What changed in this filing

/stocks — the workspaceLOADING

Item 1. Business

2022-02-24 compared with 2021-02-25 · 386 added, 355 removed, 671 unchanged (52% of the section changed)

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 of this therapy 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 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 head and neck squamous cell carcinoma, or HNSCC, and non-small cell lung cancer, or NSCLC, as well as in other solid tumor oncology indications through collaborations.

We are also investigating peripheral blood lymphocyte, or PBL, therapy for patients with relapsed or refractory chronic lymphocytic leukemia, or CLL, and small lymphocytic lymphoma, or SLL.

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

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

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

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

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

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

Our lead product candidates include lifileucel for metastatic melanoma and metastatic cervical cancer, as well as LN-145 for metastatic non-small cell lung cancer, or NSCLC.

In addition, we are investigating the effectiveness and safety of combinations of TIL therapy with immune checkpoint inhibitors, or ICIs, in metastatic melanoma, cervical cancer, NSCLC, and head and neck squamous cell carcinoma, or HNSCC.

We are investigating peripheral blood lymphocyte, or PBL, therapy for patients with relapsed or refractory chronic lymphocytic leukemia, or CLL, and small lymphocytic lymphoma, or SLL, through our sponsored trials.

We are developing first-in-class genetically edited TIL products based on the inactivation of genes that encode immune checkpoint proteins and other proteins, as well as the insertion of genes that encode immunomodulatory proteins.

We are also developing an alternative interleukin-2, or IL-2, co-therapy for use with TIL therapies.

Finally, we are investigating the potential for TIL therapy in other oncology indications and treatment settings through academic collaborations with leading cancer research centers.

Our current product candidate pipeline is summarized in the figure below:

TIL Monotherapy in Metastatic Solid Tumor Cancers

We have investigated TIL monotherapy in metastatic melanoma, cervical cancer, NSCLC and HNSCC.

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

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 biologics license application, or BLA, submission for lifileucel.

Cohort 4 of the C-144-01 clinical trial is a single-arm cohort intended to support the submission of a Biologics License Application, or BLA, to the FDA 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.

Results from Cohort 2 of the C-144-01 clinical trial were initially reported at the American Society of Clinical Oncology, or 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 objective response rate, or ORR, of 36%, as assessed by investigator, with 2 complete responses and 22 partial responses.

Results from Cohort 2 of the C-144-01 clinical trial were initially reported at the American Society of Clinical Oncology annual meeting, or ASCO, in June 2019 and most recently updated at ASCO in June 2021.

As of the data extract in April 2021, in 66 patients with metastatic melanoma in Cohort 2, treatment with lifileucel resulted in an objective response rate, or ORR, of 36%, as assessed by investigator, with 3 complete responses and 21 partial responses.

The disease control rate, or 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 duration of response, or 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.

Median duration of response, or DOR, in Cohort 2 had not been reached after 33.1 months of median study follow up.

Results from Cohort 2 presented at ASCO in June 2021 also suggest that early intervention with lifileucel at the time of initial progression on anti-PD-1 therapy may maximize benefit.

Patients in Cohort 2 were heavily pretreated and had a mean of 3.3 prior therapies.

We have previously 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.

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

In addition, detailed Cohort 2 data was published in the Journal of Clinical Oncology in May 2021.

Pivotal Cohort 4 of the C-144-01 trial was enrolled to evaluate ORR as read out by an Independent Review Committee, or IRC, as the primary endpoint based on our interpretation of discussions with the FDA as part of an End of Phase 2, or 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 Regenerative Medicine Advanced Therapy, or RMAT, designation from the FDA.

In October 2018, based on the data provided to the FDA during the EOP2 meeting, we announced that lifileucel had received a Regenerative Medicines Advanced Therapy, or 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.

A total of 87 patients were dosed with Gen 2 product released for Cohort 4.

In May 2020, we disclosed initial results from Cohort 4 for 68 patients with two radiological assessments, as determined by investigator.

Previously, we reported the submission of additional potency assay data to the FDA, and 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.

In May 2021, we announced that we had received regulatory feedback from the FDA regarding our potency assays for lifileucel.

Following FDA feedback, we have continued our ongoing work developing and validating our potency assays and have engaged in discussions with the FDA during the second half of 2021.

Our BLA submission for lifileucel in metastatic melanoma is expected to occur during the first half of 2022.

In connection with this BLA submission, the IRC is expected to independently assess responses for Cohort 4 patients through the data cut date, which must be completed prior to BLA submission or disclosure of IRC-read data.

We are also conducting a Phase 2 clinical trial, C-145-04, which is a multicenter pivotal trial to assess the safety and efficacy of our lead product candidate 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.

1 unchanged sentence

In May 2019, lifileucel received Breakthrough Therapy Designation, or 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.

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

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

4 unchanged sentences

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.

A more detailed description of these and other cohorts in the C-145-04 trial is provided in the section entitled “Lifileucel for Cervical Cancer” in this Annual Report on Form 10- K.

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.

In November 2019, we 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 chemotherapy and anti-PD-1/anti-PD-L1 therapy.

For example, because of recent regulatory approvals for pembrolizumab, there may be a potential shift from chemotherapy in front-line cervical cancer followed by pembrolizumab in second-line cervical cancer to the use of pembrolizumab in combination with chemotherapy in first-line cervical cancer.

We intend to execute our registrational strategy based on dialog and feedback from the FDA on these cohorts and continue to plan for a potential BLA submission 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 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 tumor proportion score, or 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.

Cohorts 1 and 3 of the IOV-LUN-202 clinical trial are enrolling patients with a PD-L1 TPS of less than one percent at the time they started front-line therapy, and Cohort 2 will enroll patients with a PD-L1 TPS of greater than or equal to one percent at the time they started front-line therapy.

Cohort 3 will also explore manufacturing TIL extracted from core biopsies using our third-generation, or Gen 3, manufacturing process.

In June 2021, we reported that the first patient was dosed in the IOV-LUN-202 clinical trial.

We intend to continue to enroll patients in the IOV-LUN-202 clinical trial throughout 2022.

We are engaged in regulatory discussions with the FDA on IOV-LUN-202 and intend to incorporate FDA feedback to optimize this clinical trial to support further registration in NSCLC.

In June 2021, we reported initial data for LN-145 in Cohort 3B of our IOV-COM-202 clinical trial in metastatic NSCLC.

IOV-COM-202 is a Phase 2, multicenter trial that is composed of seven cohorts.

Cohort 3B of IOV-COM-202 enrolled patients with metastatic NSCLC that had progressed on prior ICI therapy, including patients with oncogene-driven tumors who received prior tyrosine kinase inhibitor therapy.

Patients were treated with LN-145 monotherapy.

We reported results from Cohort 3B of the IOV-COM-202 trial in June 2021.

The ORR was 21.4% for the 28 patients in the analysis population, including one complete response and five partial responses, and the DCR was 64.3%, including two responders with PD-L1 negative tumors, and 3 responders who had primary refractory disease to checkpoint inhibitors.

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

All patients treated in Cohort 3B of the IOV-COM-202 trial received prior anti-PD-1/L1 therapy and all six responding patients also received prior chemotherapy.

Historically, ORRs of approximately 20% were reported with ICIs as second-line therapy in ICI-naïve patients who progressed on front-line chemotherapy.

We also provided an update on Cohort 3B at the Society for Immunotherapy in Cancer Annual Meeting, or SITC, in November 2021.

As of the data extract in August 2021, following one-time treatment with LN-145 monotherapy, the ORR remained at 21.4% for the 28 patients in the analysis population, and was 25% in the efficacy-evaluable set of 24 patients, including one complete response and five partial responses.

One complete response and one partial response were ongoing at 20.7 months and 3.0 months, respectively, at a median study follow up of 9.8 months.

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 metastatic HNSCC.

In October 2018, we reported that 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 Generation 3, or Gen 3, manufacturing process, and our PD-1 selected TIL manufacturing process.

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 non-small cell lung cancer, or 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 January 2021, we announced that we will close the C-145-03 clinical trial after the trial reached its pre-specified enrollment target.

TIL Combinations in Earlier Treatment Settings for Solid Tumors

We are investigating the potential of our TIL therapies in earlier lines of treatment in combination with pembrolizumab or other ICIs in cancer patients who are naïve to anti-PD-1 therapy.

ICIs are a class of immunotherapy drugs that seek to overcome one of cancer’s main escape mechanisms against an immune system attack.

PD-1 is a checkpoint protein found on immune cells called T cells that normally acts as a type of “off switch” which helps prevent T cells from attacking other cells in the body.

It is activated by binding to PD-L1, a protein found on both normal and cancerous cells, which thereby may shut down an attack by a T cell.

Some cancer cells have large amounts of PD-L1 expressed on their surfaces, which helps them evade T cell attack.

We are investigating the potential for our TIL therapy mechanism, together with checkpoint inhibition provided by ICIs, to improve response rates compared to ICIs alone in several sold tumor types, including in four cohorts in our IOV-COM-202 study in solid tumors as well as in one cohort in our C-145-04 clinical study in cervical cancer.

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.

A more detailed description of these and other cohorts in the C-145-04 trial is provided in the section entitled “Lifileucel and LN-145 in Combination with Pembrolizumab and Other Immunotherapies” in this Annual Report on Form 10-K.

In Cohort 1A of the IOV-COM-202 trial, we are enrolling advanced unresectable or metastatic melanoma patients who are naïve to anti-PD-1 therapy.

We reported results from ongoing Cohort 1A of the IOV-COM-202 trial at ASCO in June 2021, as follows, from the initial seven patients.

Seven patients received lifileucel in combination with pembrolizumab.

Six of the seven patients had a confirmed objective response, with an ORR of 86%, including two complete responses, one unconfirmed complete response who had not yet reached the confirmatory complete response assessment, and three partial responses, with one best response of stable disease.

The complete response rate, including the unconfirmed complete response, was 43%.

The median follow up was 8.2 months.

The Cohort 1A results also demonstrated that lifileucel can be safely combined with pembrolizumab.

In November 2021, we provided updated results from 10 patients in an oral presentation at SITC in which there was a demonstrated ORR of 60%.

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

Historically, ORRs of 33% and a CR rate of 6% have been reported for pembrolizumab monotherapy in metastatic melanoma.

Based on these results, we plan to expand enrollment in this cohort in early line melanoma in 2022.

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 Society for Immunotherapy in Cancer, or SITC, meeting in November 2020, as follows.

As of October 16, 2020, nine HNSCC patients 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.

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.

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.

Seven of the eight evaluable patients, or 87.5%, had a reduction in target lesions.

The DCR 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 human papilloma virus, or HPV,

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

The treatment emergent adverse events, or TEAEs, observed were 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 investigational new drug application, or 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.

Four patients were positive for Human Papilloma Virus, or HPV, three patients were HPV negative, and two patients had unknown HPV status.

In November 2021, we provided updated results from 18 patients in an oral presentation at SITC in which there was a demonstrated ORR of 38.9%.

Seven out of the 18 patients had an objective response, including one complete response, one unconfirmed complete response, four partial responses and one unconfirmed partial response.

Historically, ORRs of 17% have been reported for pembrolizumab monotherapy in patients with HNSCC.

Our oral presentation at SITC in November 2021 also included initial results from 14 patients treated with a combination of TIL therapy plus pembrolizumab in Cohort 3 of our C-145-04 cervical cancer study.

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

Cervical cancer patients previously treated with standard of care systemic therapy achieve an ORR of 11%-14% with pembrolizumab monotherapy.

The Cohort 1A and Cohort 2A results from the IOV-COM-202 study as well as Cohort 3 from the C-145-04 study demonstrated that lifileucel or LN-145 can be safely combined with pembrolizumab.

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

Two additional cohorts, Cohort 3A and 3C in the IOV-COM-202 study, explore LN-145/ICI combination therapies in NSCLC patients.

Cohort 3A is evaluating LN-145 in combination with pembrolizumab in patients with recurrent or metastatic NSCLC who have not received prior immunotherapy, including checkpoint inhibitors.

Cohort 3C is investigating LN-145 therapy in combination with ipilimumab and nivolumab in patients with recurrent or metastatic NSCLC who have previously received one line of approved checkpoint inhibitor monotherapy as the only prior line of systemic therapy.

In September 2021, we announced that our Iovance Cell Therapy Center, or the i CTC, had successfully manufactured and delivered its first clinical batch of LN-145 for the IOV-COM-202 trial, representing our first internally manufactured TIL product.

We continue to supply the IOV-COM-202 trial, and other ongoing trials, with both internally manufactured and externally manufactured TIL products.

Next-Generation and Genetically Modified Product Candidates

Our clinical pipeline also includes next generation TIL product candidates and manufacturing processes, as well as a cytokine-engrafted protein.

Our TIL candidate LN-145-S1, in which TIL are selected for PD-1 expression, is being investigated in post-anti-PD-1 melanoma in Cohort 1B of our IOV-COM-202 basket study as well as in post-anti-PD-1 HNSCC in Cohort 4 of our C-145-03 trial.

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

In November 2019, we announced that our Investigational New Drug, or IND, application for our PBL therapy, IOV-2001, was authorized by the FDA.

Our sponsored clinical trial using this therapy, IOV-CLL-01, was cleared to proceed and patient dosing began in 2020.

IOV-2001 is a non-genetically modified, polyclonal T cell product that is manufactured using a nine-day process starting 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 the MD Anderson Cancer Center, or 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 cancer, 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 Centre hospitalier de l’Université de Montreal, or 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, marrow infiltrating lymphocyte, or 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.

In January 2020, we announced a research collaboration and exclusive worldwide licensing agreement with Cellectis S.A., or Cellectis, a clinical-stage biopharmaceutical company focused on developing immunotherapies based on gene-edited allogeneic chimeric antigen receptor modified T cells.

The worldwide exclusive license enables us to use certain TALEN® technology addressing multiple gene targets to develop TIL that have been genetically modified to create potentially more potent cancer therapies for use in several cancer indications.

We are nearing completion of IND-enabling studies under this agreement and expect to initiate our first clinical study in 2022 of a genetically modified TIL product candidate, IOV-4001, in which the gene coding for the PD-1 protein is inactivated.

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.

In addition to IOV-4001, we are currently developing additional targets for genetic modification using the TALEN technology, including double-knock out programs in preclinical development.

We continue to explore additional transient and permanent genetic modifications of TILs.

For example, under the amended and restated patent license agreement we entered into in May 2021 with National Institutes of Health, or NIH, an agency of the U.S.

Public Health Service within the Department of Health and Human Services, we license a patent family related to cytokine-tethered TILs, which are intended to potentially expand and activate TILs to achieve better efficacy while avoiding systemic side effects of cytokines.

We are currently developing cytokine-tethered TIL products in preclinical studies.

In addition, 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 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.

We are currently conducting IND-enabling studies of this novel IL-2 analog.

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 S.A., or 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 transcription activator-like effector nuclease, or 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.

Investigator-Sponsored Trials

Through our academic collaborators, we are also exploring the potential for TIL therapies in additional indications.

As part of our collaboration program with The University of Texas M.D.

Anderson Cancer Center, or MDACC, two Phase 2 trials were initiated in 2018.

Both trials are sponsored by MDACC.

The first trial, NCT03449108, investigates 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, was previously active.

This trial treated patients with platinum resistant ovarian cancer, pancreatic and colorectal cancer with TIL manufactured by MDACC.

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

We also collaborate with many other academic institutions using our TIL therapies.

For example, a trial in collaboration with The Ohio State University, NCT05176470, is expected to start recruiting in 2022, and explores the use of lifileucel in high-risk melanoma in the neoadjuvant setting.

Corporate Strategy

Our goal is to be a leader in the development, and commercialization of TIL-based immunotherapies to treat solid tumors.

We are developing a portfolio of product candidates with the potential to meaningfully improve survival and quality of life for cancer patients.

We aim to be the global leader in innovating, developing and delivering TIL therapy for patients with cancer.

We are pioneering a 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, including gene-edited cell therapy, shorter manufacturing processes, and alternatives to IL-2 across a spectrum of tumor types including but not limited to melanoma, cervical cancer, NSCLC and HNSCC that may extend and improve life for patients with cancer.

Key elements of our strategy include:

Expedite clinical development, regulatory approval, and commercialization of our lead product candidate lifileucel for the treatment of metastatic melanoma.

Based on results of TIL therapy from trials sponsored by the NCI and our own clinical trials in metastatic melanoma, we are focused on expediting the development, regulatory approval and commercialization of our lead product candidate, lifileucel, for the treatment of patients with metastatic melanoma.

We filed an investigational new drug application, or IND, with the FDA in December 2014 to initiate a company-sponsored Phase 2 single-arm, multicenter clinical trial of lifileucel in patients with metastatic melanoma.

We began enrollment of this trial in the second half of 2015 and expanded it into three cohorts in 2017.

In 2019 we expanded into an additional cohort, Cohort 4, which serves as the basis for registration.

We held an end of Phase 2 meeting with the FDA in September 2018.

Based on the meeting and subsequent dialog with the FDA, we amended the protocol for the C-144-01 trial to include 75 patients in Cohort 4.

The primary endpoint is ORR as determined by IRC.

We have completed dosing of patients in Cohort 4, have reported preliminary results, and intend to file a BLA for lifileucel in metastatic melanoma in 2021.

Continue to improve our TIL manufacturing process and develop new TIL manufacturing technology to become the preferred provider of TIL therapy in the U.S.

Expedite clinical development, regulatory approval, and commercialization of our lead product candidate lifileucel for the treatment of metastatic melanoma as well as Iovance TIL and additional polyclonal cell therapies for cancer.

Based on results of TIL therapy from our own clinical trials in metastatic melanoma as well as trials sponsored by the NCI, we are focused on expediting the development, regulatory approval and commercialization of our lead product candidate, lifileucel, for the treatment of patients with metastatic melanoma.

We intend to file a BLA for lifileucel in metastatic melanoma in the first half of 2022.

We are also investigating TIL monotherapy as a one-time treatment for advanced cervical cancer and NSCLC patients who have progressed following standard of care treatments, TIL in combination with ICIs for melanoma, cervical, NSCLC and HNSCC as treatment in earlier disease settings, and a PBL therapy intended to address hematologic malignancies.

Continue to expand manufacturing capacity for TIL products.

We continue to invest in improving the process and efficiency of manufacturing our product candidates in the U.S.

and Europe for TIL manufacturing.

We began construction of the i CTC, our own manufacturing facility, in 2019, in Philadelphia, Pennsylvania, in order to provide for better margins and rapid implementation of innovative changes 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.

As of the end of 2021, we have completed commissioning activities and the i CTC had successfully manufactured and delivered first clinical batch of LN-145 for the IOV-COM-202 trial, representing our first internally manufactured TIL product.

Currently we use the i CTC as well as several contract manufacturing organizations, or CMOs, to supply our TIL-based products for our clinical trials under various manufacturing services agreements, or MSAs.

The use of CMOs is intended to supplement the manufacturing capacity at the i CTC.

In 2016, we entered into a three-year MSA and related statements of work with WuXi Advanced Therapies, Inc., or WuXi, for two current Good Manufacturing Practices, or cGMP, manufacturing suites to be established and operated by WuXi for us in order to increase our TIL manufacturing capacity in facilities with both clinical and commercial capability for two suites.

We have since extended our MSA with WuXi until February 2022 for the first suite and December 2022 for the second suite.

In 2017, we entered into a three-year MSA and related statements of work with PharmaCell B.V., or PharmaCell, a contract manufacturing services company based in the Netherlands, to manufacture our autologous cell therapy products for use in our

European clinical trials.

PharmaCell was subsequently acquired by Lonza Group Ltd., or Lonza.

Lonza continues to manufacture TIL products for our European clinical trials in its clinical and commercial facility in Geleen, the Netherlands.

We have since extended our agreements with Lonza until April 2022.

Also in 2017, we entered into a two-year MSA and related statements of work with Moffitt, to manufacture our autologous cell therapy products for use in clinical trials, which has since been extended until March 2025.

Moffitt continues to manufacture TIL products for our clinical trials in the U.S.

Continue to improve our TIL manufacturing processes and develop new TIL manufacturing technology to become the preferred provider of TIL therapy in the U.S.

and the rest of the world.

We are currently manufacturing TIL for our ongoing clinical studies at the i CTC and remain on track to provide commercial supply from this facility upon potential BLA approval.

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

3 unchanged sentences

The Gen 2 manufacturing process was utilized in Cohort 2 and Cohort 4 of our C-144-01 trial and has also been selected for use in most of our ongoing TIL clinical development program.

We have included Gen 2 as the manufacturing process for registration for our discussions with the FDA and eventually the anticipated BLA filing for lifileucel.

We have included Gen 2 as the manufacturing process for registration for our discussions with the FDA and the anticipated BLA filing for lifileucel.

Our strategy is to establish our Gen 2 process as a commercial manufacturing process for TIL therapies, including lifileucel.

We also continue to develop and evaluate potential future TIL manufacturing processes, including our Gen 3 process and our LN-145-S1 process.

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

Collaborate with governmental, academic and corporate partners to improve and develop TIL and PBL therapies for new indications or for use in combination with other therapies, and to evaluate new manufacturing methods.

In addition to our own research and process development efforts, we seek to collaborate with government, academic research institutions, and corporate partners to improve TIL manufacturing and to develop TIL therapies for new indications.

For example, we have ongoing licensing agreements and collaborations with Moffitt, MDACC, Yale University, Cellectis, and Novartis to evaluate several new solid tumor and hematologic indications for TIL and PBL therapy in clinical and preclinical studies as well as, in some cases, new TIL manufacturing approaches.

In August 2016, we expanded our Cooperative Research and Development Agreement, or CRADA, with the NCI for another 5-year term.

This collaboration with the NCI is directed at research on unmodified TIL therapy and also addresses human papilloma virus, or HPV-associated cancers (cervical and head and neck), lung, bladder, and breast cancer.

For example, we have ongoing licensing agreements and collaborations with Moffitt, MDACC, Yale University, Cellectis, Novartis, Melanoma Institute Australia, or MIA, and Beth-Israel Deaconess Medical Center, or BIDMC, to evaluate several new solid tumor and hematologic indications for TIL and PBL therapy in clinical and preclinical studies as well as, in some cases, new TIL manufacturing approaches.

In August 2021, we extended our Cooperative Research and Development Agreement, or CRADA, with the NCI for another 3-year term.

This collaboration with the NCI is directed at research on unmodified TIL therapy and also addresses HPV-associated cancers (cervical and head and neck), lung, bladder, and breast cancers.

This collaboration also focuses on Strategies to expand TIL with less differentiated and more stem-like attributes which may result in improved persistence, functionality, and better anti-tumor activity.

For example, in December 2021 we presented data at ESMO Immuno-oncology 2021 that demonstrated temporally inhibiting AKT signaling during ex vivo TIL expansion enhances cytokine production and function while increasing the population of less differentiated (CD39/CD69) CD8+T-Cells.

A description of certain of these collaborations and related agreements is provided in the following sections of this Annual Report on Form 10-K.

Continue to establish manufacturing capacity for TIL products.

We continue to invest in improving the process and efficiency of manufacturing our product candidates in the U.S.

and Europe for TIL manufacturing.

Currently we use several contract manufacturing organizations, or CMOs, to supply our TIL-based products for our clinical trials under various manufacturing services agreements, or MSAs.

CMOs limit the amount of upfront capital investment as they have existing manufacturing facilities that we can utilize in TIL production.

We began construction of our own manufacturing facility in 2019, in Philadelphia, Pennsylvania, in order to provide for better margins and rapid implementation of innovative changes for TIL therapies that we may develop or commercialize.

As of the start of 2021, we have completed most construction and commissioning activities and expect that our manufacturing facility will begin clinical manufacturing in 2021.

In 2016, we entered into a three-year MSA and related statements of work with WuXi AppTec, Inc., or WuXi, in order to increase our TIL manufacturing capacity in facilities with both clinical and commercial capability for two suites.

We have since extended our MSA with WuXi until November 2021.

In October 2018, we entered into a three-year MSA and related statement of work with MaSTherCell S.A., or MaSTherCell, a cell therapy CMO that is a subsidiary of Orgenesis Inc., which was acquired by Catalent, Inc.

Pursuant to the MSA, MaSTherCell agreed to provide manufacturing and other services for use in our European clinical trials.

In December 2019, we provided MaSTherCell with a notice of termination for the statement of work for cell therapy manufacturing.

We ceased manufacturing at MaSTherCell in 2020.

PharmaCell was subsequently acquired by Lonza Group Ltd., or Lonza.

Lonza continues to manufacture TIL products for our European clinical trials in its clinical and commercial facility in Geleen, the Netherlands.

We have since extended our agreements with Lonza until April 2022.

Moffitt continues to manufacture TIL products for our clinical trials in the U.S.

Iovance-Sponsored Clinical Trials

2 unchanged sentences

C-145-04, of our product candidate lifileucel for recurrent, metastatic or persistent cervical cancer;

and C-145-03, of our product candidate LN-145, for recurrent and/or metastatic HNSCC, which we are closing because the trial has reached the protocol’s defined enrollment.

During 2018, we initiated a Phase 2 clinical trial, IOV-COM-202, a basket trial that will treat checkpoint naïve patients with TIL in combination with pembrolizumab for metastatic melanoma, head and neck cancer and non-small cell lung cancer.

The trial also includes a cohort that will treat relapsed and refractory NSCLC patients with TIL alone as well as a cohort for NSCLC for TIL in combination with ipilimumab and nivolumab.

Additional melanoma cohorts

are offered in this trial as well.

In 2019, we announced that the FDA had cleared our Phase 1/2 clinical trial, IOV-CLL-01, using our PBL therapy, IOV-2001, to proceed.

In 2020, we initiated a clinical tri al, IOV-LUN-202, in NSCLC, which is now recruiting.

IOV-LUN-202, a potentially registration-supporting study of our product candidate LN-145 in NSCLC;

IOV-COM-202, a basket trial that will treat three cohorts of checkpoint naïve patients with TIL therapy in combination with pembrolizumab for metastatic melanoma, HNSCC and NSCLC, a cohort that will treat relapsed and refractory NSCLC patients with TIL monotherapy, as well as a cohort for NSCLC for TIL therapy in combination with ipilimumab and nivolumab.

Additional melanoma cohorts are offered in this trial as well to investigate Gen 3 manufacturing and PD-1 selected TIL.

In 2021, we completed enrollment in an additional study, C-145-03, of LN-145, for recurrent and/or metastatic HNSCC.

We are also investigating polyclonal T cell therapy in blood cancers.

Our Phase 1/2 clinical trial, IOV-CLL-01, is enrolling patients with CLL/SLL to receive our PBL therapy, IOV-2001.

Additional information about our clinical trials is presented as follows:

2 unchanged sentences

Melanoma is a common type of skin cancer, accounting for approximately 106,110 patients diagnosed and 7,180 deaths each year in the U.S.

according to the NCI’s Surveillance, Epidemiology and End Results program, or SEER program, as of 2020.

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

Our Phase 2 trial, C-144-01, is a prospective, registrational, four-cohort interventional study evaluating lifileucel in metastatic melanoma patients who have progressed after prior anti-PD-1 therapy and if BRAF mutant, after BRAF or BRAF/MEK inhibitor therapy.

Patients enrolled in this trial to date have failed several prior treatment regimens.

Lifileucel has received a Regenerative Medicine Advanced Therapy, or RMAT, designation from the FDA in metastatic melanoma.

Lifileucel has received a RMAT designation from the FDA in metastatic melanoma.

Patients with metastatic melanoma who have failed at least one treatment under the current standards of care have an unfavorable prognosis with very few curative treatment options.

The National Comprehensive Cancer Network, or NCCN, makes recommendations for the treatment of patients with unresectable or metastatic melanoma.

Initial therapy can include checkpoint inhibitors either alone or in combination (ipilimumab, nivolumab, pembrolizumab), targeted therapies for patients with BRAF mutations (dabrafenib/trametinib, vemurafenib/cobimetinib combinations or single agents) or participating in a clinical trial.

For patients not responding or progressing and who have an adequate clinical status, agents selected from the previous list or of a different therapeutic class can be used as well as high dose IL-2.

1 unchanged sentence

Patients who do not respond to the current second-line therapies have very few treatment options and typically have a very poor prognosis, with limited median survival measured in months.

According to estimates from SEER in the U.S.

in 2019, approximately there were 7,230 deaths due to melanoma.

According to estimates from the SEER program, there were approximately 7,180 deaths due to melanoma.

If approved, we believe lifileucel may be able to treat a portion of the patients that have received all other approved treatment options.

We are using our Gen 2 manufacturing process for most of our ongoing Phase 2 trials, and as a result, Cohort 1 of C-144-01, using our Generation 1, or Gen 1, manufacturing process, was closed to enrollment in 2017 and subsequent patients were enrolled in Cohort 2.

C-144-01 is investigating lifileucel in advanced melanoma patients who have been treated with at least one systemic therapy including an anti-PD-1 antibody, and if BRAF mutation positive, a BRAF inhibitor or BRAF inhibitor with MEK inhibitor.

The planned enrollment in C-144-01 was reached in late 2018 and Cohort 2 is closed to enrollment.

Cohort 3 is a retreatment cohort.

Cohort 4, a pivotal cohort, was added in 2019 and has completed dosing.

Updated results from Cohort 2 of the C-144-01 clinical trial were initially reported at the ASCO annual meeting in June 2019 and subsequently updated at the SITC annual meeting in November 2019.

Cohort 4, a pivotal cohort, was added in 2019 and completed dosing in January 2020.

Clinical results from Cohort 2 in the C-144-01 clinical study have been presented at several medical meetings.

Initial results from Cohort 2 were initially reported at ASCO in June 2019 and most recently updated at ASCO in June 2021.

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

1 unchanged sentence

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

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.

In June 2021, we announced that median DOR in Cohort 2 had still not been reached after 33.1 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.

We held an End of Phase 2 meeting with the FDA in September 2018 to discuss the C-144-01 study.

In its written minutes to the meeting, the FDA acknowledged that conduct of a randomized Phase 3 study may not be feasible in its intended population of advanced melanoma patients, who have been treated with at least one systemic therapy including an anti-PD-1 antibody and if BRAF mutation positive, a BRAF inhibitor or BRAF inhibitor with MEK inhibitor, and that a randomized study is not required for the registration of lifileucel.

The FDA further acknowledged that a single-arm cohort of the C-144-01 trial may be acceptable for registration in this indication.

A new cohort, Cohort 4, of 75 patients was enrolled in C-144-01 with a prospective definition of the primary endpoint of ORR to be determined by IRC, to support registration of lifileucel.

The FDA recommended that we validate a potency assay prior to starting Cohort 4, which we have done.

We initiated Cohort 4 in early 2019 in the U.S.

and in Europe and completed dosing 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.

In Cohort 4, lifileucel showed a 32.4% ORR, including one complete response and 21 partial responses, two of which are yet to be confirmed with follow up visits, 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.

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 until a date expected to occur in 2021 as a result of FDA feedback, in order to allow us to simultaneously refine existing and develop new potency assays.

Food and Drug Administration, or the FDA, as part of an End of Phase 2, or 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 Regenerative Medicines Advanced Therapy, or 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 with Gen 2 product released for Cohort 4.

In May 2020, we disclosed initial results from Cohort 4 for 68 patients with two radiological assessments, as determined by investigator.

In May 2021, we announced that we had received regulatory feedback from the FDA regarding our potency assays for lifileucel.

Following FDA feedback, we have continued our ongoing work developing and validating our potency assays and have engaged in discussions with the FDA during the second half of 2021.

Our BLA submission for lifileucel in metastatic melanoma is expected to occur during the first half of 2022.

Lifileucel for Cervical Cancer

6 unchanged sentences

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.

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

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

5 unchanged sentences

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 End of Phase 2 meeting held with the FDA in June 2019, the FDA has acknowledged that results from the C-145-04 clinical trial may be sufficient to support registration of lifileucel in 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 amended the C-145-04 trial to collect additional data on early-line patients as well as late-line patients.

These additional cohorts also allow access to TIL therapy when the pivotal Cohort 1 is completed and also may support a request from FDA to provide expanded access to lifileucel.

Enrollment in these additional cohorts will not impact the timing of the completion of the pivotal cohort nor the size of the registrational program.

Based on an EOP2 meeting held with the FDA in June 2019, the FDA has acknowledged that results from the C-145-04 clinical trial may be sufficient to support registration of lifileucel in 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 Cohort 1 as outlined below.

In November 2019, in order to evaluate lifileucel in additional lines of therapy in cervical cancer and to address the emerging treatment landscape, we amended the C-145-04 trial to collect additional data on combination therapy in early-line patients as well as TIL alone in late-line patients.

These additional cohorts also allowed access to TIL therapy when the pivotal Cohort 1 was completed.

The C-145-04 trial currently consists of the following cohorts of cervical cancer patients with recurrent, persistent, or metastatic disease:

● Cohort 1 has completed enrollment in patients who have progressed during or after chemotherapy;

● Cohort 2 has closed enrollment to patients for treatment with lifileucel who have progressed during or after treatment with anti-PD-1/anti-PD-L1 checkpoint inhibitor;

● Cohort 1 has completed enrollment in patients who have progressed during or after systematic chemotherapy;

● Cohort 2 has closed enrollment to patients for treatment with lifileucel who have progressed during or after treatment with anti-PD-1/anti-PD-L1 checkpoint inhibitor in addition to systematic chemotherapy;

● Cohort 3 is enrolling patients who have not received prior systemic therapy for recurrent, metastatic, or persistent disease , and will explore safety and efficacy of the combination of the lifileucel regimen with pembrolizumab;

● Cohort 4 includes patients who have been previously enrolled but are not considered within the registrational population, including patients dosed with product produced by our Gen 1 TIL manufacturing process;

● Cohort 5 will enroll patients for retreatment with LN-145 for patients who have progressed after initial treatment with lifileucel .

The sample size of the C-145-04 clinical trial is expected to include 138 patients from the appropriate patient populations across these five cohorts.

As we continue our work to refine existing and develop new potency assays to support our BLA submission for lifileucel in the treatment of metastatic melanoma, Cohort 2 may be supportive for an expected BLA submission for lifileucel in cervical cancer to further address the emerging treatment landscape for this disease.

● Cohort 4 includes patients who have been previously enrolled but do not fit Cohort 1-3, including patients dosed with product produced by our Gen 1 TIL manufacturing process;

● Cohort 5 is enrolling patients for retreatment with LN-145 for patients who have progressed after initial treatment with lifileucel .

Given the emerging treatment landscape in cervical cancer, including the approval of pembrolizumab in combination with chemotherapy as a first-line treatment, we are engaging with the FDA to discuss our planned BLA submission and intend to execute our strategy based on feedback from the FDA for the BLA.

LN-145 for NSCLC

We are developing LN-145 to treat NSCLC.

We are developing LN-145 alone and in combination with approved therapies to treat NSCLC.

According to estimates from the SEER program, approximately 235,760 people were diagnosed with lung and bronchus cancers, and approximately 131,880 deaths occurred related to these cancers in the U.S.

The IOV-LUN-202 clinical trial, which is open to recruitment as of January 2021, includes three cohorts.

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

The IOV-LUN-202 clinical trial, which continues to enroll patients, includes three cohorts.

Cohorts 1 and 3 of the IOV-LUN-202 clinical trial are enrolling patients who presented with a PD-L1 tumor proportion score, or TPS, of less than one percent at the time they started front-line therapy.

Cohort 2 is enrolling patients with a PD-L1 TPS of greater than or equal to one percent at the time they started front-line therapy.

In Cohort 3 we are exploring LN-145 manufactured from core biopsy using our Gen 3 manufacturing process.

Patient dosing commenced in IOV-LUN-202 in the second quarter of 2021 and we intend to continue to enroll patients in the IOV-LUN-202 clinical trial throughout 2022.

LN-145 for Head and Neck Cancer

5 unchanged sentences

The safety findings from this study were also consistent with previous reports.

The most common treatment emergent adverse events observed at the time of that data cut included chills, hypotension, pyrexia, hyponatremia, and anemia.

The most common TEAEs observed at the time of that data cut included chills, hypotension, pyrexia, hyponatremia, and anemia.

As additional results are reported for the C-145-03 study, the safety profile of LN-145 may change.

We changed the design of our C-145-03 trial so that enrolled patients would also be treated using either LN-145 produced from the Gen 3 manufacturing process or PD-1 selected TIL, or LN-145-S1, from the PD-1 selected TIL manufacturing process in two separate cohorts.

We changed the design of our C-145-03 trial in 2020 so that enrolled patients would also be treated using either LN-145 produced from the Gen 3 manufacturing process or PD-1 selected TIL, known as LN-145-S1, from the PD-1 selected TIL manufacturing process in two separate cohorts.

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

Lifileucel and LN-145 in Combination with Pembrolizumab and Other Immunotherapies

In addition to the trials for lifileucel and LN-145 mentioned above, we are developing these products in alone or in combination with pembrolizumab or other immunotherapies for melanoma, head and neck and NSCLC in our clinical trial IOV-COM-202, a Phase 2, multicenter trial that is composed of seven cohorts.

In addition to the trials for lifileucel and LN-145 mentioned above, we are developing these products alone or in combination with pembrolizumab or other ICIs for melanoma, head and neck and NSCLC in our clinical trial IOV-COM-202, a Phase 2, multicenter trial that is composed of seven cohorts.

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

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

In January 2021, we announced that we were adding two additional cohorts to the IOV-COM-202 trial, Cohorts 1C and 3C, as described below.

In addition to the U.S., the IOV-COM-202 trial has active sites in Canada and in certain European countries.

The IOV-COM-202 trial now consists of the following cohorts of patients:

● Cohort 1A is enrolling at least 12 patients with advanced unresectable or metastatic melanoma who have not received prior immunotherapy, including checkpoint inhibitors such as anti-PD-1/anti-PD-L1 therapy , for treatment with lifileucel in combination with pembrolizumab ;

● C ohort 1B is enrolling up to 27 melanoma patients who have progressed during or after treatment with anti-PD-1/anti-PD-L1 checkpoint inhibitor and if BRAF mutant, after BRAF or BRAF/MEK inhibitor therapy for treatment with LN-145-S1;

● C ohort 1C will enroll up to 27 melanoma patients who have progressed during or after treatment with anti-PD-1/anti-PD-L1 checkpoint inhibitor and if BRAF mutant, after BRAF or BRAF/MEK inhibitor therapy, for treatment with LN-145 manufactured using our Gen 3 process;

● C ohort 2A is enrolling at least 19 patients with advanced, recurrent, or metastatic HNSCC who are naïve to prior immunotherapy including anti-PD-1/anti-PD-L1 therapy, for treatment with LN-145 in combination with pembrolizumab ;

● C ohort 3A is enrolling at least 12 patients with NSCLC who are naïve to prior immunotherapy including anti-PD-1/anti-PD-L1 therapy , for treatment with LN-145 in combination with pembrolizumab ;

● C ohort 3B is enrolling at least 12 patients with NSCLC who have previously received systemic therapy, which could include checkpoint inhibitors or tyrosine kinase inhibitors, for treatment with LN-145 alone;

● C ohort 3C will enroll up to 26 patients with NSCLC who have progressed after initial treatment with lifileucel.

The sample size of the IOV-COM-202 clinical trial is expected to include up to 135 patients from the appropriate patient populations across these seven cohorts.

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, 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 human papilloma virus, or HPV, positive, three patients were HPV negative, and two patients had unknown HPV status.

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.

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

patients with advanced unresectable or metastatic melanoma who have not received prior immunotherapy, including checkpoint inhibitors such as anti-PD-1/anti-PD-L1 therapy , for treatment with lifileucel in combination with pembrolizumab ;

● C ohort 1B:

melanoma patients who have progressed during or after treatment with anti-PD-1/anti-PD-L1 checkpoint inhibitor and if BRAF mutant, after BRAF or BRAF/MEK inhibitor therapy for treatment with LN-145-S1;

● C ohort 1C:

melanoma patients who have progressed during or after treatment with anti-PD-1/anti-PD-L1 checkpoint inhibitor and if BRAF mutant, after BRAF or BRAF/MEK inhibitor therapy, for treatment with LN-145 manufactured using our Gen 3 process;

● C ohort 2A:

patients with advanced, recurrent, or metastatic HNSCC who are naïve to prior immunotherapy including anti-PD-1/anti-PD-L1 therapy, for treatment with LN-145 in combination with pembrolizumab ;

● C ohort 3A:

patients with NSCLC who are naïve to prior immunotherapy including anti-PD-1/anti-PD-L1 therapy , for treatment with LN-145 in combination with pembrolizumab ;

● C ohort 3B:

patients with NSCLC who have previously received systemic therapy, which could include checkpoint inhibitors or tyrosine kinase inhibitors, for treatment with LN-145 alone;

● C ohort 3C:

patients with NSCLC who have progressed after one prior systemic therapy for treatment with LN-145 in combination with ipilimumab/nivolumab.

IOV-2001 PBL for CLL or SLL

In November 2019, we announced that our investigational new drug application, or IND, for IOV-2001 was approved by the FDA and that 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.

In November 2019, we announced that our IND for IOV-2001 was approved by the FDA and that 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 a patient's blood sample.

IOV-2001 is under investigation in a Phase 1/2 clinical trial for the treatment of CLL or SLL.

Patients experiencing disease relapse during ibrutinib or acalabrutinib therapy treatment are eligible for this clinical trial.

Preclinical studies of IOV-2001 have shown activity against autologous leukemia cancer cells, while treatment with ibrutinib and acalabrutinib has been demonstrated to improve the proliferation and effector functions of the IOV-2001 manufactured product.

Investigator-Sponsored Clinical Trials

TIL in Other Solid Tumor Indications

We are collaborating with MDACC on clinical trials to evaluate TIL therapy in sarcomas, ovarian, colorectal, thyroid, and pancreatic cancers.

These trials, NCT03610490 and NCT03449108, began enrolling patients in 2018.

Patients in these trials are being treated with LN-145 or LN-145-S1 manufactured by us and TIL manufactured by MDACC.

We are also collaborating with Yale University on a clinical trial to evaluate TIL therapy in TNBC, which opened for enrollment in 2020.

TIL Therapy in Other Solid Tumor Indications

We are collaborating with MDACC on a clinical trial to evaluate TIL therapy in sarcomas, ovarian, and thyroid cancers.

These trials, including NCT03449108, began enrolling patients in 2018.

Patients in these trials are being treated with LN-145 or LN-145-S1 manufactured by us.

We are also collaborating with Yale University on a clinical trial to evaluate TIL therapy in triple-negative breast cancer, or TNBC, NCT04111510, which opened for enrollment in 2020.

Patients in this trial will be treated with LN-145 manufactured by us.

TIL in Combination with Other Immunotherapy Drugs

Checkpoint inhibitors are a class of immunotherapy drugs that seek to overcome one of cancer’s main defenses against an immune system attack.

PD-1 is a checkpoint protein found on immune cells called T cells.

It normally acts as a type of “off switch” that helps prevent T cells from attacking other cells in the body.

It does this by attaching to PD-L1, a protein found on both normal and cancerous cells, which may then shut down an attack by a T cell.

Some cancer cells have large amounts of PD-L1 expressed on their surfaces, which helps them evade T cell attack.

We are also collaborating with Moffitt on a clinical trial, NCT04052334, to explore MCC TIL in adolescent and young adult patients with soft tissue sarcoma.

TIL Therapy in Combination with Other Immunotherapy Drugs and/or in Earlier Lines of Therapy

We provide funding for a clinical trial, NCT03215810, conducted by Moffitt, which seeks to evaluate TIL therapy in combination with the checkpoint inhibitor nivolumab in NSCLC.

4 unchanged sentences

Under our CRADA, we are collaborating with the NCI on a clinical trial, NCT02621021, to evaluate TIL therapy in combination with the checkpoint inhibitor pembrolizumab in a 170-patient clinical trial in patients with advanced melanoma.

Enrollment in this trial is currently suspended.

We are collaborating with The Ohio State University to evaluate TIL therapy in high-risk melanoma in the neoadjuvant setting.

This trial, NCT05176470, is expected to begin recruiting patients in 2022 who are diagnosed with stage IIIB-D melanoma that has spread to nearby tissue or lymph nodes (locally advanced).

Patients in this trial will be treated with lifileucel manufactured by Iovance.

The purpose of the study is to assess the feasibility of TIL expansion from all screened eligible patients who have had tumor-involved lymph nodes removed.

TIL Therapy Background

8 unchanged sentences

Some reasons solid tumors are so difficult to treat are:

(i) in many solid tumors, multiple genes (as many

as hundreds or thousands of genes) are mutated, and solid tumors are heterogeneous, (ii) it is not always clear which particular mutations are critical, and (iii) tumors can adapt and find a way to evade treatments that target a single mutation.

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

(i) in many solid tumors, there are multiple genomic mutations, as well as intratumoral heterogeneity, (ii) there are numerous tumor neoantigens, with <1% of them being shared across patients with the same tumor histology and it is not always clear which particular mutations are critical, and (iii) solid tumors can adapt and find a way to 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.

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

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

These one-time cellular therapies may avoid the long-term side effects associated with current treatments and have the potential to be effective.

We believe TIL therapy, in particular, has the potential to treat solid tumors by increasing the effectiveness and number of a patient’s cancer-specific T cells.

TIL therapy has the potential to treat solid tumors by increasing the effectiveness and number of a patient’s cancer-specific T cells.

TIL therapy is polyclonal, and we believe that it is capable of targeting multiple tumor antigens on cancer cells.

1 unchanged sentence

Tumor-Infiltrating Lymphocytes

TIL therapy involves the following steps:

Our Gen 2 TIL therapy involves the following steps:

Remove tumor sample:

A surgical biopsy is conducted to remove about 1.5 cm of the tumor.

The tumor is fragmented and placed in media for TIL to leave the tumor

TIL are expanded exponentially ex vivo to yield 10 9 – 10 11 TIL

Preparation and Infusion:

The patient receives NMA lymphodepletion to eliminate potentially suppressive tumor microenvironment and maximize engraftment and potential potency of TIL therapy;

the patient is infused with their expanded TIL and up to 6 doses of IL-2 to promote activation, proliferation and anti-tumor cytolytic activity of TIL

Currently, our Gen 2 manufacturing process takes 22 days from receipt of the patient’s tumor at the manufacturing facility until shipping of the final TIL product to the institution for infusion of the TIL back into the patient.

We currently treat patients with a single infusion of TIL product, although our protocols allow for evaluation of more than one administration of TIL product.

Expand and rejuvenate patient-specific T cells using proprietary process:

The tumor is fragmented to facilitate a clear path for TIL to leave the tumor tissue and placed in media.

The ingredients and conditions in the culture media optimize the growth of TIL rather than other cell types.

TIL are expanded exponentially ex vivo to yield billions (10 9 – 10 11 ) of TIL using our Gen 2 process.

Our Gen 2 manufacturing process takes 22 days from receipt of the patient’s tumor at the manufacturing facility until cryopreservation of a product ready for shipping of the final TIL product to the institution for infusion of the TIL back into the patient.

Initially cells grow slowly during the pre-rapid expansion, or pre-rep, phase (day 0-11) followed by a rapid expansion, or REP phase (day 11-22).

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 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.

TIL are filtered, washed, concentrated and finally formulated with cryopreservation media on Day 22.

Up to four final product bags are then prepared on Day 22, depending on total cell count.

Lymphodepletion and infusion:

To prepare for TIL infusion, patient receives NMA lymphodepletion to eliminate potentially suppressive tumor microenvironment and maximize engraftment and potential potency of TIL therapy;

the patient is infused with their expanded TIL and subsequently administered up to 6 doses of IL 2 to promote T-cell activity.

We currently treat patients with a single infusion of TIL product, although our protocols allow for more than one administration of TIL product.

After infusion, TIL can potentially infiltrate the tumor microenvironment to eliminate large numbers of cancer cells.

TIL can also further proliferate in the body.

TIL therapy can potentially overcome several mechanisms of tumor escape to which endogenous T cells may

be susceptible due to the hostile tumor microenvironment.

TIL therapy can potentially overcome several mechanisms of tumor escape to which endogenous T cells may be susceptible due to the hostile tumor microenvironment.

In September 2020, we reported data at the European Society for Medical Oncology conference highlighting the reinvigoration of TIL during the Gen 2 manufacturing process.

1 unchanged sentence

To date, hundreds of metastatic melanoma patients have already been 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 NCI, clinical responses have been relatively consistent in several trials:

over 50% of the melanoma patients treated with TIL have an objective response (i.e., tumor regression of 30% or more, as defined by RECIST criteria) and approximately 22-24% of patients have a complete response (tumor regression of 100%) with no evidence of disease remaining after only one administration.

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

over 50% of the melanoma patients treated with TIL achieved an objective response (i.e., tumor regression of 30% or more, as defined by RECIST criteria) and approximately 22-24% of patients have a complete response (tumor regression of 100%) with no evidence of disease remaining after only one administration.

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

6 unchanged sentences

54% of the patients treated with TIL therapy achieved an objective response.

An objective response occurs when there is a complete remission or a partial remission of the tumor.

Out of the 101 patients, 24, or 24%, had experienced a complete remission and 23 of the 24, or 96%, showed ongoing durability of this response at 30 to 47 months following treatment, at the time of publication.

Out of the 101 patients, 24, or 24%, had experienced a complete response and 23 of the 24, or 96%, showed ongoing durability of this response at 30 to 47 months following treatment, at the time of publication.

Median follow-up time was approximately 40.9 months.

5 unchanged sentences

Goff presented updated findings from the trial.

Patients that had prior anti PD-1 treatment had an ORR of 20-25%.

Overall Survival of patients in TIL ± TBI clinical trial

Randomized, Prospective Evaluation Comparing Intensity of Lymphodepletion Before Adoptive Transfer of Tumor-Infiltrating Lymphocytes for Patients with Metastatic Melanoma.

Journal of Clinical Oncology, 34(20), 2389-2397.

Notably, patients that had prior anti PD-1 treatment had an ORR of 20-25%.

In August 2021, Seitter, et al., in a collaboration led by Dr.

Rosenberg from the Surgery Branch of the NCI, published in Clinical Cancer Research the patient outcomes based on two decades of experience with TIL therapy in metastatic melanoma.

The ORR in the entire cohort of 226 patients was 51%, with a complete response rate of 22%.

The median overall survival and median melanoma-specific survival were 20.6 months and 22.2 months, respectively.

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

The ORR in the 192 patients who had not received anti-PD-1 therapy as a prior line of therapy 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, there was no difference in the response rate (60%), when compared to those naïve to any immune checkpoint therapy (55%).

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

Prior therapies including refractoriness to anti-PD-1 and BRAF/MEK inhibitors affected outcome compared to patients who had no exposure to these agents.

Out of the 226 patients reported, 34 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 refractory to BRAF/MEK inhibitors regardless of prior anti-PD-1 exposure with a median survival of 8.7 months (refractory to both anti-PD-1) and 12.1 months (naïve to anti-PD-1).

Clinical Results with TIL in Other Solid Tumor Indications

The NCI has an ongoing clinical trial involving TIL therapy to treat advanced HPV-positive cervical cancer.

Data from this trial was published in the Journal of Clinical Oncology in April 2015 and in Science in April 2017 and was updated at the ASCO meeting in 2018.

Out of 18 cervical cancer patients treated with HPV-TIL, two experienced complete remissions reported as ongoing at 53 and 67 months.

Another three patients experienced a three-month partial response.

Additionally, the NCI has ongoing trials to treat patients using TIL with colorectal cancer, gastric cancer, pancreatic cancer, hepatocellular carcinoma and cholangiocarcinoma and lung cancer.

Under our CRADA with the NCI, we are providing research, development and clinical funding for the development of unmodified TIL therapy for a variety of solid tumor indications, including HPV-associated cancers (cervical, head and neck), melanoma, bladder, breast, lung cancers, glioblastoma multiforme, colorectal cancer, gastric cancer, pancreatic cancer, hepatocellular carcinoma and cholangiocarcinoma.

Depending on results from the research and development and clinical trials conducted at the NCI under our CRADA, we may pursue the development and regulatory approval of TIL therapy for additional indications.

2 unchanged sentences

Historically, the largest set of data for TIL therapy was generated by the NCI as part of their multiple clinical studies.

Per publications from the NCI, toxicities or adverse events during TIL therapy have been mostly associated with either the lymphodepletion regimen or the high-dose IL-2 therapy given after TIL infusion as described by Goff et al.

Per publications from the NCI, toxicities or adverse events during TIL therapy have been mostly associated with either the lymphodepletion regimen or the IL-2 therapy given after TIL infusion as described by Goff et al.

in the Journal of Clinical Oncology in June 2016.

The standard approach to the administration of high-dose IL-2 is to continue dosing until patients can no longer tolerate treatment.

The historical approach to the administration of IL-2 is to continue dosing until intolerance.

Our trials, however, have limited administration of IL-2 to up to 6 doses.

Next Generation TIL Product Strategies

We are developing next generation TIL products using owned and licensed intellectual property rights, in some cases in combination with collaborators such as Cellectis and CHUM, as described elsewhere in this Annual Report on Form 10-K.

These products include both genetically-modified TIL and PD-1 selected TIL therapies.

We are developing next generation TIL products using owned and licensed intellectual property rights, in some cases in combination with collaborators such as Cellectis, as described elsewhere in this Annual Report on Form 10-K.

These products include selected TIL therapies, genetically-modified and cytokine-tethered TIL therapies.

We are also developing PBL therapy for CLL and SLL.

5 unchanged sentences

We have selected Gen 2 for product registration and ongoing and future TIL clinical development, although we continue to develop new TIL manufacturing processes.

We have developed a third-generation manufacturing process, known as Gen 3 which has a shorter manufacturing process than Gen 2.

For example, at the SITC meeting in November 2021, we presented a poster on the expansion of TIL demonstrating the use of static bags for the clinical TIL manufacturing process.

Furthermore, we have developed a third-generation manufacturing process, known as Gen 3 which has a shorter manufacturing process than Gen 2.

We are testing Gen 3 in multiple clinical trials, as described elsewhere in this Annual Report on Form 10-K.

We have also developed a manufacturing process that specifically selects for TIL that are PD-1 positive.

This product is known as LN-145-S1.

We have also developed next generation manufacturing processes to genetically modify TIL using the TALEN technology licensed from Cellectis, including our lead preclinical program IOV-4001, as well as selections for TIL that are PD-1 positive, such as our product known as LN-145-S1.

The Gen 2 manufacturing process begins with the collection of the patient’s tumor, which is then sent to a central manufacturing facility, where the T cells are isolated.

These cells are stimulated to proliferate, then propagated in cell culture flasks until sufficient cells are available for infusion back into the patient.

The TIL is then washed and put in media suitable for

cryopreservation and infusion.

The TIL is then washed and put in media suitable for cryopreservation and infusion.

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

The following diagram illustrates our Gen 2 TIL manufacturing process.

We have completed most construction and commissioning activities for our own manufacturing facility to manufacture TIL product using the Gen 2 manufacturing process.

To meet projected needs for commercial quantities of TIL products, we have built our own commercial manufacturing facility, the i CTC, to manufacture TIL product using the Gen 2 manufacturing process.

As of the end of 2021, we had completed the commissioning activities at the i CTC and successfully manufactured and delivered the first clinical batch of LN-145 for the IOV-COM-202 trial, representing our first internally manufactured TIL product, as we continue our launch readiness activities to supply commercial TIL upon potential BLA approval.

In addition, we have entered into MSAs with WuXi, Moffitt, and PharmaCell, which was acquired by Lonza, 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.

4 unchanged sentences

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.

To meet projected needs for commercial quantities of TIL products, we have built our own commercial manufacturing facility, which is expected to begin clinical manufacturing of TIL products in 2021.

Developing our own manufacturing capabilities may be costlier than we anticipate or result in significant delays.

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

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.

Orphan Drug Designations

2 unchanged sentences

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.

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 elsewhere in this Annual Report on Form 10-K.

1 unchanged sentence

Fast Track Designations

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

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 based on the unmet medical need and potential advantages for this combination over available care.

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, and also potential eligibility (if criteria are met) for accelerated approval.

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

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, and also potential eligibility if certain criteria are met for accelerated approval.

Regenerative Medicine Advanced Therapy Designation

21 unchanged sentences

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

● center engagement for commercial launch;

● engagement with potential authorized treatment centers, or ATCs, for commercial launch;

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

2 unchanged sentences

● building a patient-centric organization.

To date, in the U.S., lifileucel has been administered in 20 centers for melanoma and 17 centers for cervical cancer.

We anticipate that centers with prior TIL experience will be among the initial targets for launch upon approval, as well as other centers.

To date, in the U.S., lifileucel has been administered in 19 clinical trial centers for melanoma.

We anticipate that these clinical trial centers will be among the initial 40 ATCs at launch upon approval.

Intellectual Property

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, whether developed internally or licensed from third parties.

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, whether developed internally or licensed from third parties.

We also plan to rely on regulatory protection afforded through ODDs, available regulatory exclusivities and patent term extensions where available.

3 unchanged sentences

As a result, we now own a number of pending patent applications and granted patents in the fields of TIL therapy, MIL therapy, and PBL therapy, TIL, MIL, and PBL manufacturing processes, and TIL, MIL, and PBL expansion methods.

For example, we own more than twenty granted or allowed U.S.

and international patents related to our Gen 2 TIL manufacturing process, including patents directed to compositions and methods of treatment in a broad range of cancers, such as U.S.

For example, we currently own more than 35 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 11,241,456.

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.

More than 30 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 patent applications relating to TIL, MIL, and PBL therapies;

5 unchanged sentences

stable and transient genetically-modified TIL therapies;

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

methods of using ICIs in combination with TIL therapies;

TIL selection technologies;

2 unchanged sentences

Currently, preclinical research and development is conducted primarily at our own internal research and development laboratory in Tampa, Florida, and additionally with the NCI, Moffitt, and MDACC, as described below.

We also have entered into preclinical collaborations with MDACC.

We sponsor our own clinical trials and also collaborate on investigator-sponsored clinical trials with the NCI, Moffitt, and MDACC.

In addition, we hold exclusive, co-exclusive, and non-exclusive licenses to certain patent and other intellectual property rights with the National Institutes of Health, or NIH, an agency of the U.S.

In addition, we hold exclusive, co-exclusive, and non-exclusive licenses to certain patent and other intellectual property rights with the NIH, an agency of the U.S.

Public Health Service within the Department of Health and Human Services, Moffitt, MDACC, Novartis, and Cellectis as described in this Annual Report on Form 10-K.

2 unchanged sentences

In August 2011, we signed a five-year CRADA with the NCI, to work with Dr.

Steven Rosenberg on developing adoptive cell immunotherapies that are designed to destroy metastatic melanoma cells using a patient’s tumor infiltrating lymphocytes.

Steven Rosenberg on developing adoptive cell immunotherapies that are designed to destroy metastatic melanoma cells.

In January 2015, we executed an amendment to the CRADA to include four new indications.

As amended, in addition to metastatic melanoma, the CRADA included the development of TIL therapy for the treatment of patients with bladder, lung, triple-negative breast, and Human Papilloma Virus (“HPV”)-associated cancers.

In August 2016, we entered into a second amendment to the CRADA.

The principal changes effected by the second amendment included (i) extending the term of the CRADA by another five years to August 2021, and (ii) modifying the focus on the development of unmodified TIL as a stand-alone therapy or in combination with FDA-licensed products and commercially available reagents routinely used for adoptive cell therapy.

The parties will continue the development of improved methods for the generation and selection of TIL with anti-tumor reactivity in metastatic melanoma, bladder, lung, breast, and HPV-associated cancers.

In August 2016, the NCI and we entered into a second amendment to the CRADA.

The principal changes effected by the second amendment included (i) extending the term of the CRADA by another five years to August 2021, and (ii) modifying the focus on the development of unmodified TIL as a stand-alone therapy or in combination with products licensed by the FDA, and commercially available reagents routinely used for adoptive cell therapy.

The parties have continued the development of improved methods for the generation and selection of TIL with anti-tumor reactivity in metastatic melanoma, bladder, lung, breast, and HPV-associated cancers.

In August 2021, the NCI and we entered into a third amendment to the CRADA.

The third amendment, among other things, extended the term of the CRADA by three years to August 2024.

The research plan in this amendment includes the evaluation in clinical trials of strategies for development of more potent TILs, such as selection of CD39/69 double negative cells and the use of certain inhibitors or other reagents in TIL expansion cultures.

Pursuant to the terms of the CRADA, as amended, we are required to make quarterly payments of $0.5 million to the NCI for support of research activities.

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, relating to the TIL-based product candidate.

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, where we hold the investigational new drug application for such clinical trial.

The extended CRADA has a five-year term expiring in August 2021.

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

Effective October 5, 2011, we entered into an Exclusive Patent License Agreement, or the Patent License Agreement, with the NIH, an agency of the U.S.

Public Health Service within the Department of Health and Human Services, which was subsequently amended on February 9, 2015 and October 2, 2015.

Pursuant to the Patent License Agreement as amended, the NIH granted us licenses, including exclusive, co-exclusive, and non-exclusive licenses, to certain technologies relating to autologous tumor infiltrating lymphocyte adoptive cell therapy products for the treatment of metastatic melanoma, lung, breast, bladder and HPV-positive cancers.

The Patent License Agreement requires us to pay royalties based on a percentage of net sales (which percentage is in the mid-single digits), a percentage of revenues from sublicensing arrangements, and lump sum benchmark royalty payments on the achievement of certain clinical and regulatory milestones for each of the various indications and other direct costs incurred by the NIH pursuant to the agreement.

We anticipate making a milestone payment in conjunction with the submission of a BLA for any of our product candidates covered by the Patent License Agreement.

Effective October 5, 2011, we entered into an Exclusive Patent License Agreement, or the Patent License Agreement, with the NIH, which was subsequently amended on February 9, 2015 and October 2, 2015.

The Patent License Agreement requires us to pay royalties based on a percentage of net sales (which percentage is in the mid-single digits), a percentage of revenues from sublicensing arrangements, and lump sum benchmark royalty payments on the achievement of certain clinical and regulatory milestones for each of the Indications and other direct costs incurred by the NIH pursuant to the agreement.

Effective May 6, 2021, we entered into an Amended and Restated Patent License Agreement with NIH, or the Amended and Restated Patent License Agreement, which includes the grant of additional exclusive, worldwide patent rights in the Indications to cytokine-tethered TIL technology, and expands the non-exclusive, worldwide field of use to all cancers.

The 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 Amended and Restated Patent License Agreement, as well as a percentage of revenues from sublicensing arrangements.

We anticipate making milestone payments, including a payment in the low single-digit millions of dollars, in conjunction with the approval of a BLA for any of our product candidates covered by the Amended and Restated Patent License Agreement.

The term of the Amended and Restated Patent License Agreement continues until the expiry of the last-to-expire patent rights licensed thereunder, and the agreement contains standard termination provisions.

Exclusive Patent License Agreement Related to TIL Selection

1 unchanged sentence

Unless terminated sooner, the license shall remain in effect until the last licensed patent right expires.

Under the Exclusive Patent License Agreement, we agreed to pay customary royalties based on a percentage of net sales of a licensed product (which percentage is in the mid-single digits), a percentage of revenues from sublicensing arrangements, and lump sum benchmark payments upon the successful completion of clinical studies involving licensed technologies, the receipt of the first FDA approval or foreign equivalent for a licensed product or process resulting from the licensed technologies, the first commercial sale of a licensed product or process in the U.S., and the first commercial sale of a licensed product or process in any foreign country.

arrangements, and lump sum benchmark payments upon the successful completion of clinical studies involving licensed technologies, the receipt of the first FDA approval or foreign equivalent for a licensed product or process resulting from the licensed technologies, the first commercial sale of a licensed product or process in the U.S., and the first commercial sale of a licensed product or process in any foreign country.

Lee Moffitt Cancer Center

Research Collaboration and Clinical Grant Agreements with Moffitt

In December 2016, we entered into a new three-year Sponsored Research Agreement with H.

Lee Moffitt Cancer Center, or Moffitt, which expired in December 2019.

In December 2016, we entered into a three-year 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, and under which immaterial payments will be made to Moffitt in connection with the research services thereunder.

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

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.

7 unchanged sentences

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.

We entered into a license agreement with Moffitt in May 2018, or the Second Moffitt License, under which we received a license to Moffitt’s rights to patent-pending technologies related to the use of 4-1BB agonists in conjunction with TIL manufacturing processes and therapies.

We continue to develop TIL therapies using a 4-1BB agonist in manufacturing in conjunction with M.D.

Anderson Cancer Center.

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.

We entered into a second license agreement with Moffitt effective as of May 7, 2018, or the Second Moffitt License, under which we received an exclusive license to Moffitt’s rights to patent-pending technologies related to the use of 4-1BB agonists in conjunction with TIL manufacturing processes and therapies.

Pursuant to the Second Moffitt License, we paid an upfront licensing fee in the amount of $0.1 million in 2018.

An annual license maintenance fee will be also payable commencing on the first anniversary of the effective date.

In addition, we agreed to pay an annual commercial use payment for each indication for which a first sale has occurred, which in the aggregate amounts to up to $0.4 million a year.

An annual license maintenance fee is also payable commencing on the first anniversary of the effective date.

In addition, we agreed to pay an annual commercial use payment for each indication for which a first sale has occurred.

We subsequently exercised an option to exclusively license Moffitt’s rights to patent pending technologies related to the use of tumor digests in conjunction with TIL manufacturing processes and therapies, and we and Moffitt amended and restated the Second Moffitt License in October 2021, or the Amended & Restated Second Moffit License, to include these rights.

Pursuant to the Amended & Restated Second Moffitt License, we paid an upfront licensing fee in the amount of $0.2 million in 2021.

In addition, we agreed to pay an annual commercial use payment for each indication for which a first sale has occurred for products relating to the use of 4-1BB antagonists and for products relating to the use of tumor digests covered by the license.

The University of Texas M.D.

Anderson Cancer Center

On April 2017, we entered into a Strategic Alliance Agreement, or the SAA, with MDACC under which we and MDACC agreed to conduct clinical and preclinical research studies.

Strategic Alliance Agreement

In April 2017, we entered into a Strategic Alliance Agreement, or the SAA, with MDACC agreed to conduct clinical and preclinical research studies.

We agreed in the SAA to provide total funding not to exceed approximately $14.2 million for the performance of the multi-year studies under the SAA.

In return, we acquired all rights to inventions resulting from the studies and have been granted a non-exclusive, sub-licensable, royalty-free, and perpetual license to specified background intellectual property of MDACC reasonably necessary to exploit, including the commercialization thereof.

MDACC reasonably necessary to exploit, including the commercialization thereof.

We have also been granted certain rights in clinical data generated by MDACC outside of the clinical trials to be performed under the SAA.

3 unchanged sentences

247d) by the Secretary of Health and Human Services, and which we refer to herein as the COVID-19 pandemic, MDACC temporarily suspended their research programs and decommissioned their research labs, and as a result, enrollment in our MDACC-sponsored studies under the SAA was temporarily paused in the first half 2020, but has since been restarted.

WuXi Advanced Therapies, Inc.

In November 2016, we entered into a three-year manufacturing and services agreement, or MSA, with WuXi, pursuant to which WuXi agreed to provide manufacturing and other services, which has since been amended and assigned to our subsidiary Iovance Biotherapeutics Manufacturing LLC.

Under the agreement, we entered into two statements of work for two cGMP manufacturing suites to be established and operated by WuXi for us, and both of the suites are expected to be capable of being used for the commercial manufacturing of our products.

The statements of work for the first suites were amended in 2019 and September 2020, and the second suite was amended in 2019.

The statements of work for facility include a fixed component to reserve a dedicated suite and a trained work force and a variable component, mainly materials and testing used during the manufacturing processes.

Both statements of work provide for adjustments to the targeted production capacity levels and corresponding fixed quarterly fees upon written notice from us of 30 and 90 days for the first and second dedicated suites, respectively.

The terms of the related statements of work for the first and second dedicated manufacturing suites currently extend to August 2022 and June 2021, respectively.

In June 2018, we entered into a preclinical research collaboration with Cellectis S.A., or Cellectis, a clinical-stage biopharmaceutical company, to investigate TALEN for genetic editing in conjunction with TIL therapy.

In January 2020, we entered into a research collaboration and exclusive worldwide license agreement whereby we licensed gene-editing technology from Cellectis, in order to develop TIL therapies that have been genetically edited.

The first statement of work was amended in June 2019, September 2020, and February 2021, and the second statement of work was amended in July 2019 and July 2021.

Both statements of work provide for adjustments to the targeted production capacity levels and the corresponding fixed fees upon written notice from us of 30 days and 90 days for the first and second suites, respectively.

The terms of the related statements of work currently extend to February 2022 for the first statement of work and were extended to December 2022 for the second statement of work.

Cellectis S.A.

In December 2019, we entered into a research collaboration and exclusive worldwide license agreement under which we license gene-editing technology from Cellectis.

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.

Novartis Pharma AG

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., EU and Japan.

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

7 unchanged sentences

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

In particular, we expect to compete with other new therapies for our lead indications developed by companies such as Bristol-Myers Squibb, Merck, Nektar Therapeutics, Idera Pharmaceuticals, Checkmate Pharmaceuticals, OncoSec Medical, Instil Bio, Achilles Therapeutics, WindMIL Therapeutics, Seagen, 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, Ziopharm Therapeutics, Marker Therapeutics, 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, Idera Pharmaceuticals, Checkmate Pharmaceuticals, Daiichi Sankyo, Eisai, Exelixis, 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, 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.

Competition for late-stage melanoma patients may come, if approved, from several therapies currently under development.

In 2020, Idera Pharmaceuticals reported results from an ongoing Phase 1/2 clinical trial of the TLR9 agonist tilsotolimod in combination with ipilimumab indicating an ORR of 22% in 53 melanoma patients who had previously received anti-PD-1 therapy.

Idera Pharmaceuticals is currently conducting a Phase 3 trial of tilsotolimod in combination with ipilimumab in melanoma patients refractory to anti-PD-1 therapy.

In 2020, OncoSec Medical announced preliminary results from an ongoing Phase 2 trial of intratumoral electroporation of plasmid IL-12, or tavokinogene telseplasmid, in combination with pembrolizumab, reporting an ORR of 30% in 54 melanoma patients.

Checkmate Pharmaceuticals reported preliminary results from an ongoing Phase 1b clinical trial of the TLR9 agonist CMP-001 in combination with pembrolizumab indicating an ORR of 25% in 82 patients who had received prior anti-PD-1 therapy.

Competition for late-stage cervical cancer patients also may arise from therapies under development by companies such as Seagen, which reported an ORR of 24% in 2020 from an ongoing trial of cervical cancer patients who progressed on standard therapy.

We may also face competition for NSCLC patients from a large number of therapies that target specific, emerging driver mutations in populations that overlap with our patient populations of interest.

Competition for late-stage melanoma patients may come, if approved, from several therapies currently under clinical development across our lead indications in metastatic melanoma, non-small cell lung and cervical cancers.

If we are successful in developing lifileucel for metastatic melanoma, we will compete against other investigational agents in late-stage development for use in combination with approved anti-PD-1 therapies at Bristol-Myers Squibb (relatlimab, a LAG-3-blocking antibody), Idera Pharmaceuticals (IMO-2125, a toll-like receptor, or TLR, 9 agonist), Checkmate Pharmaceuticals (CMP-001, a TLR9 agonist), Eisai (levatinib, a multiple tyrosine kinase inhibitor) and Replimune (RP1, or vusolimogene oderparepvec, an oncolytic virus therapy).

Competition for lifileucel in late-stage cervical cancer patients also may arise from approved therapy TIVDAK™ (tisotumab vedotin-tftv) from Seagen/Genmab as well as an investigational agent in clinical development at Agenus (balstilimab, an anti-PD-1 therapy) for use in combination with approved anti-CTLA-4 inhibitor zalifrelimab.

In addition, the cervical cancer treatment landscape has further evolved with the approval of KEYTRUDA + chemo + bevacizumab in front-line cervical cancer.

We may also face competition for NSCLC patients from a large number of therapies in clinical development that target specific, emerging driver mutations in populations that overlap with our patient populations of interest, including Daiichi Sankyo/Astra Zeneca (datopotamab deruxtecan, an antibody-drug candidate), as well as sponsors with anti-PD-1 combinations in clinical development such as Exelixis (cabozantinib + atezolizumab), Mirati Therapeutics (sitravatinib + nivolumab) and Merck (vibostolimab alone and in combination with pembrolizumab).

The studies for these NSCLC therapies are in various stages of the clinical pipeline, including several in Phase 3 trials.

While other types of cancer immunotherapies may potentially be used in combination with TIL, such as checkpoint inhibitors, to enhance efficacy, we also expect substantial direct competition from other types of immunotherapies.

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

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

Immunotherapies are also being pursued by several biotechnology companies as well as by large pharmaceutical companies.

15 unchanged sentences

We seek to protect our proprietary technology and processes, in part, by entering into confidentiality agreements with our employees, consultants, scientific advisors and contractors.

We also seek to preserve the integrity and confidentiality of our data and trade secrets by maintaining physical security of our premises and physical and electronic security of our information technology systems.

We also seek to preserve the integrity and confidentiality of our data and

trade secrets by maintaining physical security of our premises and physical and electronic security of our information technology systems.

While we have confidence in these individuals, organizations and systems, agreements or security measures may be breached, and we may not have adequate remedies for any breach.

17 unchanged sentences

● a determination by the FDA within 60 days of its receipt of a BLA to file the application for review;

preserve the biological product’s continued safety, purity and potency, and of selected clinical sites to assess compliance with current Good Clinical Practices, or cGCPs;

● satisfactory completion of an FDA pre-approval inspection of the manufacturing facility or facilities at which the proposed product is produced to assess compliance with cGMP, and to assure that the facilities, methods and controls are adequate to preserve the biological product’s continued safety, purity and potency, and of selected clinical sites to assess compliance with current Good Clinical Practices, or cGCPs;

● FDA review and approval of the BLA to permit commercial marketing of the product for particular indications for use in the U.S., which must be updated periodically when changes are made.

3 unchanged sentences

The central focus of an IND submission is on the general investigational plan and the protocol(s) for clinical studies.

The IND also includes results of animal and in vitro studies assessing the toxicology, pharmacokinetics, pharmacology, and pharmacodynamic characteristics of the product;

The IND also includes results of animal and in vitro studies assessing the toxicology,

pharmacokinetics, pharmacology, and pharmacodynamic characteristics of the product;

chemistry, manufacturing, and controls information;

23 unchanged sentences

For purposes of BLA approval, human clinical trials are typically conducted in three sequential phases that may overlap.

Although these are the typical phases for progression, and characteristics of the phases of a clinical development program, certain

expedited programs allow for variations that could support a marketing application based on surrogate endpoints, intermediate clinical endpoints, or single-arm as opposed to comparative or placebo-controlled studies.

Although these are the typical phases for progression, and characteristics of the phases of a clinical development program, certain expedited programs allow for variations that could support a marketing application based on surrogate endpoints, intermediate clinical endpoints, or single-arm as opposed to comparative or placebo-controlled studies.

● 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.

● 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.

safety risks.

Multiple Phase 2 clinical trials may be conducted to obtain information prior to beginning larger and more expensive Phase 3 clinical trials.

23 unchanged sentences

In addition, under the Pediatric Research Equity Act, or PREA, a BLA or supplement to a BLA for a new active ingredient, indication, dosage form, dosage regimen, or route of administration, must contain data that are adequate to assess the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

must submit, with the application, reports from molecularly targeted pediatric cancer investigations designed to yield clinically meaningful pediatric study data, using appropriate formulations, to inform potential pediatric labeling.

Also, under the FDA Reauthorization Act of 2017, beginning in 2020, sponsors submitting applications for product candidates intended for the treatment of adult cancer which are directed at molecular targets that the FDA determines to be substantially relevant to the growth or progression of pediatric cancer must submit, with the application, reports from molecularly targeted pediatric cancer investigations designed to yield clinically meaningful pediatric study data, using appropriate formulations, to inform potential pediatric labeling.

The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements.

27 unchanged sentences

Before approving a BLA, the FDA will typically inspect the facility or facilities where the product is manufactured.

The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.

The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent commercial production of the product within required specifications.

Additionally, before approving a BLA, the FDA will typically inspect one or more clinical sites to assure compliance with cGCP.

If the FDA determines that the application, manufacturing process or manufacturing facilities are not acceptable, it will outline the deficiencies in the submission and often will request additional testing, clinical studies, application modifications, or information in a complete response letter, or CRL.

A CRL indicates that the review cycle for the application is complete and that the application is

not ready for approval.

A CRL indicates that the review cycle for the application is complete and that the application is not ready for approval.

If a CRL is issued, the applicant may either:

6 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.

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.

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

20 unchanged sentences

involving senior managers and experienced review staff, as appropriate, in a collaborative, cross-disciplinary review;

assigning a cross-disciplinary project lead for the FDA review team to facilitate an efficient review of the development program and to serve as a scientific liaison between the review team and the

assigning a cross-disciplinary project lead for the FDA review team to facilitate an efficient review of the development program and to serve as a scientific liaison between the review team and the sponsor;

and considering alternative clinical trial designs when scientifically appropriate, which may result in smaller trials or more efficient trials that require less time to complete and may minimize the number of patients exposed to a potentially less efficacious treatment.

Breakthrough Therapy designation 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 Regenerative Medicine Advanced Therapy, or RMAT, designation.

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

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

To qualify for this program, the product must be a cell therapy, therapeutic tissue engineering product, human cell and tissue product, or a combination of such products, and not a product solely regulated as a human cell and tissue product.

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.

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.

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

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

The Fast Track designation does not change the standards for approval but may expedite the development or approval process.

In October 2018, we announced that lifileucel had received an RMAT designation for metastatic melanoma.

In 2019, the FDA granted us a Fast Track designation and BTD for lifileucel for metastatic cervical cancer.

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.

15 unchanged sentences

The FDA may also approve a product deemed to be the same as an approved orphan product for the same orphan indication, despite periods of exclusivity, if the new product is demonstrated to be clinically superior to the former product.

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

to treat malignant melanoma stages IIB-IV.

We plan to seek ODD for some or all of our other product candidates in specific orphan indications in which there is a medically plausible basis for the use of such products.

During 2018, we received an ODD from the FDA for lifileucel for the treatment of cervical cancer with a tumor size of greater than 2 cm in diameter.

Market and Data Exclusivity and Biosimilars

34 unchanged sentences

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.

Recent court decisions have impacted FDA’s enforcement activity regarding off-label promotion in light of First Amendment considerations;

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.

1 unchanged sentence

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.

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.

7 unchanged sentences

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 exercise enforcement discretion on certain aspects due to the COVID-19 pandemic.

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.

5 unchanged sentences

To help reduce the increased risk of the introduction of adventitious agents, the PHSA emphasizes the importance of manufacturing controls for products whose attributes cannot be precisely defined.

The PHSA also provides authority to the FDA to immediately suspend licenses in situations where there exists a danger to public health, to prepare or procure products in the event of

shortages and critical public health needs, and to authorize the creation and enforcement of regulations to prevent the introduction or spread of communicable diseases in the U.S.

The PHSA also provides authority to the FDA to immediately suspend licenses in situations where there exists a danger to public health, to prepare or procure products in the event of shortages and critical public health needs, and to authorize the creation and enforcement of regulations to prevent the introduction or spread of communicable diseases in the U.S.

and between states.

7 unchanged sentences

Our sales, promotion, medical education and other activities following product approval will be subject to regulation by numerous regulatory and law enforcement authorities in the U.S., and in addition to the FDA, these entities may include the Federal Trade Commission, the Department of Justice, the Centers for Medicare & Medicaid Services, other divisions of the Department of Health and Human Services and state and local governments.

Our promotional and scientific/educational programs must comply with the federal Anti-Kickback Statute, or AKS, the Foreign Corrupt Practices Act, or FCPA, the False Claims Act, or FCA, the Veterans Health Care Act, physician payment transparency laws, privacy laws, security laws, and additional state laws similar to the foregoing.

Our promotional and scientific/educational programs must comply with

the federal Anti-Kickback Statute, or AKS, the Foreign Corrupt Practices Act, or FCPA, the False Claims Act, or FCA, the Veterans Health Care Act, physician payment transparency laws, privacy laws, security laws, and additional state laws similar to the foregoing.

The federal AKS prohibits, among other things, any person or entity, from knowingly and willfully offering, paying, soliciting or receiving any remuneration, directly or indirectly, overtly or covertly, in cash or in kind, to induce or in return for purchasing, leasing, ordering or arranging for the purchase, lease or order of any item or service reimbursable under Medicare, Medicaid or other federal healthcare programs, in whole or in part.

16 unchanged sentences

The civil FCA has been or can be used to assert liability on the basis of kickbacks and other improper referrals, improperly reported government pricing metrics such as Best Price and Average Manufacturer Price, improper promotion of uses not expressly approved by the FDA in a drug’s label, false statements associated with government grants, and allegations of misrepresentations with respect to services rendered, as well as claims for payment that are inaccurate or fraudulent, that are for services not provided as claimed, or for services that are not medically necessary.

FCA claims may be based on noncompliance with

regulatory requirements under an implied certification theory if material to the government’s decision to buy or pay for a drug.

FCA claims may be based on noncompliance with regulatory requirements under an implied certification theory if material to the government’s decision to buy or pay for a drug.

Intent to deceive is not required to establish liability under the civil FCA.

10 unchanged sentences

Additionally, the FCPA, and similar worldwide anti-bribery laws, generally prohibit companies and their intermediaries from making, offering or authorizing improper payments or other items of value, directly or indirectly, to foreign officials, political parties, or candidates for the purpose of obtaining or retaining business.

The FCPA also obligates companies whose securities are listed in the U.S.

The FCPA also obligates companies whose securities are listed in the

to comply with accounting provisions requiring us to maintain books and records that accurately and fairly reflect all transactions of the corporation, including international subsidiaries, and to devise and maintain an adequate system of internal accounting controls for international operations.

14 unchanged sentences

The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which imposes criminal and civil penalties prohibits, among other actions, knowingly and willfully executing, or attempting to execute, a scheme to defraud or to obtain, by means of false or fraudulent pretenses, representations, or promises, any of the money or property owned by, or under the custody or control of, any healthcare benefit program, regardless of whether the payor is public or private third-party, knowingly and willfully embezzling or stealing from a health care benefit program, willfully obstructing a criminal investigation of a health care offense, and knowingly and willfully falsifying, concealing, or covering up by any trick or device a material fact or making any materially false statements in connection with the delivery of, or payment for, healthcare benefits, items, or services relating to healthcare matters.

person or entity does not need to have actual knowledge of the statute, or the specific intent to violate it, to have committed a violation.

A person or entity does not need to have actual knowledge of the statute, or the specific intent to violate it, to have committed a violation.

We may also be subject to data privacy and security laws and regulation by both the federal government and the states in which we conduct our business.

16 unchanged sentences

Failure to submit required information may result in civil monetary penalties of up to an aggregate of $150,000 per year and up to an additional aggregate of $1 million per year for “knowing failures,” for all payments, transfers of value or ownership or investment interests that are not timely, accurately and completely reported in an annual submission.

As of 2021, applicable manufacturers are subject to tracking payments and transfers of value to physician assistants, nurse practitioners, and other mid-level HCPs as well as physicians, with reporting relative to these mid-level practitioners beginning in 2022.

The Sunshine Act was amended requiring applicable manufacturers, in 2021, to begin tracking payments and transfers of value to physician assistants, nurse practitioners, and other mid-level HCPs as well as physicians, with reporting relative to these mid-level practitioners first due in 2022.

Additionally, certain states also mandate implementation of commercial compliance programs, impose restrictions on drug manufacturer marketing practices and/or require the tracking and reporting of gifts, compensation and other remuneration to physicians and other HCPs.

1 unchanged sentence

Some state laws require pharmaceutical companies to comply with the pharmaceutical industry's voluntary compliance guidelines, known as the PhRMA Code, and the relevant compliance program guidance promulgated by the federal government in addition to requiring drug manufacturers to report pricing and marketing information, including, among other things, information related to gifts, payments, or other remuneration to physicians and other healthcare providers or marketing expenditures, state and local laws that require the registration of pharmaceutical sales representatives, and state laws governing the privacy and security of health information and the use of prescriber-identifiable data in certain circumstances, many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.

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

CPRA, passed on November 3, 2020.

For example, California enacted the California Consumer Privacy Act, or CCPA, which went into effect on January 1, 2020 and was recently amended and expanded by the California Privacy Rights Act, or CPRA, passed on November 3, 2020.

While the majority of the CPRA’s substantive provisions will not take effect until January 1, 2023, the CPRA’s expansion of the “Right to Know” impacts personal information collected on or after January 1, 2022.

7 unchanged sentences

The scope and enforcement of each of these laws is uncertain and subject to rapid change in the current environment of healthcare reform, especially in light of the lack of applicable precedent and regulations.

Federal and state enforcement bodies have recently increased their scrutiny of interactions between healthcare companies and healthcare providers, which has led to a number of investigations, prosecutions, convictions and settlements in the healthcare industry.

Federal and state enforcement bodies have recently increased their scrutiny of

interactions between healthcare companies and healthcare providers, which has led to a number of investigations, prosecutions, convictions and settlements in the healthcare industry.

Ensuring that business arrangements with third parties comply with applicable healthcare laws, as well as responding to possible investigations by government authorities, can be time- and resource-consuming and can divert management's attention from the business.

17 unchanged sentences

Medicaid is an insurance program for certain categories of low income patients who are otherwise uninsured and is both federally and state funded and managed by each state.

The federal government sets general guidelines for Medicaid and requires rebates on outpatient drugs and biological products, including those

administered by physicians if the cost is billed separately.

The federal government sets general guidelines for Medicaid and requires rebates on outpatient drugs and biological products, including those administered by physicians if the cost is billed separately.

Each state creates specific regulations that govern its individual program, including supplemental rebate programs that prioritize coverage for drugs on the state Preferred Drug List.

7 unchanged sentences

Third-party payors are increasingly challenging the price and examining the medical necessity and cost-effectiveness of medical products and services, in addition to their safety and efficacy, and are developing increasingly sophisticated methods of controlling healthcare costs.

They may limit coverage to specific drug products on an approved list, or formulary, which might not include all the FDA-approved drug products for a particular indication, or they may control costs, particularly for new expensive therapies, by requiring prior authorization or imposing other restrictions before covering certain products, or they may condition payment based on achieving performance metrics.

They may limit coverage to specific drug products on an approved

list, or formulary, which might not include all the FDA-approved drug products for a particular indication, or they may control costs, particularly for new expensive therapies, by requiring prior authorization or imposing other restrictions before covering certain products, or they may condition payment based on achieving performance metrics.

Legislative proposals to reform healthcare or reduce costs under government programs may result in lower reimbursement for our product candidates or exclusion of our product candidates from coverage.

15 unchanged sentences

Among policy makers and payors in the U.S.

and elsewhere, there is significant interest in promoting changes in healthcare systems with the stated goals of containing

healthcare costs, improving quality and/or expanding access.

and elsewhere, there is significant interest in promoting changes in healthcare systems with the stated goals of containing healthcare costs, improving quality and/or expanding access.

In the U.S., the pharmaceutical industry has been a particular focus of these efforts and has been significantly affected by major federal and state legislative initiatives.

33 unchanged sentences

Our future performance depends significantly upon the continued service of our key scientific, technical and senior management personnel and our continued ability to attract and retain highly skilled employees.

We provide our employees with competitive salaries and bonuses, opportunities for equity

ownership, development programs that enable continued learning and growth and a robust employment package that promotes well-being across all aspects of their lives.

We provide our employees with competitive salaries and bonuses, opportunities for equity ownership, development programs that enable continued learning and growth and a robust employment package that promotes well-being across all aspects of their lives.

In addition to salaries, these programs include potential annual discretionary bonuses, stock awards, a 401(k) plan, healthcare and insurance benefits, health savings and flexible spending accounts, paid time off, family leave, and flexible work schedules, among other benefits.

6 unchanged sentences

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 1. Business