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Item 7. Management’s Discussion and Analysis

2021-02-25 compared with 2020-02-25 · 195 added, 69 removed, 111 unchanged (70% of the section changed)

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Actual results and the timing of events could differ materially from those anticipated in these forward-looking statements as a result of a number of factors, including those set forth under the “Business” section and elsewhere in this report.

We use words such as “anticipate,” “estimate,” “plan,” “project,” “continuing,” “ongoing,” “expect,” “believe,” “intend,” “may,” “will,” “should,” “could,” and similar expressions to identify forward-looking statements.

All forward-looking statements included in this report are based on information available to us on the date hereof and, except as required by law, we assume no obligation to update any such forward-looking statements.

We use words such as “may,” “will,” “might,” “could,” “would,” “should,” “expect,” “intend,” “plan,” “anticipate,” “believe,” “estimate,” “predict,” “project,” “aim,” “potential,” “continue,” “ongoing,” “goal,” “forecast,” “guidance,” “outlook,” or the negative of these terms or other similar expressions to identify forward-looking statements, although not all forward-looking statements contain these words.

All forward-looking statements included in this report are based on information

available to us on the date hereof and, except as required by law, we assume no obligation to update any such forward-looking statements.

We are a clinical-stage biopharmaceutical company focused on the development and commercialization of cell therapies as novel cancer immunotherapy products designed to harness the power of a patient’s own immune system to eradicate cancer cells.

Tumor infiltrating lymphocyte, or TIL, therapy is an autologous cell therapy platform technology that was originally developed by the National Cancer Institute, or NCI, which conducted initial clinical trials in diseases such as metastatic melanoma and cervical cancer.

We have developed a new, shorter manufacturing process for TIL known as Generation 2 or Gen 2, which yields a cryopreserved TIL product.

This proprietary and scalable manufacturing method is being further investigated in multiple indications.

Our lead product candidates include lifileucel for metastatic melanoma and LN-145 for metastatic cervical cancer.

In addition to metastatic melanoma and metastatic cervical cancer, we are investigating the effectiveness and safety of TIL for the treatment of squamous cell carcinoma

of the head and neck, non-small cell lung cancer, and peripheral blood lymphocyte, or PBL, therapy for chronic lymphocytic leukemia through our sponsored trials, as well as in other oncology indications through collaborations.

TIL therapy is an autologous cell therapy platform technology that was originally developed by the NCI, which conducted initial clinical trials of this therapy in diseases such as metastatic melanoma and cervical cancer.

We have developed a new, shorter manufacturing process for TIL known as Gen 2, which yields a cryopreserved TIL product.

This proprietary and scalable manufacturing method is being investigated in multiple indications.

Our lead product candidates include lifileucel for metastatic melanoma and metastatic cervical cancer.

In addition to metastatic melanoma and metastatic cervical cancer, we are investigating the effectiveness and safety of TIL for the treatment of squamous cell carcinoma of the head and neck, non-small cell lung cancer, and are investigating PBL therapy for CLL or SLL through our sponsored trials, as well as in other oncology indications through collaborations.

We are conducting a Phase 2 clinical trial, C-144-01, of our lead product candidate, lifileucel, for the treatment of metastatic melanoma.

This multicenter pivotal trial enrolled patients with melanoma whose disease has progressed following treatment with at least one systemic therapy, including a PD-1 inhibitor and if BRAF mutated, a BRAF inhibitor, or a combination of BRAF and MEK inhibitors (National Clinical Trial identification number NCT02360579).

Cohort 4 of the C-144-01 clinical trial is a single-arm cohort intended to be used for the registration of lifileucel.

The C-144-01 trial uses our proprietary Gen 2 manufacturing process.

This multicenter pivotal trial enrolled melanoma patients with disease progression following treatment with at least one systemic therapy, including a PD-1 inhibitor and if BRAF mutated, a BRAF inhibitor, or a combination of BRAF and MEK inhibitors.

Cohort 4 of the C-144-01 clinical trial is a single-arm cohort intended to support a BLA submission for lifileucel.

Cohorts 2 and 4 of the C-144-01 trial use our Gen 2 manufacturing process.

We completed and closed enrollment of patients into Cohort 2 of the C-144-01 trial in 2018.

We announced that the last patient was dosed in Cohort 4 of this trial in January 2020.

Cohort 4 was enrolled with a prospective definition of objective response rate, or ORR, read out by an Independent Review Committee, or IRC, as the primary endpoint based on our interpretation of discussions with the U.S.

Food and Drug Administration, or FDA.

In addition to our ongoing trial in metastatic melanoma, we are conducting clinical trials of LN-145, TIL therapy in cervical, head and neck cancers, lung and other cancers.

C-145-04 is an ongoing Phase 2, multicenter pivotal trial that will assess the safety and efficacy of LN-145 for the treatment of patients with recurrent, metastatic or persistent cervical cancer (NCT03108495).

In February 2019, LN-145 received Fast Track designation from the FDA for development in the treatment of cervical cancer with disease progression on or after chemotherapy.

Results from Cohort 2 of the C-144-01 clinical trial were initially reported at the ASCO annual meeting on June 1, 2019 and subsequently updated at the ASCO annual meeting on May 29, 2020.

In 66 patients with metastatic melanoma, treatment with lifileucel resulted in an ORR of 36%, as assessed by investigator, with 2 complete responses and 22 partial responses.

The DCR was 80.3%.

Patients were heavily pretreated and had a mean of 3.3 prior therapies.

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

We have provided several updates on the median DOR for Cohort 2 and most recently, in January 2021, we announced that median DOR in Cohort 2 had still not been reached after 28.1 months of median study follow up, as assessed by investigator.

The adverse event profile was generally consistent with the underlying advanced disease and the profile of the lymphodepletion and IL-2 regimens.

Pivotal Cohort 4 of the C-144-01 trial was enrolled to evaluate ORR as read out by an IRC as the primary endpoint based on our interpretation of discussions with the FDA as part of an EOP2 meeting held with the FDA in the third quarter of 2018.

In October 2018, based on the data provided to the FDA during the EOP2 meeting, we announced that lifileucel had received a RMAT designation from the FDA.

Enrollment in Cohort 4 of the C-144-01 trial commenced in March 2019 and patient dosing was completed in January 2020.

A total of 87 patients were dosed in Cohort 4.

Initial results from Cohort 4 are available for 68 patients with two radiological assessments, as determined by investigator.

Lifileucel showed a 32.4% ORR, including one complete response and 21 partial responses, two of which were yet to be confirmed with follow up visits at the time of the data cut, and a DCR of 72.1% as of the data cut off of March 16, 2020, corresponding to 5.3 months of median study follow up.

This data is consistent with the Cohort 2 data read out at a similar median duration of study follow up.

The ORR of Cohort 2 at a median study follow up of 6 months was 33%.

In October 2020, after a Type B meeting with the FDA, we announced that we had delayed our BLA submission for lifileucel in metastatic melanoma as a result of FDA feedback, in order to allow us to simultaneously refine existing and develop new potency assays, and we anticipate submitting our BLA in 2021.

At the same time, we also announced that we had reached agreement with the FDA on the minimum duration of follow up for Cohort 4 to support our BLA submission for lifileucel in the treatment of metastatic melanoma.

We are also conducting a Phase 2 clinical trial, C-145-04, which is a multicenter pivotal trial that will assess the safety and efficacy of lifileucel for the treatment of patients with recurrent, metastatic or persistent cervical cancer.

In February 2019, lifileucel received Fast Track designation from the FDA for development in the treatment of cervical cancer with disease progression on or after chemotherapy.

In March 2019, the protocol for this trial was amended to modify the primary endpoint of ORR to be determined by IRC.

In May 2019, LN-145 received Breakthrough Therapy designation, or BTD, from the FDA for the development in the treatment of cervical cancer.

Our current product candidate pipeline and selected investigator-sponsored proof-of-concept studies are summarized in the graph below:

Financial Overview

In May 2019, lifileucel received BTD from the FDA for development in the treatment of cervical cancer.

Updated results from the C-145-04 clinical trial were reported at the ASCO annual meeting on June 1, 2019.

In 27 patients with metastatic cervical cancer, treatment with lifileucel resulted in an ORR of 44%.

At the time of the study data cut, there were 3 complete responses and 9 partial responses.

The DCR was 85%.

Patients were heavily pretreated and had a mean of 2.4 prior therapies.

The median DOR had not been reached.

The adverse event profile was generally consistent with the underlying advanced disease and the profile of the lymphodepletion and IL-2 regimens.

Based on an EOP2 meeting held with the FDA in June 2019, we believe that results from the C-

145-04 clinical trial may be sufficient to support registration of lifileucel for the treatment of patients with metastatic cervical cancer.

In accordance with the FDA’s recommendations, the protocol was amended to further define the patient population.

In November 2019, in order to evaluate lifileucel in broader lines of therapy in cervical cancer, we have further amended the C-145-04 trial to collect additional data on early-line patients as well as late-line patients by adding additional cohorts, in anticipation of a changing landscape in this indication, including Cohort 2 for patients that had previously received anti-PD-1 therapy.

These additional cohorts also allow access to TIL therapy after completion of the enrollment in the registrational cohorts.

In January 2021, we announced that Cohort 2 of the C-145-04 trial had completed enrollment and that data from this cohort may be supportive of registration because of the expected changing landscape of care for cervical patients.

We intend to initiate a dialog with the FDA in 2021 to discuss BLA submission plans for lifileucel in cervical cancer.

In November 2020, we announced that we had finalized the protocol for our potential registrational clinical trial in NSCLC, IOV-LUN-202, to investigate LN-145 in patients with recurrent or metastatic NSCLC, without driver mutations, who previously received a single line of approved systemic therapy of combined checkpoint inhibitor and chemotherapy.

The IOV-LUN-202 clinical trial includes three cohorts.

Cohorts 1 and 3 of the IOV-LUN-202 clinical trial will enroll patients with a PD-L1 TPS of less than one percent, and Cohort 2 will enroll patients with a PD-L1 TPS of greater than or equal to one percent.

We intend to enroll patients in the IOV-LUN-202 clinical trial throughout 2021.

C-145-03 is our Phase 2, multicenter trial to assess the safety and efficacy of our product candidate LN-145 for the treatment of patients with recurrent metastatic HNSCC.

In October 2018, we reported that, to date, preliminary data for 13 patients in the C-145-03 clinical trial yielded an ORR of 31% with a DOR ranging from 2.8 to 7.6 months.

The adverse event profile remained consistent with previous reports.

We redesigned our C-145-03 trial to include multiple cohorts, in order to allow for dosing of TIL therapies produced by multiple manufacturing methods, including our Gen 2 manufacturing process, our Gen 3 manufacturing process, and our PD-1 selected TIL manufacturing process.

Our PD-1 selected TIL manufacturing process results in a product that we refer to as LN-145-S1.

In January 2021, we announced that we are closing the C-145-03 clinical trial after the trial reached its pre-specified enrollment target.

We are also investigating the potential of our TIL therapies in earlier lines of treatment and in combination with pembrolizumab, and are studying LN-145 as a monotherapy in relapsed refractory NSCLC patients.

IOV-COM-202 is a Phase 2, multicenter trial that is composed of seven cohorts that can enroll up to a total of 135 patients.

In May 2019, we reported that the first patient was dosed in the IOV-COM-202 trial.

In addition to its ongoing enrollment in the U.S., the IOV-COM-202 trial has also received regulatory approval in Canada and in certain European countries.

In Cohort 2A of the IOV-COM-202 trial, we are enrolling advanced, recurrent, or metastatic HNSCC patients who are naïve to prior immunotherapy including anti-PD-1/anti-PD-L1 therapy.

The patients receive LN-145 in combination with pembrolizumab.

We reported results from ongoing Cohort 2A of the IOV-COM-202 trial at the SITC meeting in November 2020, as follows.

As of October 16, 2020, nine HNSCC patients have received LN-145 plus pembrolizumab with a median duration of follow up of 8.6 months.

Nine and eight patients were evaluable for safety and efficacy, respectively.

Four patients had a confirmed, objective response with an ORR of 44% including one complete response and three partial responses.

Median DOR was not reached.

The disease control rate at data cutoff was 89% in nine patients, and seven of the eight evaluable patients, or 87.5%, had a reduction in target lesions.

The median number of prior therapies was 1.0 with 89% of the patients having received prior chemotherapy.

Four patients were HPV positive, three patients were HPV negative, and two patients had unknown HPV status.

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

The most common TEAEs, occurring in more than 50% of evaluable subjects, were chills, anemia, hypotension, nausea, pyrexia, and thrombocytopenia.

In November 2019, we announced that our IND for our PBL therapy, IOV-2001, was authorized by the FDA and our sponsored clinical trial using this therapy, IOV-CLL-01, was cleared to proceed.

IOV-2001 is a non-genetically modified, polyclonal T cell product that is manufactured using a nine-day process from 50 mL of patient's blood.

IOV-CLL-01 is a Phase 1/2 clinical trial evaluating the safety and efficacy of IOV-2001 in patients with relapsed or refractory CLL or SLL.

The IOV-CLL-01 trial is expected to enroll up to approximately 70 patients.

As part of our collaboration program with MDACC, two Phase 2 trials were initiated in 2018.

Both trials are sponsored by MDACC.

The first trial, NCT03449108, is intended to allow for investigation of LN-145 manufactured by us using our manufacturing processes to treat patients with soft tissue sarcoma, osteosarcoma, platinum resistant ovarian cancer, and thyroid cancer.

A second trial under the collaboration with MDACC, NCT03610490, is active as well.

This trial is treating patients with platinum resistant ovarian cancer, pancreatic and colorectal cancer.

This trial uses TIL manufactured by MDACC using urelumab, a 4-1BB agonistic antibody, as part of the manufacturing process.

The data obtained using this manufacturing process may not be representative of our data using our Gen 2 manufacturing process.

We are also collaborating with CHUM, Yale University, and Moffitt on investigator-sponsored clinical trials of TIL therapies in other indications.

The clinical trials sponsored by CHUM and Moffitt use, or will use, TIL manufactured by different manufacturing processes, which may not be representative of our data using our Gen 2 manufacturing process.

Our current product candidate pipeline and selected investigator-sponsored proof-of-concept studies are summarized in the figure below:

We have developed a third-generation manufacturing process known as Gen 3.

Gen 3 is a shorter process than Gen 2.

We are using Gen 3 manufacturing in Cohort 1C of the IOV-COM-202 trial in melanoma and in Cohort 3 of the IOV-LUN-202 trial in NSCLC and have previously used it in the C-145-03 trial in HNSCC.

We currently own more than twenty granted or allowed U.S.

and international patents for compositions and methods of treatment in a broad range of cancers relating to our Gen 2 manufacturing process, including U.S.

10,130,659, 10,166,257, 10,272,113, 10,363,273, 10,398,734, 10,420,799, 10,463,697, 10,537,595, 10,646,517, 10,653,723, 10,693,330, 10,695,372, 10,894,063, and 10,905,718.

We anticipate that the terms of these patents related to Gen 2 manufacturing processes 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 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 treatment of a broad range of cancers using TIL therapies;

methods of manufacturing TIL, MIL, and PBL therapies;

the use of costimulatory molecules in TIL therapy and manufacturing;

stable and transient genetically-modified TIL therapies;

methods of using immune checkpoint inhibitors in combination with TIL therapies;

TIL selection technologies;

and methods of treating patient subpopulations.

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.

Under the agreement, we paid an upfront payment to Novartis and may pay milestones involved in initiation of patient dosing in various phases of clinical development for IOV-3001 and approval of a potential product in the U.S., EU and Japan.

Novartis is also entitled to low-to-mid single digit percentage royalties from commercial sales of IOV-3001.

In addition, in January 2020, we announced a research collaboration and exclusive worldwide licensing agreement with Cellectis, a clinical-stage biopharmaceutical company focused on developing immunotherapies based on gene-edited allogeneic chimeric antigen receptor modified T cells, whereby we licensed certain TALEN technology from Cellectis in order to develop TIL that have been genetically edited to create potentially more potent cancer therapeutics.

The worldwide exclusive license enables us to use TALEN technology addressing multiple gene targets to modify TIL for therapeutic use in several cancer indications.

Financial terms of the license include

development, regulatory and sales milestone payments from us to Cellectis, as well as royalty payments based on net sales of TALEN-modified TIL products.

Results of Operations for the Years Ended December 31, 2020 and 2019

Research and development activities are central to our business model.

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Our major sources of funding to date have been proceeds from various public and private offerings of our equity securities (both common stock and preferred stock), option and warrant exercises, and interest income.

Results of Operations for the Years Ended December 31, 2019 and 2018

We did not generate any revenues during the years ended December 31, 2019 and 2018, respectively, and we currently do not anticipate that we will generate any revenues during 2020 from the sale or licensing of our product candidates.

Since 2017 our primary source of funds has been from the public sale of our common stock.

We did not generate any revenues during the years ended December 31, 2020 and 2019, respectively, and we currently do not anticipate that we will generate any significant revenues from the sale or licensing of our product candidates during the 12 month period from the date these financial statements are issued.

Our ability to generate revenues in the future will depend on our ability to complete the development of our product candidates and to obtain regulatory approval for them.

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Increase (Decrease)

Research and development expenses

Research and development

Stock-based compensation expense included in research and development expense

Research and development expense for the year ended December 31, 2020 increased by $35.7 million, or 22%, compared to the year ended December 31, 2019.

The increase was primarily attributable to (i) a $27.4 million increase in manufacturing costs due to increased production runs and additional manufacturing capacity costs to support the ongoing clinical trials, (ii) a $20.3 million increase in clinical trial costs due to an increase in the number of patients in the clinical trials and purchases of clinical trial drugs, and (iii) a $12.6 million increase in payroll and related expenses driven by a higher number of full-time research and development employees and dedicated consultants as we expanded our internal research and clinical development programs in 2019.

The increase was primarily attributable to (i) a $20.9 million increase in payroll and related expenses driven by a higher number of full-time research and development employees and outside services, (ii) a $10.0 million increase for the license to further develop IOV-3001 obtained from Novartis, (iii) a $8.3 million increase in stock-based compensation expenses, and (iv) a $6.6 million increase in clinical trial costs due to an increase in enrollment across all the trials and initiation of new clinical trials.

Further, a $0.8 million increase in research consumables cost contributed to the increase.

These increases were partially offset by lower manufacturing costs by $9.1 million due to decreased production runs in 2020 as a result of completion of enrollment in the melanoma pivotal program and a $2.3 million decrease in research alliance expenses due to the COVID-19 pandemic’s impact on patient enrollment in the clinical trials with our research alliance partners.

We expect our research and development expenses to increase over the next several years as we prepare for commercial manufacturing of our products and continue to conduct our clinical trials for other indications.

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Increase (Decrease)

General and administrative expenses

Stock-based compensation expense included in general and administrative expense

General and administrative

Stock-based compensation expense included in general and administrative

General and administrative expense for the year ended December 31, 2020 increased by $19.4 million, or 47%, compared to the year ended December 31, 2019.

The change was primarily attributable to a $3.8 million increase in payroll and related expenses, $2.2 million increase in stock-based compensation expenses driven by a higher number of full-time general and administrative employees, a $3.2 million increase in intellectual property legal costs and a $2.0 million increase in market research activities as we prepare for commercialization.

The increase was primarily attributable to (i) a $8.3 million increase in stock-based compensation expenses and a $7.1 million increase in payroll and related expenses driven by a higher number of full-time general and administrative employees and higher average stock price, (ii) a $2.1 million increase in director’s and officer’s insurance premiums, (iii) a $1.1 million increase in intellectual property legal costs, and (iv) a $1.1 million in market research activities as we prepare for commercialization.

These increases were partially offset by a $0.7 million decrease in travel expenses.

General and administrative expenses include personnel costs for our employees engaged in general and administrative activities, legal fees, and expenses related to marketing and commercial activities, audit and tax fees, consultants and professional services, and general corporate expenses.

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Increase (Decrease)

Interest income, net

Net interest income

Interest income results from our interest-bearing cash and investment balances.

Net interest income increased by $4.7 million due to the higher interest income earned from full-year short-term investments for a full-year as compared to the prior year when we started purchasing short-term investments during the second half of 2018.

As our cash, cash equivalents and short term investment balance decrease we anticipate interest income to decrease.

Net interest income decreased by $7.0 million, or 75%, due primarily to a decrease in interest rates in 2020 as compared to the same period in 2019.

Net Loss (in thousands)

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Net loss for the year ended December 31, 2020 increased by $62.0 million or 31%, compared to the year ended December 31, 2019.

The increase in our net loss was due to the continued expansion of our research and development activities, increased clinical trials and manufacturing activities, and the overall growth of our corporate infrastructure.

We anticipate that we will continue to incur net losses in the future as we further invest in our research and development activities, including our clinical development.

The increase in our net loss was due to the continued expansion of our research and development activities, increased clinical trials, and the overall growth of our corporate infrastructure.

We anticipate that we will continue to incur net losses in the future as we further invest in our research and development activities, including our commercial readiness and clinical development.

Results of Operations for the Years Ended December 31, 2019 and 2018

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Research and development expense for the year ended December 31, 2019 increased by $66.2 million, or 66%, compared to the year ended December 31, 2018.

The increase was primarily attributable to a $14.0 million increase in payroll and related expenses, including stock-based compensation expenses, due to a higher number of full-time employees and dedicated consultants as we expanded our internal research efforts and clinical development programs.

Further, clinical trial costs increased by $12.9 million due to:

higher patient enrollment and an increase in the number of clinical sites in the clinical trial of lifileucel for the treatment of melanoma, LN-145 for the treatment of cervical and head and neck cancers, and the initiation of clinical trials in 2018 for new indications.

In addition, research and alliance costs increased by $0.8 million for clinical trials run by our alliance partners and new research initiatives.

These increases were partially offset by a $0.5 million decrease in manufacturing costs due to a termination of a contract manufacturing organization early in 2018.

The increase was primarily attributable to (i) a $27.4 million increase in manufacturing costs due to increased production runs and additional manufacturing capacity costs to support the ongoing clinical trials, (ii) a $21.4 million increase in clinical trial costs due to an increase in the number of patients in the clinical trials and purchases of clinical trial drugs, and (iii) a $12.6 million increase in payroll and related expenses and $2.1 million increase in share-based compensation expenses driven by a higher number of full-time research and development employees and dedicated consultants as we expanded our internal research and clinical development programs in 2019.

General and Administrative Expense (in thousands)

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General and administrative expense for the year ended December 31, 2019 increased by $12.4 million, or 44%, compared to the year ended December 31, 2018.

The change was primarily attributable to a $4.0 million increase in stock-based compensation expenses, $1.7 million increase in payroll and related expenses, driven by a higher number of full-time employees and higher stock prices during 2018, and a $0.2 million increase in professional service fees.

Interest Income (in thousands)

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Interest income results from our interest-bearing cash and investment balances.

Net interest income increased by $3.7 million due to the higher average cash balances as a result of the proceeds received from our equity financings in January 2018 and October 2018, and higher interest rates in 2018.

As our cash, cash equivalents and short term investment balance decrease, we anticipate interest income to decrease.

Net Loss (in thousands)

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We expect to continue to incur significant losses in 2021 and may incur significant losses and negative cash flows from operations for the foreseeable future.

We have funded our operations from various public and private offerings of our equity securities (both common stock and preferred stock), from option and warrant exercises, and from interest income.

Historically, we have funded our operations from various public and private offerings of our equity securities (both common stock and preferred stock), from option and warrant exercises, and from interest income.

Since 2017, our primary source of funds has been from the public sale of our common stock.

Corporate Capitalization

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The 2018 Shelf Registration Statement is no longer available for future offerings.

On September 17, 2019, we filed a shelf registration statement with the SEC for the issuance of common stock, preferred stock, warrants, rights, debt securities and units up to an aggregate amount of $400 million, which we refer to as the 2019 Shelf Registration Statement.

On September 17, 2019, we filed a shelf registration statement with the SEC for the issuance up to an aggregate amount of $400 million, which we refer to as the 2019 Shelf Registration Statement.

The 2019 Shelf Registration Statement was declared effective on September 24, 2019.

We have not yet sold any securities pursuant to the 2019 Shelf Registration Statement.

The 2019 Shelf Registration Statement was terminated upon effectiveness of the 2020 Automatic Shelf Registration Statement (as discussed below).

No shares were sold under the 2019 Shelf Registration Statement prior to its termination.

On May 27, 2020, we filed an automatic shelf registration statement with the SEC for the issuance of an indeterminate amount of Shelf Securities, which we refer to as the 2020 Automatic Shelf Registration Statement.

The 2020 Automatic Shelf Registration Statement was immediately effective upon filing with the SEC, and the 2019 Shelf Registration Statement was simultaneously terminated.

On June 2, 2020, we sold 19,475,806 shares of our common stock at a public offering price of $31.00 per share pursuant to the 2020 Automatic Shelf Registration Statement.

We received gross proceeds of $603.7 million and net proceeds of $567.0 million, after deducting underwriting discounts and offering expenses.

Following the public offering, the 2020 Automatic Shelf Registration Statement remains available for the future issuance of an indeterminate amount of Shelf Securities.

In the future, we may periodically offer one or more of these securities in amounts, prices and terms to be announced when and if the securities are offered.

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We do not have any commercial products and have not yet generated any revenues from our biopharmaceutical business.

We currently do not anticipate that we will generate any revenues during 2020 from the sale or licensing of any products.

We currently do not anticipate that we will generate any

significant revenues from the sale or licensing of any products during the 12 months from the date these financial statements are issued.

We have incurred a net loss of $259.6 million for the year ended December 31, 2020 and used $205.1 million of cash in our operating activities for the year ended December 31, 2020.

As of December 31, 2019, we had $14.0 million of cash and cash equivalents, $293.1 million of short-term investments, $5.5 million of restricted cash, $299.0 million of stockholders’ equity and had working capital of $277.4 million.

We expect to further increase our research and development activities, which will increase the amount of cash we will use during 2020 and beyond.

Specifically, we expect increased spending on clinical trials, research and development activities, higher payroll expenses as we increase our professional and scientific staff and continue our expansion of manufacturing activities.

As of December 31, 2020, we had $629.4 million of cash, cash equivalents, and short-term investments ($67.3 million of cash and cash equivalents and $562.1 million of short-term investments), $656.5 million of stockholders’ equity and had working capital of $581.2 million.

We expect to further increase our research and development activities, especially continuing pre-commercial activities and completing the construction of our tenant improvements to our new commercial manufacturing facility, which will increase the amount of cash we will use during 2021 and beyond.

Based on the funds we have available as of the date of the filing of this Annual Report on Form 10-K, we believe that we have sufficient capital to fund our anticipated operating expenses and capital expenditure for at least 12 months from the date of filing this report.

We have latitude as to the timing and amount of expenditures for our commercial-scale production facility under construction in Philadelphia, Pennsylvania.

Cash Flows from Operating, Investing and Financing Activities (in thousands):

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Financing activities

Net increase (decrease) in cash, cash equivalents and restricted cash

Net increase in cash, cash equivalents and restricted cash

Operating Activities

Net cash used in operating activities of $158.9 million for the year ended December 31, 2019, resulted primarily from our net loss of $197.6 million, adjusted by a noncash charge of $3.4 million for accretion of discounts on short-term investments, $24.3 million for stock-based compensation expense, $7.0 million for noncash lease expense, and $1.2 million in noncash depreciation expenses.

Further, it was adjusted for a $17.1 million increase in accounts payable and accrued liabilities primarily due to increases in activities by our company, a $6.1 million increase in right-of-use assets due to adoption of the new lease accounting standard, and a $1.0 million decrease in prepaid expenses and other assets due to timing of certain upfront payments associated with our research agreements.

Net cash used in operating activities of $101.2 million for the year ended December 31, 2018, resulted primarily from our net loss of $123.6 million, adjusted by a noncash charge of $20.0 million for stock-based compensation expense, $1.0 million in noncash depreciation expenses, and $1.3 million in noncash accretion of premium on short-term investments.

Further, it was adjusted for a $4.7 million increase in accounts payable and accrued liabilities primarily due to increases in activities by our company and a $2.0 million increase in prepaid expenses and other assets due to timing of certain upfront payments associated with our research agreements.

Net cash used in operating activities of $78.7 million for the year ended December 31, 2017, resulted primarily from our net loss of $92.1 million, adjusted by a noncash charge of $12.0 million for stock-based compensation expense, $1.0 million in noncash depreciation expenses, a $4.9 million increase in accounts payable and accrued liabilities primarily due to increases in activities by our company, and a $4.5 million increase in prepaid expenses and other assets due to timing of certain upfront payments associated with our research agreements.

Net cash used in operating activities represents cash disbursements related to all of our activities other than investing and financing activities.

Operating cash flow is derived by adjusting our net loss for non-cash items and changes in operating assets and liabilities.

Net cash used in operating activities for the year ended December 31, 2020 increased by $46.2 million to $205.1 million in 2020 from $158.9 million for the same period in 2019.

The increase was primarily attributable to (i) a $62.0 million increase in net loss due to increased costs in research and development activities and growth of our corporate infrastructure, which was adjusted by (ii) a $16.6 million increase in stock-based compensation costs.

Included in $46.2 million of the increase in cash used in operating activities was the $10.0 million upfront payment we made to Novartis in connection with the license for IOV-3001.

Net cash used in operating activities for the year ended December 31, 2019 increased by $57.6 million to $158.9 million in 2019 from of $101.2 million for the same period in 2018.

The increase was primarily attributable to (i) a $73.4 million increase in net loss, which was adjusted by (ii) a $4.2 million increase in stock-based compensation expense, (iii) a $7.0 million increase in noncash lease expense.

Further, it was adjusted for a $11.2 million increase in accounts payable primarily due to increases in activities by our company and the timing of payments, which were offset by a $6.1 million increase in right-of-use assets due to the adoption of the new lease accounting standard.

Net cash used in operating activities for the year ended December 31, 2018 increased by $22.5 million to $101.2 million from $78.8 million in 2017.

The increase was primarily attributable to a $31.5 million increase in net loss, which was adjusted by a $8.1 million increase in stock-based compensation costs.

Investing Activities

Net cash provided by investing activities of $90.0 million for the year ended December 31, 2019, consisted primarily of $514.6 million of proceeds from the maturities of short-term investments, which was partially offset by $417.7 million used for the purchases of short-term investments and $6.9 million used for the purchase of property and equipment.

Net cash provided by investing activities of $386.3 million for the year ended December 31, 2018, consisted primarily of $426.1 million used for the purchase of short-term investments, $1.2 million used for the purchase of property and equipment, which was partially offset by $41.0 million of proceeds from the maturities of short-term investments

Net cash provided by investing activities of $58.7 million for the year ended December 31, 2017, consisted primarily of $59.7 million of proceeds from the maturities of short-term investments, offset by $1.0 million used for the purchase of property and equipment.

Net cash (used in) / provided by investing activities primarily consists of purchases, maturities of our short-term investments and capital expenditures.

Net cash used in investing activities for the year ended December 31, 2020 was $317.9 million compared to net cash provided by $90.0 million for the same period in 2019.

The increase in net cash used in investing activities was due primarily to a $368.0 million increase in net purchases of short-term investments from our June 2020 public offering and a $39.9 million increase in the purchase of property and equipment for the commercial manufacturing facility.

Net cash provided by investing activities for the year ended December 31, 2019 was $90.0 million compared to net cash used in investing activities of $386.3 million for the same period in 2018.

The increase in net cash provided in 2019 was due primarily to $482.0 million increase in net maturities of short-term investments, which was partially offset by a $5.7 million increase in the purchases of property and equipment.

Net cash used in investing activities for the year ended December 31, 2018 was $386.3 million compared to net cash provided in investing activities of $58.7 million for the same period in 2017.

The increase in net cash used in 2018 was due to our reinvestment of the proceeds from January 2018 public offering.

Financing Activities

Net cash provided by financing activities of $6.1 million for the year ended December 31, 2019, consisted primarily of $6.4 million of proceeds from the exercise of stock options, partially offset by $0.3 million in connection with tax payments made by our company in connection with vested restricted stock.

Net cash provided by financing activities of $424.3 million for the year ended December 31, 2018, consisted primarily of net proceeds of $162.0 million from the issuance of shares in January 2018 public offering at $11.50 per share after deducting expenses of the offering and $236.7 million from the issuance of shares in October 2018 public offering at $9.97 per share after deducting expenses of the offering, $15.8 million of proceeds from the exercise of warrants, and $10.0 million from the exercise of options.

Net cash provided by financing activities of $58.7 million for the year ended December 31, 2017, consisted primarily of net proceeds of $53.7 million from the issuance of shares in a private offering at $6.50 per share after deducting expenses of the offering, $5.6 million from the exercise of options, $0.7 million of proceeds exercise of warrants, offset by $1.3 million in connection with tax payments made by our company in connection with vested restricted stock.

Net cash provided by financing activities for the year ended December 31, 2020 was $576.4 million compared to net cash provided of $6.1 million for the same period in 2019.

The increase in net cash provided was primarily due to the cash proceeds of $567.0 million from the June 2020 public offering and a $3.2 million increase in proceeds from the exercise of stock options.

Net cash provided by financing activities for the year ended December 31, 2019 was $6.1 million compared to net cash provided of $424.3 million for the same period in 2018.

The decrease in net cash provided was due primarily to higher proceeds in 2018 obtained from the January 2018 public offering and exercise of warrants.

Net cash provided by financing activities of for the year ended December 31, 2018 was $424.3 million compared to $58.7 million for the same period in 2017.

The increase was primarily due to a $345.2 million increase in cash proceeds from the public offering in January 2018 as compared to the October 2017 public offering, and a $19.4 million increase in cash proceeds from the exercise of warrants and stock options.

Significant Accounting Policies and Recent Accounting Standards

See Note 2 of the financial statements for a discussion of our significant accounting policies, including the discussion of recently issued and adopted accounting standards.

The preparation of our consolidated financial statements requires us to make estimates and judgments that affect the reported amounts in the financial statements and related disclosures.

On an ongoing basis, we evaluate our significant accounting policies and estimates.

We base our estimates on historical experience and on various market-specific and other relevant assumptions that we believe to be reasonable under the circumstances, the results of which form the basis for making judgments about the carrying value of assets and liabilities that are not readily apparent from other sources.

Estimates are assessed each period and updated to reflect current information.

Actual results may differ from these estimates.

See Note 2 of the financial statements for a discussion of our significant accounting policies.

Contractual Obligations

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Milestone payments may be required, contingent upon the successful achievement of an important point in the development life-cycle of the pharmaceutical product (e.g., approval of the product for marketing by a regulatory agency).

If required by the arrangement, we may have to make royalty payments based upon a percentage of the sales of the pharmaceutical product in the

event that regulatory approval for marketing is obtained.

If required by the arrangement, we may have to make royalty payments based upon a percentage of the sales of the pharmaceutical product in the event that regulatory approval for marketing is obtained.

Because of the contingent nature of these milestone payments, they are not included in the table of contractual obligations.

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In addition, these arrangements often give us the discretion to unilaterally terminate development of the product, which would allow us to avoid making the contingent payments.

Our current non-cancelable contractual obligations as of December 31, 2019 that will require future cash payments are as follows (in thousands):

Our current non-cancellable contractual obligations as of December 31, 2020 that will require future cash payments are as follows (in thousands):

Payments due by period

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Operating lease obligations

Capital lease obligations

CMO contractual obligations

Purchase obligations

Operating lease obligations consist of obligations under non-cancelable operating leases for our facilities in San Carlos, CA, Philadelphia, PA, Tampa, FL, and New York, NY.

Contract Manufacturing Organization, or CMO, contractual obligations consist of embedded lease obligations for the manufacturing facilities and minimum fixed commitment fees included in our manufacturing contracts, such as personnel, general support fee, and minimum production or material fees.

See Note 10 in the notes to the consolidated financial statements.

Purchase obligations include purchase commitments primarily relating to our contract manufacturing with vendors for clinical materials with minimum purchase requirements.

Purchase orders for goods and services that are cancellable upon notice and without significant penalties are not included in the amounts above.

The contractual obligations table above excludes approximately $75 million to $85 million over three years for equipment and construction costs for our commercial-scale production facility under construction in Philadelphia, PA, for which we have latitude as to the timing and amount of expenditure.

See Note 10 of the financial statements.

The contractual obligations table above excludes approximately $40 million over the next year for equipment and construction costs for our commercial-scale production facility in Philadelphia, PA.

Impact of COVID-19 on our Business

Operations and Liquidity

The full impact of the COVID-19 pandemic is unknown and rapidly evolving.

While the potential economic impact brought by and over the duration of the COVID-19 pandemic may be difficult to assess or predict, the COVID-19 pandemic has resulted in significant disruption of global financial markets, which could in the future negatively affect our liquidity.

In addition, a recession or market volatility resulting from the COVID-19 pandemic could affect our business.

We have taken proactive, aggressive action throughout the COVID-19 pandemic to protect the health and safety of our employees, and expect to continue to implement these measures until we determine that the COVID-19 pandemic is adequately contained for purposes of our business.

We may take further actions as government authorities require or recommend or as we determine to be in the best interests of our employees.

We do not believe that the COVID-19 pandemic had a material impact on our liquidity or results of operations for the year ended December 31, 2020.

Further, to date, the COVID-19 pandemic has not had significant effects on our clinical trial enrollment.

Given the nature and type of our short-term investments in U.S.

government securities, we do not believe that the COVID-19 pandemic will have a material impact on our current investment liquidity.

Although there is uncertainty related to the anticipated impact of the recent COVID-19 pandemic on our future results, we believe our current cash reserves leave us well-positioned to manage our business through this crisis as it continues to unfold.

However, the impacts of the COVID-19 pandemic are broad-reaching and continuing and the financial impacts associated with the COVID-19 pandemic are still uncertain.

The COVID-19 pandemic is ongoing, and its dynamic nature, including uncertainties relating to the ultimate geographic spread of the virus, the severity of the disease, the duration of the pandemic, and actions that would be taken by governmental authorities to contain the pandemic or to treat its impact, makes it difficult to forecast any effects on our results for the fiscal year ending December 31, 2021.

Despite the economic uncertainty resulting from the COVID-19 pandemic, we intend to continue to focus on the development of our product candidates.

We continue to monitor the rapidly evolving situation and guidance from international and domestic authorities, including federal, state and local public health authorities and may take additional actions based on their recommendations.

In these circumstances, there may be developments outside our control requiring us to adjust our operating plan.

As such, given the dynamic nature of this situation, we cannot reasonably estimate the impacts of COVID-19 on our financial condition, results of operations or cash flows in the future.

Off-Balance Sheet Arrangements

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Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 7. Management’s Discussion and Analysis