory discussions and positive regulatory feedback received by the FDA regarding the design of the IOV-LUN-202 trial, we plan to enroll a total of approximately 120 patients into the registrational Cohorts 1 and 2 of the IOV-LUN-202 trial.

In July 2023, we announced a preliminary analysis of the IOV-LUN-202 trial from 23 NSCLC patients treated with LN-145.

An objective response rate of 26.1% per RECIST 1.1 was observed in six patients, with one complete response and five partial responses, and a disease control rate of 82.6%.

While still early on study, the median duration of response, or DOR, was not reached.

The DOR ranged from 1.4+ months to 9.8+ months.

Treatment-emergent adverse events were consistent with the underlying disease and known adverse event profiles of non-myeloablative lymphodepletion and interleukin-2.

We also reported additional ongoing responses, and duration of response greater than six months for 71% of the confirmed responders in the trial, in an updated analysis from November of 2023.

We believe the results from IOV-LUN-202 in previously treated patients with advanced NSCLC continue to support the potential benefit of one-time TIL cell therapy, including the opportunity for more durable responses than available second line chemotherapies.

The opportunity for TIL cell therapy in NSCLC is also supported by clinical results for LN-145 in heavily pre-treated patients with NSCLC (Cohort 3B) in our IOV-COM-202 trial in solid tumors.

At the Society for Immunotherapy of Cancer, or SITC, in November 2021, we reported Cohort 3B results from 28 patients who had progressed on or after prior immune checkpoint inhibitor, or ICI, therapy, including patients with oncogene-driven tumors who received prior tyrosine kinase inhibitor, or TKI, therapy.

The ORR was 21.4% per RECIST 1.1, including one complete response and five partial responses.

The complete response remained ongoing at 37 months following treatment in a subsequent data extract from November of 2022.

All Cohort 3B patients had received prior anti-PD-1/-L1 therapy, and all six responding patients had also received prior chemotherapy.

The TEAE profile was consistent with the underlying disease and known adverse event profiles of non-myeloablative lymphodepletion and IL-2.

As of a data extract in November 2022 provided in a corporate slide deck, one complete response remained ongoing at 37 months following treatment with LN-145.

In a January 2023 press release, we shared initial topline results in 17 patients from Cohort 3A which comprises three distinct clinical subsets of anti-PD-1 naïve patients:

1) treatment-naïve, 2) post-chemotherapy, and 3) estimated glomerular filtration rate, or EGFR, -mutant after prior treatment with TKIs.

Confirmed ORR by RECIST v1.1 was 47%, with an objective response observed in 8 patients treated with LN-145 in combination with pembrolizumab.

Responses were observed regardless of PD-L1 status.

Two patients achieved complete responses and remain on study, including one patient who was post-chemotherapy and anti-PD-1 naive, and one patient who was EGFR-mutant after prior treatment with TKI.

Safety was consistent with other studies of Iovance TIL therapies in combination with pembrolizumab.

On December 22, 2023, the FDA placed a partial clinical hold on the IOV-LUN-202 trial in response to a reported Grade 5 (fatal) serious adverse event, or SAE, potentially related to the non-myeloablative lymphodepletion pre-conditioning regimen.

We have paused enrollment and the LN-145 treatment regimen for new patients in IOV-LUN-202 during the clinical hold.

Patients previously treated with LN-145 in the IOV-LUN-202 trial continue to be monitored and followed according to the trial protocol.

While enrollment is currently paused due to an FDA-imposed clinical hold, enrollment is expected to be completed in 2025.

We are working closely with the FDA to safely resume enrollment in the IOV-LUN-202 trial as soon as possible in 2024.

Frontline NSCLC Development and Regulatory Strategy

We are preparing to meet with the FDA in 2024 to discuss a randomized confirmatory trial of LN-145 in frontline advanced NSCLC patients.

This confirmatory trial in frontline advanced NSCLC is expected to be well underway at the time of a potential approval of LN-145 in advanced post-anti-PD-1 NSCLC.

Our goal is to improve frontline NSCLC therapy by adding TIL cell therapy to standard of care pembrolizumab maintenance therapy, administered after completion of the initial chemo-immunotherapy.

This approach is supported by initial results from Cohort 3A in the IOV-COM-202 trial in solid tumors.

Cohort 3A is evaluating LN-145 in combination with pembrolizumab in patients who have not received prior immunotherapy, including ICIs.

In September 2023, we reported preliminary Cohort 3A data in an oral presentation at the International Association for the Study of Lung Cancer, or IASLC, 2023 World Conference on Lung Cancer.

The confirmed ORR per RECIST 1.1 was 58.3% in twelve treatment-naïve or post-chemotherapy patients with EGFR wild-type disease, regardless of PD-L1 status.

Duration of responses of 15.4+, 10.2 +, 7.1, 6.9, 6.9+, 4.6, and 3.7 months were observed in seven patients, and three of these responses remained ongoing.

Safety was consistent with other studies of Iovance TIL cell therapies in combination with pembrolizumab.

Study enrollment remains ongoing.

Observed differences between the patient subsets are informing the design of a subsequent potential registration study.

Detailed clinical results will be shared at a future medical meeting.

We plan to continue to discuss registrational strategies for LN-145 with the FDA in 2023.

Based on initial results from Cohort 3A, we plan to meet with the FDA in 2023 to discuss Cohort 3A results and a potential registration clinical trial of lifileucel in frontline advanced NSCLC.

In addition to Cohort 3A, a separate patient cohort, Cohort 3C, in COM-202 is investigating LN-145 in combination with ipilimumab or nivolumab in patients who previously received only a prior line of approved systemic ICI monotherapy.

Gynecological Cancers

According to the SEER program estimates, in 2023, 66,200 women were diagnosed with uterine cancer and approximately 13,030 uterine cancer-related deaths occurred in the U.S.

Moreover, approximately 13,960 women were diagnosed with cervical cancer, and approximately 4,310 cervical cancer-related deaths occurred in the U.S.

Advanced endometrial cancer, the most common form of uterine cancer, represents a significant opportunity for TIL cell therapy.

Analogous to other tumor types, TIL cell therapy may offer benefit in the emerging treatment setting of patients who have no currently approved therapies for progression after post-anti-PD1 therapy and chemotherapy.

We plan to begin a Phase 2 trial of lifileucel in post-anti-PD-1 and post-chemotherapy advanced endometrial cancer, including mismatch repair, or MMR, deficient and MMR proficient patient populations in the first half of 2024.

Based on the TIL mechanism of action, the benefit of TIL cell therapy is likely to extend across patients with tumors that are MMR mechanism deficient and proficient.

The potential for TIL cell therapy in gynecological cancers is also supported by our clinical data for lifileucel alone and in combination with pembrolizumab in advanced cervical cancer.

C-145-04 is a Phase 2, multicenter pivotal clinical trial that included patient previously treated with chemotherapy (Cohort 1), previously treated with chemo and ICIs (Cohort 2), and patients who had not received prior systemic therapy (Cohort 3).

Cohorts 1 and 2 received lifileucel monotherapy and Cohort 3 received lifileucel in combination with pembrolizumab.

Initial results from the C-145-04 clinical trial were reported at the American Society of Clinical Oncology in June 2019 and the SITC in November 2021.

Following our assessment of the current treatment landscape in gynecological cancers, we are prioritizing endometrial cancer over cervical cancer.

The C-145-04 clinical trial is expected to close during 2024.

We plan to continue to explore the use of TIL cell therapies in cervical cancer, including using genetically modified TIL products and using TIL products in combination with anti-PD-1/PD-L1 blocking antibody therapies in frontline cervical cancer, with the goal of returning to clinical development in the future.

IOV-4001 for Advanced Melanoma and NSCLC

Our lead genetically modified TIL therapy, IOV-4001, utilizes the gene-editing TALEN® technology licensed from Cellectis, to inactivate the gene coding for PD-1.

The worldwide exclusive license enables us to use certain TALEN® technology addressing multiple gene targets in several cancer indications, to develop genetically edited and potentially more potent TIL therapies.

We are investigating the safety and efficacy of IOV-4001 in the IOV-GM1-201 multicenter, first-in-human Phase 1/2 clinical trial in previously treated patients with advanced melanoma, who have progressed following anti-PD-1/PD-L1 blocking antibody therapy and, in those patients with BRAF mutations, after BRAF/MEK inhibitor therapy in Cohort 1, or metastatic NSCLC who have received no more than three prior lines of therapy, with or without oncogene driver mutations in Cohort 2.

We treated the first patient with IOV-4001 in the third quarter of 2022.

We published posters that highlight the “trial in progress” for IOV-GM1-201 at SITC in November 2022 and preclinical results for antitumor activity of IOV-4001 at the AACR Annual Meeting in April 2022.

TIL Therapy for HNSCC

In metastatic head and neck cancer squamous cell carcinoma, or HNSCC, we are evaluating LN-145 as monotherapy and in combination with pembrolizumab.

The Phase 2 C-145-03 trial began in June 2017 and closed in January 2021 after reaching its pre-specified enrollment target to investigate LN-145 using various manufacturing processes.

Cohort 2A in IOV-COM-202 is evaluating

LN-145 in combination with pembrolizumab in patients with HNSCC who are naïve to anti-PD-1 therapy.

Initial and updated Cohort 2A results were presented at the SITC Annual Meetings in November 2020 and 2021, respectively.

PBL Therapy in Blood Cancers

In blood cancers, our clinical trial IOV-CLL-01 is a Phase 1/2 clinical trial evaluating the safety and efficacy of IOV-2001, our polyclonal PBL therapy, in patients with relapsed or refractory chronic lymphocytic leukemia, or CLL, and small lymphocytic lymphoma, or SLL, to receive IOV-2001.

Next-Generation Product Candidates

We are committed to innovating individualized T-cell therapies that may recognize a multitude of diverse patient-specific cancer cells.

Our current next-generation technology platforms are designed to optimize TIL therapy across four key initiatives:

genetic modifications, potency, process optimization and new treatment regimens.

We have a worldwide exclusive license from Cellectis that enables us to use certain TALEN® technology addressing multiple gene targets in several cancer indications, to develop genetically edited and potentially more potent TIL cell therapies.

Our lead genetically modified TIL cell therapy, IOV-4001, utilizes this TALEN® technology to inactivate the gene coding for PD-1.

We are investigating the safety and efficacy of IOV-4001 in IOV-GM1-201, a multicenter, first-in-human Phase 1/2 clinical trial in two patient cohorts.

Cohort 1 includes patients with advanced melanoma, who were previously treated with anti-PD-1/PD-L1 blocking antibody therapy and, in those patients with BRAF mutations, after BRAF/MEK inhibitor therapy.

In Cohort 2, we are investigating IOV-4001 in patients with metastatic NSCLC who have received no more than three prior lines of therapy, with or without oncogene driver mutations.

We treated the first patient with IOV-4001 in the third quarter of 2022 and the Phase 1 safety portion of the clinical trial is ongoing.

Additional Clinical Trials

We previously investigated the potential for TIL cell therapy in metastatic HNSCC.

The Phase 2 C-145-03 trial investigated LN-145 as monotherapy, using various manufacturing processes.

The trial began in June 2017 and closed in January 2021 after reaching its pre-specified enrollment target.

We also investigated LN-145 in combination with pembrolizumab in patients with HNSCC who are naïve to anti-PD-1 therapy in IOV-COM-202 Cohort 2A.

The results from Cohort 2A are supportive of our strategies to develop TIL cell therapy in combination with pembrolizumab in earlier treatment settings for solid tumor cancers.

We have also explored the potential for polyclonal T cell immunotherapies in blood cancers.

A first-in-human clinical trial, IOV-CLL-01, evaluated the safety and efficacy of IOV-2001, our polyclonal PBL therapy, in patients with relapsed or refractory chronic lymphocytic leukemia, or CLL, and small lymphocytic lymphoma, or SLL.

Next-Generation TIL Cell Therapy Product Candidates

Our next-generation technology platforms are designed to optimize outcomes with TIL cell therapy across three key initiatives:

genetic modifications, potency, and new treatment regimens.

● Genetic modifications:

We are pursuing several targets for genetic modification that utilize the gene-editing TALEN ® platform licensed from the clinical-stage biotechnology company, Cellectis.

Single- and multiple- knockouts may further harness the immune system response to cancer and potentially increase the efficiency, potency and application of TIL therapy.

Single- and multiple- knockouts may further harness the immune system response to cancer and potentially increase the potency of TIL cell therapy.

Preclinical development is also ongoing with cytokine-tethered TIL products and additional TIL products and TIL-cell lines using transient and stable gene insertion and inactivation, which may expand and activate TIL to achieve better efficacy while avoiding systemic side effects of cytokines.

We are exploring potential approaches to increase potency of the final TIL product through sorting and selection of specific TIL, such as PD-1+ selected TIL and CD39/69 double-negative TIL, and the use of certain inhibitors or other reagents in TIL expansion cultures.

Our TIL candidate LN-145-S1 is manufactured from TIL selected for PD-1 expression and has been investigated in patient cohorts in our clinical trials.

● Process optimization:

We are committed to further improving and streamlining the processes for TIL therapy manufacturing and tumor sample collection.

We are investigating a 16-day Gen 3 manufacturing process in patient cohorts included in the C-145-03 clinical trial in HNSCC and the IOV-COM-202 clinical trial.

We are also exploring our Gen 3 process to manufacture TIL from core biopsy as a less-invasive collection of tumor samples in a cohort of patients with NSCLC in our IOV-LUN-202 clinical trial.

We are exploring potential approaches to increase potency of the final TIL product through sorting and selection of specific TIL, such CD39/69 double-negative TIL, and the use of certain inhibitors or other reagents in TIL expansion cultures.

We have also manufactured and investigated patient cohorts treated with TIL candidate, LN-145-S1, manufactured from TIL selected for PD-1 expression.

● New treatment regimens:

We are exploring potential avenues to improve aspects of the TIL treatment regimen.

In 2020, we licensed an antibody cytokine-engrafted protein, or IL-2 analog, which we refer to as IOV-3001, from Novartis.

IOV-3001 is in IND-enabling studies supporting its use as part of the TIL treatment regimen following TIL infusion.

Collaborations for New Tumor Types and Treatment Settings

Our ongoing academic collaborations with leading cancer research centers as well as government and corporate partners are exploring the potential for TIL therapy in other tumor types and treatment settings, such as in the following example studies:

● MDACC has sponsored two Phase 2 clinical trials that were initiated in 2018.

The first clinical trial, NCT03449108, is underway to investigate LN-145 or LN-145-S1 manufactured using our proprietary processes to treat patients with soft tissue sarcoma, osteosarcoma, platinum resistant ovarian cancer, anaplastic thyroid cancer, and triple negative breast cancer.

The second clinical trial, NCT03610490, was previously active to investigate TIL manufactured by MDACC in patients with platinum resistant ovarian cancer, pancreatic and colorectal cancer, which may not be representative of our data using our Iovance manufacturing process.

● Yale Comprehensive Cancer Clinical is sponsoring a trial, NCT04111510, exploring LN-145 in triple-negative breast cancer.

● Memorial Sloan Kettering Cancer Center, or MSKCC, is investigating TIL therapy LN-144 manufactured by Iovance in patients with uveal melanoma in the NCT05607095 clinical trial, and asymptomatic melanoma brain metastases in the NCT05640193 clinical trial.

● Moffitt is conducting several clinical trials with funding from Iovance.

Two clinical trials, which have closed to enrollment, are evaluating TIL therapy in combination with the checkpoint inhibitor nivolumab in NSCLC in the NCT03215810 clinical trial and metastatic melanoma in the NCT02652455 clinical trial.

We previously collaborated on the NCT01701674 clinical trial to evaluate TIL therapy in combination with the CTLA-4 checkpoint inhibitor ipilimumab.

A Phase 1 clinical trial, NCT04052334, completed enrollment in 2022 and is investigating TIL therapy manufactured by Moffitt in adolescent and young adult patients with soft tissue sarcoma.

● The Ohio State University is investigating lifileucel manufactured by Iovance in high-risk melanoma patients in the neoadjuvant setting in the NCT05176470 clinical trial.

The trial began recruiting in 2022 to assess the feasibility of TIL expansion from tumor-involved lymph nodes patients who are diagnosed with stage IIIB-D melanoma that has spread to nearby tissue or locally advanced lymph nodes.

● NCI, under our CRADA, is conducting the NCT02621021 clinical trial to evaluate TIL therapy in combination with the checkpoint inhibitor pembrolizumab in a 170-patient clinical trial in patients with advanced melanoma.

Immune System and Cancer Surveillance

The immune system recognizes danger signals and responds to threats at a cellular level.

The most significant components of the cellular aspect of the adaptive immune response are T-cells, or T lymphocytes, so called because they mature in the thymus and are distinguished from B-cells which mature in the bone marrow.

T-cells can be distinguished from other white blood cells by T-cell receptors present on their cell surface.

These receptors contribute to tumor surveillance by helping T-cells recognize infected as well as cancerous cells.

T-cells are involved in both sensing and killing infected or cancerous cells, as well as coordinating the activation of other cells in an immune response.

Challenges for Cancer Immunotherapy

Despite progress over the past several decades, effective treatment of solid tumors continues to be challenging for several reasons, including:

(i) intratumoral heterogeneity, (ii) numerous mutations and tumor neoantigens, with <1% shared across patients and lack of clarity on which mutations or neoantigens are critical, and (iii) ability to adapt and evade treatments that target a single mutation.

In addition, the tumor itself and the tumor microenvironment can suppress the patient’s natural immune response.

When T-cells with cancer-specific receptors are absent, present in low numbers, of poor quality, or rendered inactive by suppressive mechanisms employed by tumor tissue, the cancer can grow and spread to various organs.

In addition, standard of care treatments for cancer can be deleterious to T-cells’ ability to kill cancer.

Advancing Immuno-Oncology with Our Tumor-Infiltrating Lymphocyte Technology Platforms

Our T-cell-based immunotherapy technology platforms are potentially applicable to many solid tumor types and blood cancers.

Each platform is focused on leveraging patient-specific cells to recognize and attack diverse cancer cells that are unique to each patient.

We believe that adoptive cell therapy, specifically with the use of human polyclonal TIL cells to reengage the immune system, may be a significant advancement in the treatment of cancer.

Using our lead TIL immunotherapy platform, our initial strategy is to deliver polyclonal T-cell-based therapies for patients with late-stage solid tumor cancers.

After infusion, TIL can potentially infiltrate the tumor to eliminate cancer cells, further proliferate in the body and potentially overcome several mechanisms of tumor escape to which endogenous T-cells may be susceptible due to the immune-suppressive tumor microenvironment.

For earlier intervention, we are investigating the potential of our TIL therapy in combination with a class of immunotherapy drugs called ICIs that seek to overcome one of the main escape mechanisms of cancer against an immune system attack.

TIL therapy and ICIs may work synergistically to target and attack cancer cells while breaking down barriers for the immune system to mount a response.

There are three key steps in the TIL therapy process.

Sample Collection.

A tumor sample of about 1.5 cm in diameter is removed during a surgical biopsy and shipped to our centralized manufacturing facility, where the TIL are isolated.

Manufacturing.

Patient-specific TIL are amplified and reinvigorated using our proprietary Gen 2 manufacturing process, reflecting our successful efforts to centralize and streamline TIL manufacturing from several weeks to 22 days.

Additional detail on Gen 2 is provided below in the Manufacturing Process section of our Annual Report on Form 10-K.

The patient begins with a preparative regimen of non-myeloablative lymphodepletion, or NMA-LD, to suppress the immunosuppressive tumor microenvironment, which we believe will enhance the efficacy of TIL therapy.

After NMA-LD, the expanded and rejuvenated, patient-specific TIL cells are delivered back into the body by infusion.

The treatment regimen is completed with a short course of IL-2 of up to 6 doses to promote T-cell activity in the body after TIL infusion.

If a patient is receiving TIL as a monotherapy, their treatment may be complete.

If a patient is receiving TIL therapy as part of the combination approach, they will continue treatment with ICIs following TIL infusion.

Historical Clinical Results with Other TIL Therapies in Metastatic Melanoma

To date, more than 600 patients have been treated with TIL therapies manufactured using our proprietary processes.

Prior to our clinical trials, hundreds of advanced melanoma patients were treated with TIL therapy produced locally using different manufacturing methods at different academic institutions and hospitals in the U.S., Europe, Canada, and Israel.

At the NCI, clinical responses have been relatively consistent in several trials of TIL therapy in anti-PD-1 naïve melanoma patients that were conducted prior to anti-PD-1 treatment becoming the available standard of care for melanoma patients.

Over 50% of patients achieved an objective response, and approximately 22-24% of patients had a complete response, as defined by RECIST v1.1 criteria.

Most patients who have had a complete response remained in response in 3-7 years of follow up.

In August 2021, patient outcomes based on two decades of experience with TIL therapy in a cohort of 226 patients with metastatic melanoma were published by Seitter, et al., in a collaboration led by Dr.

Steven Rosenberg from the Surgery Branch of the NCI, in Clinical Cancer Research.

The ORR was 51%, with a complete response rate of 22%.

The 49 patients achieving a complete response had a 10-year melanoma-specific survival of 96%.

In the 192 patients who had not received prior anti-PD-1 therapy, ORR was 56% with a median melanoma-specific survival of 28.5 months.

Of the 43 patients who were refractory to anti-CTLA-4 therapy without exposure to anti-PD-1, the 60 % response rate showed no difference when compared to the 55% response rate in those naïve to any immune checkpoint therapy.

Baseline demographic features, including BRAF status, did not influence outcome.

Exposure to prior therapies, including refractoriness to anti-PD-1 and BRAF/MEK inhibitors, affected outcome.

In the population most comparable to Cohorts 2 and 4 of our C-144-01 trial, 34 of the reported patients were refractory to anti-PD-1 therapy and had an ORR of 24%, with a median melanoma-specific survival of 11.6 months.

Decreased melanoma-specific survival was seen in patients that are refractory to BRAF/MEK inhibitors regardless of prior anti-PD-1 exposure with a median survival of 8.7 months in patients who were refractory to anti-PD-1 and 12.1 months in patients who were naïve to anti-PD-1.

In December 2022, in the New England Journal of Medicine, a team from The Netherlands Cancer Institute and the National Center for Cancer Immune Therapy, Department of Oncology, of the Copenhagen University Hospital published the results of a multicenter, open-label phase 3 clinical trial of 168 patients with unresectable stage IIIC-IV melanoma randomized 1:1 to TIL or single agent ipilimumab.

The study began in 2014.

Patients in the study had received a maximum of one line of prior therapy, of which 86% were refractory to anti-PD-1 therapy.

With a median follow-up of 33.0 months, median PFS was 7.2 months for TIL compared to 3.1 months for ipilimumab.

ORR was 49% for TIL with 20% complete responses, compared to 21% ORR and 7% complete response rate for ipilimumab.

mOS for TIL was 25.8 months compared to 18.9 months for ipilimumab.

Grade 3 and higher treatment-related adverse events occurred in all TIL and 57% of ipilimumab patients.

We are exploring potential improvements to the TIL treatment regimen.

IND-enabling studies are investigating IOV-3001, an antibody cytokine-engrafted protein, or IL-2 analog, which we licensed from Novartis Pharma AG.

Manufacturing Processes

Iovance was founded to deliver broad access to TIL therapy for people with cancer by conducting multicenter clinical trials and developing centralized, scalable manufacturing processes to enable regulatory approvals and commercial launches.

The NCI and other academic centers have historically manufactured TIL therapies for research purposes.

To date, these site-specific processes have not been scalable or standardized to serve sizeable patient populations.

Our Gen 1 TIL manufacturing process modified the NCI’s original TIL manufacturing and processing so that it could be reproduced in a current good manufacturing practice, or cGMP, environment.

TIL expansion occurred over a 5-to-6-week period and produced a non-cryopreserved product.

Our internal research and process development team developed our proprietary Gen 2 technology to include manufacturing and logistical efficiencies aimed at further optimizing treatment and streamlining distribution processes.

Gen 2 manufacturing takes 22 days while allowing for a cryopreserved product.

We currently use Gen 2 in almost all Iovance clinical trials for product registration and our BLA submission.

We also continue to develop new processes.

We have developed a shorter, 16-day, Gen 3 manufacturing process as well as next generation manufacturing processes to genetically modify TIL and to select for TIL that potentially more potent.

Iovance was founded to build upon the promise of TIL cell therapy that was previously demonstrated in single-center clinical trials at academic centers.

The NCI and other academic centers have historically manufactured TIL cell therapies for research purposes;

using site-specific processes that have not been scalable or standardized to serve sizeable patient populations.

Our multicenter trials and manufacturing processes have transformed TIL cell therapy into a commercially viable treatment which many more patients with cancer can access.

At the end of 2023, more than 700 patients had been treated with an Iovance TIL cell therapy manufactured using our proprietary processes.

Our internal research and process development team has innovated TIL manufacturing and processing.

Our initial Gen 1 manufacturing process modified the NCI’s original TIL manufacturing and processing so that it could be reproduced in a cGMP environment.

Gen 1 TIL expansion occurred over a 5-to-6-week period and produced a non-cryopreserved product.

Building upon initial success with the Gen 1 process, our proprietary Gen 2 technology introduces manufacturing and logistical efficiencies aimed at further optimizing treatment and streamlining distribution processes.

Gen 2 manufacturing takes 22 days and produces a cryopreserved final product.

We currently use Gen 2 to manufacture our commercial product, Amtagvi™, and in most ongoing Iovance clinical trials.

We are also committed to further improving and streamlining the processes for TIL cell therapy manufacturing and tumor sample collection.

For example, we have developed a proprietary process for genetic modification to manufacture IOV-4001 and other next generation TIL cell therapy candidates, as well as a 16-day Gen 3 process to manufacture TIL from core biopsy as a less invasive collection of tumor samples.

Gen 2 Manufacturing Process

During the Gen 2 process, TIL are expanded exponentially ex vivo to yield billions or 10 9 – 10 11 of TIL.

The process begins with the collection of the patient’s tumor by surgical biopsy, which is sent to a central manufacturing facility.

The tumor is fragmented to facilitate a clear path for TIL to leave the tumor tissue and placed in media that optimizes the growth of TIL rather than other cell types.

Initially, from days 0-11, cells grow slowly during the pre-rapid expansion, or pre-rep phase.

Following the pre-rep phase, the cells are transferred to a larger bioreactor and feeder cells are introduced to further activate the TIL to proliferate during the rapid expansion, or REP phase, from days 11-22.

During the REP phase, on day 16, the TIL are harvested while maintaining a closed system before they are counted and placed into multiple bioreactors which are incubated one last time until day 22.

On day 22, TIL are filtered, washed, concentrated and finally formulated with cryopreservation media before being placed in up to four final product bags, depending on total cell count.

The final product is shipped back to the center where it can be administered to the patient.

The following diagram illustrates our Gen 2 TIL manufacturing process.

Our Iovance Cell Therapy Center, or iCTC, for Large-Scale Centralized Manufacturing

Our i CTC is the first centralized and scalable cGMP manufacturing facility dedicated to producing TIL as a potential therapy for patients with solid tumors.

At 136,000 square feet, the i CTC is among the largest cell therapy manufacturing facilities in existence.

It currently supplies investigational TIL therapy for Iovance clinical trials, with commercial manufacturing expected to begin after initial product approval.

The proximity of the i CTC to multiple airports facilitates delivery of TIL therapies to treatment centers, with the i CTC expected to cover logistics and delivery of TIL therapy in both North America and Europe.

This location may also offer future tax savings under Pennsylvania’s Keystone Opportunity Improvement Zone, or KOIZ.

Clinical Manufacturing

In 2021, we completed the commissioning activities at the i CTC and successfully initiated manufacturing of clinical batches of lifileucel and LN-145.

In addition, we have entered into MSAs with WuXi Advanced Therapies, Inc., or WuXi, and Moffitt pursuant to which they have agreed to manufacture, package, ship and handle quality assurance and quality control of certain clinical trials for our TIL products working closely with our employees.

In the future, we may rely on them or other third parties, or our own manufacturing capabilities, for the manufacturing and processing of TIL-based product candidates for our clinical trials.

Commercial Manufacturing Preparations

To meet projected needs for commercial quantities, we continue our launch readiness and scale up activities to supply commercial TIL upon potential BLA approval.

We expect to rely primarily on our own i CTC facility for commercial supply, with flexibility to use CMOs to meet anticipated clinical trial and, if approved, commercial demands.

For example, we expect to be able to use two suites for clinical or commercial manufacturing at WuXi in Philadelphia if needed based on demand.

If we are unable to meet manufacturing capabilities and demand at our own commercial manufacturing facility, we may need to rely on CMOs, including both current and alternate suppliers, to ensure sufficient capacity is available for commercial purposes.

Our CMO relationship is described in more detail in the Research, Development, Manufacturing and License agreements section of this Annual Report on Form 10-K.

Cell processing activities are conducted at all facilities under cGMP, using qualified equipment and materials.

During the Gen 2 process, TILs are multiplied into the billions or 10 9 – 10 11 of TIL.

The process begins by collecting the patient’s tumor tissue by surgical biopsy for shipment to a central manufacturing facility, the i CTC or our CMO.

The tumor is fragmented to facilitate a clear path for TILs to leave the tumor tissue and placed in media that optimizes the growth of TIL rather than other cell types.

From days 0-11, cells grow slowly during the pre-rapid expansion, or pre-rep phase.

The rapid expansion phase occurs from days 11-22.

On Day 11, the cells are transferred to a larger bioreactor and feeder cells are introduced to further activate the TILs to proliferate.

On day 16, the TILs are harvested while maintaining a closed system before they are counted and placed into multiple bioreactors which are incubated one last time.

On day 22, TILs are filtered, washed, concentrated, and formulated with cryopreservation media before being placed in the final product bags and shipped back to the patient’s treatment center.

Our commercial product, Amtagvi™, undergoes additional analytical and quality testing to meet certain criteria for commercial release prior to shipment to the ATCs.

Large-Scale Centralized Manufacturing for TIL Cell Therapies

The cell processing activities for our TIL cell therapies are conducted at centralized facilities under cGMP, using qualified equipment and materials.

We are manufacturing our commercial product, Amtagvi™, at both our internal facility and a CMO to meet manufacturing capabilities and the current and expected demand for commercialization and clinical trials.

The i CTC is the first FDA-approved, centralized and scalable cGMP manufacturing facility dedicated to producing TIL cell therapies.

Through a manufacturing service agreement, or MSA, with WuXi Advanced Therapies, Inc., or WuXi, WuXi manufactures, packages, ships and handles quality assurance and quality control of our commercial product, Amtagvi™, working closely with our employees.

Certain clinical trials for our investigational TIL cell therapies are also supported by our MSA with WuXi as well as our Sponsored Research Agreement with the H.

Lee Moffitt Cancer Center, or Moffitt.

These relationships are described in more detail in the Research, Development, Manufacturing and License Agreements for TIL Cell Therapy section of this Annual Report on Form 10-K.

We expect to rely on our own manufacturing capabilities, together with other third parties, for the manufacturing and processing of commercial and investigational TIL cell therapy products to ensure sufficient capacity is available for commercial purposes and clinical trials.

As an alternative, we also believe that, given sufficient time to hire staff and increase production, we have the ability to move our production of commercial and investigational TIL cell therapy products entirely in house.

We believe that all materials and components utilized in the production of the final TIL product are readily available from qualified suppliers.

Intellectual Property

We aim to lead in the field of T-cell-based immunotherapy by building and augmenting the patent rights for our proprietary TIL technology platform, which we have developed internally and licensed from third parties.

Intellectual property is of importance in our field and in biotechnology generally.

We seek to protect and enhance proprietary technology, inventions, and improvements that are commercially important to the development of our business by seeking, maintaining, and defending patent rights.

We also plan to rely on regulatory protection afforded through Orphan Drug Designation, or ODD, available regulatory exclusivities and patent term extensions where available.

To achieve this objective, our strategic focus has been to develop our own intellectual property, while also identifying and licensing patents from third parties that provide protection and serve as an optimal platform to enhance our intellectual property and technology base.

We expect to further develop our patent portfolio as a strategic focus in 2023.

We currently own more than 60 U.S.

patents related to TIL therapy, including patents directed to compositions and methods of treatment in a broad range of cancers, such as U.S.

11,141,438 11,168,303;

and 11,541,077.

More than 35 of these patents are related to our Gen 2 TIL manufacturing processes and have terms that we anticipate will extend to January 2038, not including any patent term extensions or adjustments that may be available.

Our owned and licensed intellectual property portfolio also includes patents and patent applications relating to TIL, MIL, and PBL therapies;

frozen tumor-based TIL technologies;

remnant TIL and digest TIL compositions, methods and processes;

methods of manufacturing TIL, MIL, and PBL therapies;

the use of costimulatory and T-cell modulating molecules in TIL therapy and manufacturing;

stable and transient genetically-modified TIL therapies, including genetic knockouts of immune

cytokine-tethered TIL therapies;

methods of using ICIs in combination with TIL therapies;

TIL selection technologies;

and methods of treating patient subpopulations.

Research, Development, Manufacturing and License Agreements

Research, Development, Manufacturing and License Agreements for TIL Cell Therapy

WuXi Advanced Therapies, Inc.

2 unchanged sentences

Under the First Wuxi MSA, we entered into two statements of work for two cGMP manufacturing suites to be operated by WuXi for us.

The terms of one of these statements of work was extended to December 2022.

In October 2022, Iovance Biotherapeutics Manufacturing LLC entered into an additional three-year MSA, or the Second WuXi MSA, with WuXi and its parent company WuXi Apptec, Co, Ltd.

The Second WuXi MSA and its related statement of work will supersede the statement of work under the First WuXi MSA with respect to commercial and clinical manufacturing for the two existing manufacturing suites.

Both suites are expected to be capable of being used for the commercial manufacture of our products.

The terms of one of these statements of work were extended to December 2022.

In October 2022, Iovance Biotherapeutics Manufacturing LLC entered into an additional three-year MSA, or the Second WuXi MSA, with WuXi and its parent company WuXi Apptec, Co.

The Second WuXi MSA and its related statement of work superseded the statement of work under the First WuXi MSA with respect to commercial, clinical manufacturing and related testing services for the two existing manufacturing suites.

Both suites are expected to be capable of use for the commercial manufacture of our products.

National Institutes of Health and the National Cancer Institute

Cooperative Research and Development Agreement

We entered into a CRADA with the NCI to develop adoptive cell immunotherapies in multiple solid tumor types, including unmodified TIL as a stand-alone therapy or in combination, improved methods for the generation and selection of TIL with anti-tumor reactivity, and strategies for more potent TILs.

In August 2011, we signed a five-year CRADA with the NCI, to work on the development of adoptive cell immunotherapies that are designed to destroy metastatic melanoma cells.

In August 2011, we signed a five-year Cooperative Research and Development Agreement, or CRADA, with the NCI to work on the development of adoptive cell immunotherapies in multiple solid tumor types, including unmodified TIL as a stand-alone therapy or in combination, improved methods for the generation and selection of TIL cell therapy with anti-tumor reactivity and strategies for more potent TILs.

The CRADA was amended in 2015 and 2016, to, among other things, extend the term of the CRADA through August 2021, include new indications such as bladder, lung, triple-negative breast, and Human Papilloma Virus, or HPV, associated cancers and modify the focus on the development of unmodified TIL as a stand-alone therapy or in combination.

4 unchanged sentences

To the extent we license patent rights relating to a TIL-based product candidate, we will be responsible for all patent-related expenses and fees, past and future.

In addition, we may be required to supply certain test articles, including TIL, grown and processed under Current Good Manufacturing, or cGMP, conditions, suitable for use in clinical trials.

In addition, we may be required to supply certain test articles, including TIL,

grown and processed under cGMP conditions, suitable for use in clinical trials.

We or the NCI may unilaterally terminate the CRADA for any reason or for no reason, at any time, by providing written notice at least 60 days before the desired termination date.

Patent License Agreement Related to the Development and Manufacture of TIL Therapies

We have licensed exclusive, co-exclusive, and non-exclusive licenses from NIH to certain technologies relating to autologous tumor infiltrating lymphocyte adoptive cell therapy products.

Patent License Agreement Related to the Development and Manufacture of TIL Cell Therapies

We have licensed exclusive, co-exclusive, and non-exclusive licenses from the National Institutes of Health, or the NIH, to certain technologies relating to autologous tumor infiltrating lymphocyte adoptive cell therapy products.

We entered into an Exclusive Patent License Agreement, or the Patent License Agreement, with the NIH, in 2011, which was amended in 2015.

3 unchanged sentences

The Second Amended and Restated Patent License Agreement requires us to pay royalties based on a percentage of net sales in jurisdictions where patent rights exist, which percentage can fall into a tier that may be less than one percent to mid-single digits depending upon certain events, including the exclusivity of the rights, and we expect lower overall royalty payments as a result.

We also agreed to pay potential milestone payments on the achievement of certain clinical, regulatory, and commercial sales milestones for each of the indications and other direct costs incurred by the NIH pursuant to the Second Amended and Restated Patent License Agreement.

We anticipate making milestone payments, including payments ranging from several hundred thousand dollars to the mid-single-digit millions of dollars, in conjunction with certain development milestones, the approval of a BLA or its foreign equivalent, or the first U.S.

We also agreed to pay potential milestone payments on the achievement of certain clinical, regulatory, and commercial sales milestones for each of the exclusive indications and other direct costs incurred by the NIH pursuant to the Second Amended and Restated Patent License Agreement.

We have made and anticipate making additional milestone payments pursuant to the Second Amended and Restated Patent License Agreement, including payments ranging from several hundred thousand dollars to the mid-single-digit millions of dollars, in conjunction with certain development milestones, the approval of a BLA or its foreign equivalent, or the first U.S.

and foreign commercial sales of any of our product candidates covered by the Second Amended and Restated Patent License Agreement.

4 unchanged sentences

Lee Moffitt Cancer Center

Sponsored Research Agreement

In June 2016, we entered into a Sponsored Research Agreement with Moffitt, which expired in December 2019.

In June 2020, we entered into a new Sponsored Research Agreement with Moffitt, with a term that ends either upon completion of the research thereunder or on July 1, 2022, whichever is sooner.

In June 2022, this agreement was extended until the later of December 19, 2022 or a mutually acceptable completion of the Research Agreement, which is currently expected in mid-2023.

Clinical Grant Agreements

In December 2016, we entered into a clinical grant agreement with Moffitt to support an ongoing clinical trial at Moffitt that combines TIL therapy with nivolumab for the treatment of patients with metastatic melanoma.

In June 2017, we entered into a second clinical grant agreement with Moffitt to support a new clinical trial at Moffitt that combines TIL therapy with nivolumab for the treatment of patients with non-small cell lung cancer, under which we obtained a non-exclusive, royalty-free license to any new Moffitt inventions made in the performance of the agreement.

Under both clinical grant agreements with Moffit, we have non-exclusive rights to clinical data arising from the respective clinical trials.

Research Collaboration and Clinical Grant Agreement

In June 2020, we entered into a Sponsored Research Agreement with Moffitt, with a term that ends either upon completion of the research thereunder or on July 1, 2022, whichever is sooner.

In August 2023, this agreement was extended until September 2023.

In December 2023, this agreement was extended until the later of November 30, 2024 or a mutually agreed determination of the completion of the Sponsored Research Agreement.

In December 2016, we entered into a clinical grant agreement with Moffitt to support an ongoing clinical trial at Moffitt that combines TIL cell therapy with nivolumab for the treatment of patients with metastatic melanoma.

In June 2017, we entered into a second clinical grant agreement with Moffitt to support a new clinical trial at Moffitt that combines TIL cell therapy with nivolumab for the treatment of patients with non-small cell lung cancer, under which we obtained a non-exclusive, royalty-free license to any new Moffitt inventions made in the performance of the agreement.

Under both clinical grant agreements with Moffit, we have non-exclusive rights to clinical data arising from the respective clinical trials, which are now concluded.

Exclusive License Agreements

We have exclusive license agreements to Moffitt’s patent-pending technologies related to methods for improving TIL for adoptive cell therapy using toll-like receptor, or TLR, agonists, the use of 4-1BB agonists in conjunction with TIL manufacturing processes and therapies, and tumor digests in conjunction with TIL manufacturing processes and therapies.

We have exclusive license agreements to Moffitt’s patent-pending and patented technologies related to methods for improving TIL for adoptive cell therapy using toll-like receptor, or TLR, agonists, the use of 4-1BB agonists in conjunction with TIL manufacturing processes and therapies, and tumor digests in conjunction with TIL manufacturing processes and therapies.

We entered into a license agreement with Moffitt, or the First Moffitt License, effective as of June 28, 2014, under which we received a worldwide license to Moffitt’s rights to patent-pending technologies related to methods for improving TIL for adoptive cell therapy using TLR agonists.

Unless earlier terminated, the term of the license extends until the earlier of the expiration of the last issued patent related to the licensed technology or 20 years after the effective date of the license agreement.

Pursuant to the First Moffitt License, we paid an upfront licensing fee, and a patent issuance fee will also be payable under the First Moffitt License, upon the issuance of the first U.S.

Pursuant to the First Moffitt License, we paid an upfront licensing fee and a patent issuance fee upon the issuance of the first U.S.

patent covering the subject technology.

In addition, we agreed to pay

milestone license fees upon completion of specified milestones, customary royalties based on a specified percentage of net sales, which percentage is in the low single digits, and sublicensing payments, as applicable, and annual minimum royalties beginning with the first sale of products based on the licensed technologies, which minimum royalties will be credited against the percentage royalty payments otherwise payable in that year.

In addition, we agreed to pay milestone license fees upon completion of specified milestones, customary royalties based on a specified percentage of net sales, which percentage is in the low single digits, and sublicensing payments, as applicable, and annual minimum royalties beginning with the first sale of products based on the licensed technologies, which minimum royalties will be credited against the percentage royalty payments otherwise payable in that year.

We will also be responsible for all costs associated with the preparation, filing, maintenance and prosecution of the patent applications and patents covered by the First Moffitt License related to the treatment of any cancers in the U.S., Europe and Japan and in other countries designated by us in agreement with Moffitt.

15 unchanged sentences

Research Collaboration and Exclusive Worldwide License Agreement

In December 2019, we entered into a research collaboration and exclusive worldwide license agreement whereby we will license gene-editing technology from Cellectis, a clinical-stage biopharmaceutical company, to develop TIL therapies that have been genetically edited, including a PD-1 inactivated product that we refer to as IOV-4001.

In December 2019, we entered into a research collaboration and exclusive worldwide license agreement whereby we will license gene-editing technology from Cellectis, a clinical-stage biopharmaceutical company, to develop TIL cell therapies that have been genetically edited, including a PD-1 inactivated product that we refer to as IOV-4001.

Financial terms of the license include annual license payments and development, regulatory and sales milestone payments from us to Cellectis, as well as royalty payments based on net sales of TALEN ® modified TIL products.

1 unchanged sentence

License Agreement

In January 2020, we obtained a license from Novartis, to develop and commercialize an antibody cytokine engrafted protein, which we refer to as IOV-3001.

In January 2020, we obtained a license from Novartis Pharma AG, or Novartis, to develop and commercialize an antibody cytokine engrafted protein, which we refer to as IOV-3001.

Under the agreement, we have paid an upfront payment to Novartis and may pay future milestones related to initiation of patient dosing in various phases of clinical development for IOV-3001 and approval of the product in the U.S., the European Union, or EU, and Japan.

Novartis is also entitled to low-to-mid single digit percentage royalties from commercial sales of the product.

Regulatory Designations

The FDA has granted ODD for lifileucel in the U.S.

to treat malignant melanoma stages IIB-IV and for the treatment of cervical cancer with a tumor size of greater than 2 cm in diameter;

Fast Track and RMAT designations for lifileucel to treat advanced metastatic melanoma;

Fast Track and Breakthrough Therapy Designations, or BTD, for lifileucel to treat metastatic cervical cancer;

and Fast Track designation for lifileucel in combination with pembrolizumab for the treatment of ICI naïve metastatic melanoma.

Orphan Drug Designations

During 2015, we received ODD for lifileucel in the U.S.

to treat malignant melanoma stages IIB-IV, and in 2018, we received an ODD for lifileucel for the treatment of cervical cancer with a tumor size of greater than 2 cm in diameter.

If approved, an ODD provides seven years of market exclusivity in the U.S., subject to certain limited exceptions.

However, an ODD does not convey any advantage in, or shorten the duration of, the regulatory review or approval process.

The benefits and limitations of ODD are described in more under the Government Regulations section in this Annual Report on Form 10-K.

Fast Track Designations

In August 2017, we announced that the FDA had granted Fast Track designation for lifileucel for the treatment of advanced metastatic melanoma.

In February 2019, we announced that the FDA had granted Fast Track designation for lifileucel in the treatment of metastatic cervical cancer.

Additionally, in November 2021, we announced that the FDA granted Fast Track designation for lifileucel in combination with pembrolizumab for the treatment of ICI-naïve metastatic melanoma.

The FDA’s Fast Track process is designed to facilitate the development and expedite the review of drugs that treat serious conditions and fill an unmet medical need.

Fast Track designation allows more frequent meetings and communications with the FDA to discuss the drug’s development plans and review process.

The Fast Track designation also allows for the possibility for rolling review of a BLA by FDA, where the FDA may consider beginning review portions of a marketing application before the full submission is complete, and also potential eligibility if certain criteria are met for accelerated approval.

Regenerative Medicine Advanced Therapy Designation

In October 2018, we announced that the FDA had granted RMAT designation for lifileucel for the treatment of patients with metastatic melanoma.

The RMAT designation is based on data provided to the FDA from our C-144-01 trial.

RMAT designation is granted for regenerative medicine drugs and allows for increased access to FDA during development.

Under this designation, surrogate endpoints can be used to receive approval for a product, accelerated approval may be granted, and a rolling review of a BLA may be permitted by FDA.

Breakthrough Therapy Designation

In May 2019, we announced that the FDA had granted BTD for lifileucel for the treatment of patients with metastatic cervical cancer.

The BTD was granted based on data provided to the FDA from our C-145-04 clinical trial.

Under a BTD, the FDA may take actions that help expedite the development and review of the application for a product candidate, including seeking to provide timely advice and interactive communications to the sponsor with intensive guidance during development, to help the sponsor design and conduct a more efficient development program.

Product candidates with BTD may be suitable for alternative clinical trial designs when scientifically appropriate, which may result in smaller clinical trials or more efficient clinical trials that require less time to complete.

BTD also allows the sponsor to submit portions of the BLA on an ongoing basis for rolling review.

In addition, BTD status allows for the potential to request priority review of our BLA at the time of BLA submission if supported by clinical data.

The clinical evidence needed to support breakthrough designation is preliminary, and the FDA has authority to rescind a BTD if a product candidate no longer meets the qualifying criteria.

Boehringer Ingelheim Biopharmaceuticals GmbH

In May 2023, as part of the completion of the acquisition of the worldwide rights to Proleukin ® , we inherited a manufacturing and supply agreement from Clinigen with Boehringer Ingelheim Biopharmaceuticals GmbH, or BI, pursuant to which BI will carry out the processing, manufacturing and supply of Proleukin ® in unlabeled vials.

The term of this agreement is through October 2025, with automatic renewals for a period of two years unless terminated as permitted by the contract.

Under this agreement, we must purchase a minimum number of vials each calendar year at fixed prices determined by vial batch size.

TIL Cell Therapy Landscape in Solid Tumors

Immune System and Cancer Surveillance

The immune system recognizes danger signals and responds to threats at a cellular level.

The most significant components of the cellular aspect of the adaptive immune response are T cells, or T lymphocytes, so called because they mature in the thymus and are distinguished from B-cells which mature in the bone marrow.

T cells can be distinguished from other white blood cells by T cell receptors present on their cell surface.

These receptors contribute to tumor surveillance by helping T cells recognize infected as well as cancerous cells.

T cells are involved in both sensing and killing infected or cancerous cells, as well as coordinating the activation of other cells in an immune response.

Challenges for Cancer Immunotherapy

According to the SEER program, solid tumor cancers represent more than 90 percent of all cancers diagnosed in the U.S.

Despite progress over the past several decades, effective treatment of solid tumors continues to be challenging for several reasons, including:

In addition, the tumor itself and the tumor microenvironment can suppress the patient’s natural immune response.

When T cells with cancer-specific receptors are absent, present in low numbers, of poor quality, or rendered inactive by suppressive mechanisms employed by tumor tissue, the cancer can grow and spread to various organs.

In addition, certain standard of care treatments for cancer can be deleterious to T cells’ ability to kill cancer.

Advancing Immuno-Oncology with Our TIL Technology Platform

We believe that adoptive cell therapy, specifically the use of human polyclonal TIL cells to reengage the immune system, may be a significant advancement in the treatment of cancer.

Our TIL technology platform was validated by the first FDA approval of a TIL cell therapy and is potentially applicable to many solid tumor cancers.

This platform is focused on leveraging patient-specific cells to recognize and attack diverse cancer cells that are unique to each patient.

Unlike cell therapies that act on a single or small number of shared antigen targets common to certain tumors, TIL cell therapy is an individualized, polyclonal T cell therapy designed to target a variety of neoantigens that are unique to the patient or tumor .

Our initial strategy is to deliver our commercial product, Amtagvi™, as well as investigational TIL cell therapies for patients with late-stage solid tumor cancers.

After infusion, TIL can potentially infiltrate the tumor to eliminate cancer cells, further proliferate in the body and potentially overcome several mechanisms of tumor escape to which endogenous T cells may be susceptible due to the immune-suppressive tumor microenvironment.

For earlier intervention, we are investigating our TIL cell therapy in combination with ICIs.

These ICIs seek to overcome one of the main escape mechanisms of cancer against an immune system attack.

TIL cell therapy and ICIs may work in combination to target and attack cancer cells while breaking down barriers for the immune system to mount a response.

The biotechnology and pharmaceutical industries put significant resources into developing novel and proprietary therapies for the treatment of cancer.

2 unchanged sentences

and Europe 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 University Hospital at Herlev, and the University of Manchester.

Results from the M14TIL clinical trial were presented at the European Society for Medical Oncology Congress in September 2022 and published in the New England Journal of Medicine in December 2022, as described in the Historical Clinical Results with Other TIL Therapies in Metastatic Melanoma section of this Annual Report on Form 10-K.

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 University Hospital at Herlev, and the University of Manchester.

Results from the M14TIL clinical trial were presented at the European Society for Medical Oncology Congress in September 2022 and published in the New England Journal of Medicine in December 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.

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/-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, Mirati Therapeutics, OncoSec Medical, Replimune, Regeneron Pharmaceuticals, Seagen, and Genmab.

We also may compete with other TIL 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 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.

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, 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.

Furthermore, we 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.

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 novel IL-2 treatments in development by Alkermes, Werewolf, Merck, Sanofi, Neoleukin 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.

2 unchanged sentences

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.

Our lead product candidate lifileucel is a TIL therapy for the treatment of advanced melanoma and advanced cervical cancer.

Currently, there are numerous companies that are developing various alternate treatments for melanoma and cervical cancer, including patients that have progressed after prior treatment with checkpoint inhibitors and chemotherapy.

Accordingly, lifileucel faces significant competition in the melanoma and cervical cancer treatment space from multiple companies.

Even if we obtain regulatory approval for lifileucel, the availability and price of our competitors’ products could limit the demand and the price we are able to charge for our therapies.

Our portfolio includes our commercial products Amtagvi™ and Proleukin ® as well as our pipeline of investigational TIL cell therapies.

Currently, there are numerous companies that are developing various alternate treatments for advanced melanoma, NSCLC and other solid tumor cancers that we are seeking to address, including patients that have progressed after prior treatment with checkpoint inhibitors and chemotherapy.

Accordingly, our TIL cell therapies face significant competition from multiple companies.

Even with the regulatory approval for Amtagvi™, the availability and price of our competitors’ products could limit the demand and the price we are able to charge for our therapies.

Mergers and acquisitions in the biotechnology and pharmaceutical industries may result in even more resources being concentrated among a smaller number of our competitors.

14 unchanged sentences

To the extent that our consultants, contractors or collaborators use intellectual property owned by others in their work for us, disputes may arise as to the rights in related or resulting know-how and inventions.

Intellectual Property

We aim to lead in the field of T cell-based immunotherapy by building and augmenting the patent rights for our proprietary TIL technology platform, which we have developed internally and licensed from third parties.

Intellectual property is of importance in our field and in biotechnology generally.

We also plan to rely on regulatory protection afforded through Orphan Drug Designation, or ODD, available regulatory exclusivities and patent term extensions where available.

We expect to further develop our patent portfolio as a strategic focus in 2024.

We have established a leading intellectual property portfolio developed internally and licensed from third parties.

We currently own more than 60 U.S.

patents related to TIL cell therapy, including patents directed to compositions and methods of treatment in a broad range of cancers, such as U.S.

and 11,866,688.

More than 40 of these patents are related to our Gen 2 TIL manufacturing processes and have terms that we anticipate will extend to January 2038, not including any patent term extensions or adjustments that may be available.

Our owned and licensed intellectual property portfolio also includes patents and patent applications relating to TIL, marrow infiltrating lymphocytes, or MIL, and peripheral blood lymphocyte, or PBL, therapies;

frozen tumor-based TIL technologies;

remnant TIL and digest TIL compositions, methods and processes;

methods of manufacturing TIL, MIL, and PBL therapies;

the use of costimulatory and T cell modulating molecules in TIL cell therapy and manufacturing;

stable and transient genetically-modified TIL cell therapies, including genetic knockouts of immune checkpoints;

cytokine-tethered TIL cell therapies;

methods of using ICIs in combination with TIL cell therapies;

TIL selection technologies;

and methods of treating patient subpopulations.

Government Regulations

17 unchanged sentences

The testing and approval process requires substantial time, effort and financial resources, and we cannot be certain that any approvals for our product candidates will be granted on a timely basis, if at all.

Prior to beginning the first clinical trial with a new

product candidate, we must submit an IND to the FDA.

Prior to beginning the first clinical trial with a new product candidate, we must submit an IND to the FDA.

An IND is a request for authorization from the FDA to administer an investigational new drug product to humans.

6 unchanged sentences

In such a case, the IND may be placed on clinical hold and the IND sponsor, and the FDA must resolve any outstanding concerns or questions before the clinical trial can begin.

Clinical holds also may be imposed by the FDA at any time before or during clinical trials due to safety concerns or non-compliance.

Clinical holds also

may be imposed by the FDA at any time before or during clinical trials due to safety concerns or non-compliance.

Submission of an IND therefore may or may not result in FDA authorization to begin a clinical trial.

19 unchanged sentences

● Phase 1 - The investigational product is initially introduced into healthy human subjects or patients with the target disease or condition.

These studies are designed to test the safety, dosage tolerance, absorption, metabolism and distribution of the

investigational product in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness.

These studies are designed to test the safety, dosage tolerance, absorption, metabolism and distribution of the investigational product in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness.

● Phase 2 - The investigational product is administered to a limited patient population with a specified disease or condition to evaluate the preliminary efficacy, optimal dosages and dosing schedule and to identify possible adverse side effects and safety risks.

1 unchanged sentence

● Phase 3 - The investigational product is administered to an expanded patient population in adequate and well-controlled studies to further evaluate dosage, to provide statistically significant evidence of clinical efficacy and to further test for safety, generally at multiple geographically dispersed clinical trial sites.

These clinical trials are intended to establish the overall risk/benefit relationship of the investigational product and to provide an adequate basis for product approval.

These clinical trials are intended to establish the overall

risk/benefit relationship of the investigational product and to provide an adequate basis for product approval.

Typically, two Phase 3 studies are required by the FDA for product approval.

27 unchanged sentences

Following product approval, a REMS may also be required by the FDA if new safety information is discovered, and the FDA determines that a REMS is necessary to ensure that the benefits of the biologic outweigh the risks.

BLA Approval and Post-Approval Requirements

BLA Submission and Review by the FDA

2 unchanged sentences

Data can come from company-sponsored clinical studies intended to test the safety and effectiveness of a use of the product, or from a number of alternative sources, including studies initiated by investigators.

The submission of a BLA requires payment of a substantial user fee to the FDA, under the Prescription Drug User Fee Act, and the sponsor of an approved BLA is also subject to annual program fees.

The submission of a BLA requires payment of a substantial user fee to the FDA, under PDUFA, and the sponsor of an approved BLA is also subject to annual program fees.

These fees are typically increased annually.

28 unchanged sentences

An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications.

However, even if the FDA approves a product, it may limit the approved indications for use of the product, require that contraindications, warnings, or precautions be included in the product labeling, including a boxed warning, require that post-approval studies, including Phase 4 clinical trials, be conducted to further assess a product’s safety and efficacy after approval, require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution restrictions or other risk management mechanisms under a REMS which can materially affect the potential market and profitability of the product.

commercialization, or impose other conditions, including distribution restrictions or other risk management mechanisms under a REMS which can materially affect the potential market and profitability of the product.

The FDA may also not approve label statements that are necessary for successful commercialization and marketing.

14 unchanged sentences

Sponsors of products under the Accelerated Approval Pathway must further submit promotional materials to the FDA before dissemination.

In addition, the Food and Drug Administration Safety and Innovation Act, or FDASIA, which was enacted and signed into law in 2012, established the new BTD.

In addition, the Food and Drug Administration Safety and Innovation Act, or FDASIA, which was enacted and signed into law in 2012, established the new Breakthrough Therapy Designation, or BTD.

A sponsor may seek FDA designation of its product candidate as a Breakthrough Therapy if the product candidate is intended, alone or in combination with one or more other drugs or biologics, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the therapy may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.

6 unchanged sentences

BTD also allows the sponsor to file sections of the BLA for review on a rolling basis.

Through the 21st Century Cures Act, or Cures Act, Congress also established another expedited program, called a RMAT designation.

Through the 21st Century Cures Act, or Cures Act, Congress also established another expedited program, called a Regenerative Medicine Advanced Therapy, or RMAT, designation.

The Cures Act directs the FDA to facilitate an efficient development program for and expedite review of RMATs.

1 unchanged sentence

The product must be intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition, and preliminary clinical evidence must indicate that the product has the potential to address an unmet need for such disease or condition.

Advantages of the RMAT designation include all the benefits of the Fast Track and breakthrough therapy designation programs, including early interactions with the FDA.

Advantages of the RMAT designation include all the benefits of the Fast Track and breakthrough therapy designation programs, including early interactions

with the FDA.

These early interactions may be used to discuss potential surrogate or intermediate endpoints to support accelerated approval.

Post-Approval Requirements

Any products for which we receive FDA approvals are subject to continuing regulation by the FDA, including, among other things, record-keeping requirements, reporting of adverse experiences with the product and deviations, annual reporting and monitoring and providing the FDA with updated safety and efficacy information, product sampling and distribution requirements, certain electronic records and signature requirements, fulfilling post-marketing clinical trial and REMS commitments, and complying with FDA promotion and advertising requirements, which include, among other things, standards for direct-to-consumer advertising, restrictions on promoting products for uses or in patient populations that are not described in the product’s approved uses or otherwise consistent with the FDA-approved product labeling (known as “off-label use”), limitations on industry-sponsored scientific and educational activities, rules regarding communication of health care economic information regarding biopharmaceutical products to payors and formularies, and requirements for promotional activities involving the internet.

Although physicians may prescribe legally available products for off-label use, if they deem such use to be appropriate in their professional medical judgment, manufacturers may not market or promote such off-label uses.

In the past several years, certain court decisions have impacted FDA’s enforcement activity regarding off-label promotion in light of First Amendment considerations;

however, there are still significant risks in this area, in part due to the potential for False Claims Act exposure.

In addition, quality control and manufacturing procedures must continue to conform to applicable manufacturing requirements after approval to ensure the long-term stability of the product.

cGMP regulations require among other things, quality control and quality assurance as well as the corresponding maintenance of records and documentation and the obligation to investigate and correct any deviations from cGMP.

Manufacturers and other entities involved in the manufacture and distribution of approved products are required to register their establishments and list their products with the FDA and certain state agencies and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP and other applicable laws.

Accordingly, manufacturers must continue to expend time, money, and effort in the areas of production and quality control to maintain cGMP compliance.

Discovery of problems with a product after approval may result in restrictions on a product, manufacturer, or holder of an approved BLA, including, among other things, withdrawal of approval, recall or withdrawal of the product from the market.

In addition, changes to the manufacturing process are strictly regulated, and depending on the significance of the change, may require prior FDA approval or notification before being implemented.

Other types of changes to the approved product, such as adding new indications and claims to the product labeling, are also subject to further FDA review and approval.

Commercial products must meet the requirements of the Drug Supply Chain Security Act, or DSCSA, which imposes obligations on manufacturers of prescription biopharmaceutical products for commercial distribution, regulating the distribution of the products at the federal level, and sets certain standards for federal or state registration and compliance of entities in the supply chain, including manufacturers and repackagers, wholesale distributors, third-party logistics providers, and dispensers.

The DSCSA preempts previously enacted state laws and the pedigree requirements of the Prescription Drug Marketing Act, or PDMA.

Trading partners within the drug supply chain must now ensure certain product tracing requirements are met that they are doing business with other authorized trading partners;

and they are required to exchange transaction information, transaction history, and transaction statements.

Product identifier information, an aspect of the product tracing scheme, is required.

The DSCSA requirements, development of standards, and the system for product tracing have been and will continue to be phased in over a period of years, with the FDA indicating that it would permit certain exemptions and exclusions, and exercise enforcement discretion on certain aspects of the law due to the COVID-19 pandemic, although this situation may continue to evolve.

The distribution of product samples continues to be regulated under the PDMA, and some states also impose regulations on drug sample distribution.

As previously mentioned, the FDA may also require Phase 4 testing and surveillance to monitor the effects of an approved product.

Discovery of previously unknown problems with a product or the failure to comply with applicable FDA requirements can have negative consequences, including adverse publicity, judicial or administrative enforcement, warning letters from the FDA, mandated corrective advertising or communications with doctors, and civil or criminal penalties, among others.

Newly discovered or developed safety or effectiveness data may require changes to a product’s approved labeling, including the addition of new warnings and contraindications, and may require the implementation of other risk management measures.

Also, new government requirements, including those resulting from new legislation, may be established, or the FDA’s policies may change, which could delay or prevent regulatory approval of our products under development.

Regulatory Designations

The FDA has granted ODD for lifileucel in the U.S.

to treat malignant melanoma stages IIB-IV and for the treatment of cervical cancer with a tumor size of greater than 2 cm in diameter;

Fast Track and RMAT designations for lifileucel to treat advanced metastatic melanoma;

Fast Track and BTD for lifileucel to treat metastatic cervical cancer;

and Fast Track designation for lifileucel in combination with pembrolizumab for the treatment of ICI naïve metastatic melanoma.

Orphan Drug Designations

During 2015, we received ODD for lifileucel in the U.S.

to treat malignant melanoma stages IIB-IV, and in 2018, we received an ODD for lifileucel for the treatment of cervical cancer with a tumor size of greater than 2 cm in diameter.

If approved, an ODD provides seven years of market exclusivity in the U.S., which means that the FDA may not approve any other applications, including a full BLA, to market the same biologic, as sameness is defined in the FDA’s regulations, for the same indication for seven years, subject to certain limited exceptions.

However, an ODD does not convey any advantage in, or shorten the duration of, the regulatory review or approval process.

The benefits and limitations of ODD are described in more detail under the Government Regulations section in this Annual Report on Form 10-K.

Fast Track Designations

In August 2017, we announced that the FDA had granted Fast Track designation for lifileucel for the treatment of advanced metastatic melanoma.

In February 2019, we announced that the FDA had granted Fast Track designation for lifileucel in the treatment of metastatic cervical cancer.

Additionally, in November 2021, we announced that the FDA granted Fast Track designation for lifileucel in combination with pembrolizumab for the treatment of ICI-naïve metastatic melanoma.

The FDA’s Fast Track process is designed to facilitate the development and expedite the review of drugs that treat serious conditions and fill an unmet medical need.

Fast Track designation allows more frequent meetings and communications with the FDA to discuss the drug’s development plans and review process.

Regenerative Medicine Advanced Therapy Designation

In October 2018, we announced that the FDA had granted RMAT designation for lifileucel for the treatment of patients with metastatic melanoma.

The RMAT designation is based on data provided to the FDA from our C-144-01 trial.

RMAT designation is granted for regenerative medicine drugs and allows for increased access to FDA during development.

Under this designation, surrogate endpoints can be used to receive approval for a product, accelerated approval may be granted, and a rolling review of a BLA may be permitted by FDA.

Breakthrough Therapy Designation

In May 2019, we announced that the FDA had granted BTD for lifileucel for the treatment of patients with metastatic cervical cancer.

The BTD was granted based on data provided to the FDA from our C-145-04 clinical trial.

BTD also allows the sponsor to submit portions of the BLA on an ongoing basis for rolling review.

In addition, BTD status allows for the potential to request priority review of our BLA at the time of BLA submission if supported by clinical data.

The clinical evidence needed to support breakthrough designation is preliminary, and the FDA has authority to rescind a BTD if a product candidate no longer meets the qualifying criteria.

Under the Orphan Drug Act, the FDA may grant ODD to a drug or biologic intended to treat a rare disease or condition, defined as a disease or condition with a patient population of fewer than 200,000 individuals in the U.S., or a patient population greater than 200,000 individuals in the U.S.

and when there is no reasonable expectation that the cost of developing and making available the drug or biologic in the U.S.

and when there is no reasonable expectation that the cost of developing and making available the drug

or biologic in the U.S.

will be recovered from sales in the U.S.

21 unchanged sentences

The PHSA also includes provisions governing patent litigation over patents that are directed to the reference products.

The biosimilar product sponsor and reference product sponsor may, but are not required to, exchange certain patent and product information for the purpose of negotiating and determining the scope of patent litigation, including the patents to be asserted and

Based on the outcome of negotiations surrounding the exchanged information, the reference product sponsor may bring a patent infringement suit and injunction proceedings against the biosimilar product sponsor.

5 unchanged sentences

There must be no difference between the reference product and a biosimilar in conditions of use, route of administration, dosage form, and strength.

Further, a biosimilar product may be deemed interchangeable with a prior approved product if it meets the higher hurdle of demonstrating that it can be expected to produce the same clinical results as the reference product and, for products administered multiple times, the biologic and the reference biologic may be switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.

switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.

Pediatric Exclusivity and Patent Term Extension

17 unchanged sentences

Even if any of our product candidates are found to be eligible for patent term protection, the applicable authorities may subsequently determine that we are not eligible for such restoration periods.