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Item 1. Business

2021-02-25 compared with 2020-02-25 · 449 added, 359 removed, 577 unchanged (58% 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 in diseases such as metastatic melanoma and cervical cancer.

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 further investigated in multiple indications.

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

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

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.

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

The C-144-01 trial has National Clinical Trial identification number NCT02360579.

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

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

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

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

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

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

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

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

Food and Drug Administration, or FDA.

FDA also acknowledged the potential acceptability of single-arm data from Cohort 4 for registration.

In October 2018, we announced that lifileucel had received a Regenerative Medicine Advanced Therapy, or RMAT, designation from the FDA.

Updated 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 Society for Immunotherapy of Cancer, or SITC, annual meeting in November 2019.

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

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.

The disease control rate, or DCR, was 80.3%.

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

For both the ASCO and SITC updates, the median duration of response, or DOR, had not been reached.

In January 2020, with a median follow up of 15.5 months for Cohort 2 patients,the median DOR has not been reached per investigator assessment.

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.

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

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

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

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

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.

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

A total of 87 patients were dosed in Cohort 4.

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

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

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

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

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

our BLA in 2021.

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

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

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

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

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

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.

In 27 patients with metastatic cervical cancer, treatment with LN-145 resulted in an ORR of 44%.

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

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

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

The DCR was 85%.

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

The DOR had not been reached.

The median follow-up was 7.4 months.

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 in the treatment of patients with metastatic cervical cancer.

The median DOR had not been reached.

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

Based on an EOP2 meeting held with the FDA in June 2019, we believe that results from the C-145-04 clinical trial may be sufficient to support registration of lifileucel for the treatment of patients with metastatic cervical cancer.

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

In November 2019, in order to position LN-145 for potential future use 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 later-line patients.

Enrollment in these additional cohorts is not expected to impact the timing of the completion of Cohort 1.As a result of this amendment, the C-145-04 trial now consists of the following cohorts of cervical cancer patients with recurrent, persistent, or metastatic disease:

● Cohort 1 is the expected pivotal cohort for LN-145 and is anticipated to enroll 75 patients who have progressed during or after chemotherapy;

● Cohort 2 will enroll patients for treatment with LN-145 who have progressed during or after treatment with anti-PD-1/anti-PD-L1 checkpoint inhibitor;

● Cohort 3 will enroll patients who have not received prior systemic therapy for recurrent, metastatic, or persistent disease.

This Cohort will explore safety and efficacy of the combination of the LN-145 regimen with pembrolizumab;

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

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

As a result of these changes, we have also expanded the sample size of the C-145-04 clinical trial to include 138 patients from the appropriate patient populations across these five cohorts.

We plan on completing enrollment into Cohort 1 of C-145-04 at approximately mid-year 2020.

We currently plan to submit a BLA for this indication by the end of 2020 subsequent to consultation with the FDA.

C-145-03 , or NCT03083873, is an ongoing Phase 2, multicenter trial that we are conducting to assess the safety and efficacy of LN-145 for the treatment of patients with recurrent metastatic squamous cell carcinoma of the head and neck .

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.

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.

The adverse event profile remained consistent with previous reports.

We continue to enroll patients in this study.

We have 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 are also investigating the potential of our TIL therapies in earlier lines of treatment and in combination with pembrolizumab.

We are also studying LN-145 as a monotherapy in relapsed refractory non-small cell lung cancer, or NSCLC, patients.

IOV-COM-202 , or NCT03645928, is a Phase 2, multicenter trial that is composed of four cohorts to enroll up to a total of 48 patients.

In Cohort 1A, we are enrolling advanced unresectable or metastatic melanoma patients who have not received prior immunotherapy, including checkpoint inhibitors such as anti-PD-1/anti-PD-L1 therapy.

The patients receive lifileucel in combination with pembrolizumab.

In Cohort 2A, we are enrolling advanced head and neck squamous cell carcinoma patients who are naïve to prior immunotherapy including anti-PD-1/anti-PD-L1 therapy.

The patients will receive LN-145 in combination with pembrolizumab.

Cohort 3A is enrolling non-small cell lung cancer patients who are naïve to prior immunotherapy including anti-PD-1/anti-PD-L1 therapy.

The patients in Cohort 3A will receive LN-145 in combination with pembrolizumab.

In Cohort 3B, we are enrolling non-small cell lung cancer patients who have previously received systemic therapy which could include checkpoint inhibitors.

The patients are receiving LN-145.

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.

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

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

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 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.

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 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.

IOV-CLL-01 , or NCT04155710, is Phase 1/2 clinical trial evaluating the safety and efficacy of IOV-2001 in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic leukemia.

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 April 2019, we closed the IOV-LUN-201 clinical trial, investigating TIL therapy in NSCLC, in combination with anti-PD-L1 therapy, and instead opened Cohorts 3A and 3B of the IOV-COM-202 trial as described above, to adapt our clinical development plans to reflect advances in the treatment landscape for non-small cell lung cancer.

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, 2017-0672 or NCT03449108, is intended to allow for investigation of LN-145 manufactured by us using our manufacturing process to treat patients with soft tissue sarcoma, osteosarcoma and platinum resistant ovarian cancer.

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

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

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

This trial 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.

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

We have also entered into a collaboration with a Canadian institution, Centre hospitalier de l’Université de Montreal, or CHUM, under which CHUM agreed to conduct a clinical study using a PD-1 selected TIL product manufactured by a CHUM collaborator using a process developed by CHUM.

We are also developing a PD-1 selected TIL product to be manufactured by Iovance.

This product, known as LN-145-S1, will initially be tested in the C-145-03 trial in head and neck cancer patients.

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 in the C-145-03 trial in head and neck cancers.

We currently own ten granted or allowed U.S.

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

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.

Our owned and licensed intellectual property portfolio also includes patent applications relating to TIL, marrow infiltrating, and peripheral blood lymphocyte therapies, methods of manufacturing, the use of costimulatory molecules in TIL therapy and manufacturing, stable and transient genetically-modified TIL therapies, and methods of treating patient subpopulations.

We previously collaborated with Roswell Park Cancer Institute, or RPCI, on a clinical trial using our LN-145 product for the treatment of patients with bladder cancer in combination with the anti-PD-1 antibody pembrolizumab.

This trial was closed in 2019 because of a lack of enrollment.

We are also collaborating with Yale University on a clinical trial using our LN-145 product for the treatment of patients with metastatic triple negative breast, or TNBC, cancer (NCT04111510).

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.

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

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

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

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

In addition, in January 2020, we announced a research collaboration and exclusive worldwide licensing agreement with Cellectis 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.

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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 TIL-based product candidates with the potential to meaningfully improve survival and quality of life for cancer patients.

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

Key elements of our strategy include:

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

Cohort 1 evaluated our first-generation TIL manufacturing process, Cohort 2 evaluated our second-generation, Gen 2, TIL manufacturing process and Cohort 3 evaluated retreatment of certain patients with a second dose of TIL.

We presented updated data from Cohort 2 in November 2018 at the SITC annual meeting, in June 2019 at the ASCO annual meeting, and in November 2019 at the SITC annual meeting.

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

In addition, we received an RMAT designation for lifileucel.

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.

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.

and the rest of the world.

We believe that we are the only company in the United States to have a centralized and commercially-viable TIL manufacturing process.

In 2018, we utilized our second generation TIL manufacturing process, known as Gen 2, which reduced TIL manufacturing time from 5-6 weeks to 22 days, allowing for a more commercially-viable product candidate.

Gen 2 also produces a cryopreserved product for ease of administration and handling.

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 other ongoing TIL clinical development.

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

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

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

In 2018, we first utilized our Gen 2 TIL manufacturing process, which reduced TIL manufacturing time from 5-6 weeks to 22 days, allowing for a commercially viable product candidate.

The Gen 2 process also produces a cryopreserved TIL product for ease of administration and handling.

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.

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.

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 announced licensing agreements and collaborations with Yale University, Cellectis, and Novartis, as described above or in the following sections, and continued our collaborations with Moffitt, MDACC, and the Ohio State University, 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.

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.

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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 United States 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 MSAs.

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 order to provide for better margins and rapid implementation of innovative changes for TIL therapies that we may develop or commercialize.

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.

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.

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 .

that was recently acquired by Catalent, Inc.

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 intend to cease manufacturing at MaSTherCell in 2020.

We ceased manufacturing at MaSTherCell in 2020.

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.

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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.

The terms of the related statements of work for the first and second dedicated manufacturing suites currently extend to May 2020 and June 2021, respectively.

We intend to use WuXi as the initial manufacturer for commercial production of lifileucel and potentially LN-145 for cervical cancer.

Iovance-Sponsored Clinical Trials

We currently have five ongoing Phase 2 clinical studies.

We currently have six ongoing Phase 2 clinical studies.

The ongoing studies include C-144-01, of our lead product candidate, lifileucel, for the treatment of metastatic melanoma;

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

and C-145-03, of our product candidate LN-145, for recurrent and/or metastatic squamous cell carcinoma of the head and neck.

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 pembro 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.

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.

Additional information about our clinical trials is presented as follows:

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We are developing lifileucel to treat metastatic melanoma.

Melanoma is a common type of skin cancer, accounting for approximately 96,000 patients diagnosed and 7,230 deaths each year in the United States according to the NCI’s Surveillance,

Epidemiology and End Results program, or SEER program, as of 2019.

Melanoma is a common type of skin cancer, accounting for approximately 100,350 patients diagnosed and 6,850 deaths each year in the U.S.

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

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.

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,has recommendations for the treatment of patients with unresectable or metastatic melanoma.

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.

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

According to estimates from SEER in the U.S.

in 2019, approximately there were 7,230 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 Gen 1 manufacturing process, was closed to enrollment in 2017 and subsequent patients were enrolled in Cohort 2.

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.

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.

We have completed dosing in Cohort 4.

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.

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

The disease control rate, or DCR, was 80%.

The DCR was 80%.

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

For both the ASCO and SITC updates, the median duration of response, or DOR, had not been reached.

In January 2020, with a median follow up of 15.5 months for Cohort 2 patients, we have reported that median DOR has not been reached as assessed by investigator.

In January 2021, we announced that median DOR in Cohort 2 had still not been reached after 28.1 months of median study follow up, as assessed by investigator.

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

We have not reported any results from Cohort 4.

A BLA submission to the FDA including Cohort 4 results is expected in late 2020.

Lifileucel had received a Regenerative Medicine Advanced Therapy, or RMAT, designation from the FDA.

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

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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 United States and in Europe and completed dosing in January 2020.

LN-145 for Cervical Cancer

We are developing LN-145 to treat cervical cancer.

According to estimates from the SEER program, approximately 13,000 women were diagnosed with cervical cancer, and approximately 4,300 cervical cancer-related deaths occurred in the United States in 2019.

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

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

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.

Lifileucel for Cervical Cancer

We are also developing lifileucel, for the treatment of cervical cancer.

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

According to estimates from the SEER program, approximately 13,800 women were diagnosed with cervical cancer, and approximately 4,290 cervical cancer-related deaths occurred in the U.S.

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

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

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

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

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

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

In 27 patients with metastatic cervical cancer, treatment with LN-145 resulted in an ORR of 44%.

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

In the study there were 3 complete responses and 9 partial responses.

The DCR was 85%.

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

The DOR had not been reached.

The median DOR had not been reached.

The median follow-up was 7.4 months.

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.

We plan to include in the BLA, patients who have progressed following initial systemic therapy for recurrent or metastatic disease.

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 LN-145.

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.

As a result of this amendment, the C-145-04 trial now consists of the following cohorts of cervical cancer patients with recurrent, persistent, or metastatic disease:

● Cohort 1 is the expected pivotal cohort for LN-145 and is anticipated to enroll 75 patients who have progressed during or after chemotherapy;

● Cohort 2 will enroll patients for treatment with LN-145 who have progressed during or after treatment with anti-PD-1/anti-PD-L1 checkpoint inhibitor;

● Cohort 3 will enroll patients who have not received prior systemic therapy for recurrent, metastatic, or persistent disease.

This Cohort will explore safety and efficacy of the combination of the LN-145 regimen with pembrolizumab;

● Cohort 4 is intended for patients who have been previously enrolled but are not considered within the registrational population, including patients dosed with product produced by first generation, or 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 LN-145.

As a result of these changes, we have also expanded the sample size of the C-145-04 clinical trial to include 138 patients from the appropriate patient populations across these five cohorts.

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 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.

LN-145 for NSCLC

We are developing LN-145 to treat NSCLC.

According to estimates from the SEER program, approximately 228,820 people were diagnosed with lung and bronchus cancers, and approximately 136,000 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.

LN-145 for Head and Neck Cancer

According to estimates from the SEER program, approximately 53,000 people were diagnosed with head and neck-related cancers, and approximately 11,000 head and neck- related cancer deaths occurred in the United States in 2019.

We are developing LN-145 to treat head and neck cancers.

We are also developing LN-145 to treat head and neck cancer.

According to estimates from the SEER program, approximately 65,630 people were diagnosed with head and neck-related cancers, which are referred to by the SEER program as oral cavity, pharynx and larynx cancers, and approximately 14,500 head and neck-related cancer deaths occurred in the U.S.

In June 2017, we enrolled our first patient in our ongoing Phase 2 trial, C-145-03, for the treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck, who have failed one prior therapy.

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

As additional patients are enrolled in the C-145-03 study, the safety profile of LN-145 may change.

We continue to enroll patients to the full target sample size of 55 patients.

The trial is enrolling patients in the United States.

We have since changed the design of our C-145-03 trial so that enrolled patients will 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.

Lifileucel and LN-145 in combination with pembrolizumab

In addition to the monotherapy trials for lifileucel and LN-145 mentioned above, we are developing these products in combination with pembrolizumab for melanoma, head and neck and NSCLC.

We also have a monotherapy arm for LN-145 in NSCLC.

According to estimates from the SEER program, approximately 228,000 people were diagnosed with lung and bronchus cancers, and approximately 143,000 deaths occurred related to these cancers in the United States in 2019.

IOV-COM-202 is a Phase 2, multicenter trial that is composed of four cohorts to enroll up to a total of 48 patients.

In Cohort 1A, we are enrolling advanced unresectable or metastatic melanoma patients who have not received prior immunotherapy, including checkpoint inhibitors such as anti-PD-1/anti-PD-L1 therapy.

The patients receive lifileucel in combination with pembrolizumab.

Cohort 2A, we are enrolling advanced head and neck squamous cell carcinoma patients who are also naïve to prior immunotherapy including anti-PD-1/anti-PD-L1 therapy.

The patients will receive LN-145 in combination with pembrolizumab.

Cohort 3A is enrolling non-small cell lung cancer patients who are naïve to prior immunotherapy including anti-PD-1/anti-PD-L1 therapy.

The patients in Cohort 3A will receive LN-145 in combination with pembrolizumab.

In Cohort 3B, we are enrolling non-small cell lung cancer patients who have previously received systemic therapy which could include checkpoint inhibitors.

The patients are receiving LN-145.

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.

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 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.

IOV-2001 PBL for CLL/SLL

In November 2019, we announced that our investigational new drug application, or IND, for IOV-2001 was approved by the FDA and our sponsored clinical trial using this therapy, IOV-CLL-01, was cleared to proceed.

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.

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.

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 Phase 1/2 clinical trial evaluating the safety and efficacy of IOV-2001 in patients with relapsed or refractory chronic lymphocytic leukemia, or CLL, or small lymphocytic leukemia, or SLL.

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.

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TIL in Other Solid Tumor Indications

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

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 will be treated with LN-145 or TIL manufactured by MDACC.

We are collaborating with Yale University on a clinical trial to evaluate TIL therapy in TNBC cancer.

This trial is expected to begin enrolling patients in 2020.

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

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.

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

TIL in Combination with Other Immunotherapy Drugs

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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.

This study is closed to enrollment.

An additional clinical trial, NCT02652455, is being conducted by Moffitt to evaluate TIL therapy in combination with nivolumab in metastatic melanoma.

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In 2019, we entered into a collaboration with Moffitt to fund a Phase 1 trial of lymphodepletion plus TIL therapy with high-dose IL-2 in adolescent and young adult patients with soft tissue sarcoma in clinical trial NCT04052334.

Under our CRADA, we are collaborating with the NCI on the 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.

This study is currently enrolling.

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.

TIL Therapy Background

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

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

well as cancerous cells.

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

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

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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.

(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.

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

Furthermore, the non-myeloablative lymphodepleting chemotherapy administered prior to TIL infusion is capable of suppressing the hostile tumor microenvironment, which we believe will enhance the efficacy of TIL therapy.

Furthermore, the non-myeloablative, or NMA, lymphodepleting chemotherapy administered prior to TIL infusion is capable of suppressing the hostile tumor microenvironment, which we believe will enhance the efficacy of TIL therapy.

Tumor-Infiltrating Lymphocytes

Adoptive cell therapy with TIL involves the following steps:

After a surgical resection of a lesion, a patient’s TIL are removed from the tumor

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

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

TIL therapy involves the following steps:

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:

Patient receives non-myeloablative lymphodepletion to eliminate potentially suppressive tumor microenvironment and maximize engraftment and potential potency of TIL therapy;

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

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, although our protocols allow for evaluation of more than one administration of TIL.

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.

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.

Historical Clinical Results with TIL in Metastatic Melanoma

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 United States, 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.

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.

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

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In September 2015, Dr.

Rosenberg, a recognized pioneer in immuno-oncology and adoptive cell therapy using TIL, presented updated findings from a Phase 2 clinical trial of TIL therapy in metastatic melanoma at the American Association for Cancer Research Inaugural International Cancer Immunotherapy Conference.

Steven Rosenberg, a recognized pioneer in immuno-oncology and adoptive cell therapy using TIL, presented updated findings from a Phase 2 clinical trial of TIL therapy in metastatic melanoma at the American Association for Cancer Research Inaugural International Cancer Immunotherapy Conference.

Data was presented from a 101 patient, Phase 2 clinical trial conducted at the NCI.

In the trial, patients with advanced metastatic melanoma were equally divided in two groups.

Both groups were treated according to a standard TIL protocol using nonmyeloablative, or NMA, chemotherapy, with the second group also receiving total body irradiation.

Both groups were treated according to a standard TIL protocol using NMA chemotherapy, with the second group also receiving total body irradiation, or TBI.

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

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Median progression-free survival was approximately 8-10 months.

This observation was

also presented by Dr.

This observation was also presented by Dr.

Stephanie Goff at the 2016 ASCO meeting and published in the Journal of Clinical Oncology in June 2016.

At the ASCO 2018 meeting, Dr.

Goff presented updated findings from the study.

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 study

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.

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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.

We continue to enroll patients in our ongoing TIL programs and we closely monitor our studies to learn about all safety events occurring, as described elsewhere in this Annual Report on Form 10-K.

We continue to enroll patients in our ongoing clinical programs and we closely monitor our studies to learn about all safety events occurring, as described elsewhere in this Annual Report on Form 10-K.

Some of these events may be associated with TIL therapy.

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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 the University of Montreal, as described elsewhere in this Annual Report on Form 10-K.

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 also developing PBL therapy for chronic lymphocytic leukemia.

We are also developing PBL therapy for CLL and SLL.

Process Development, Manufacturing, and Manufacturing Agreements

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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 the C-145-03 head and neck study.

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 and is currently being studied in the C-145-03 head and neck study.

This product is 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 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.

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

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.

We have two suites for clinical manufacturing at WuXi, and one of two suites is also available to manufacture TIL for commercial use.

Cell processing activities will be conducted at all companies under cGMP, using qualified equipment and materials.

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

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

We expect to rely on these CMOs, to meet anticipated clinical trial and if approved, commercial demands.

We expect to rely on our own manufacturing facility and these CMOs to meet anticipated clinical trial and if approved, commercial demands.

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 sale quantities, we are building our own commercial manufacturing facility to supply and process products.

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.

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.

Under the agreement, we entered into two statements of work for two cGMP manufacturing suites to be established and operated by WuXi for our product manufacturing.

The statements of work for each of the suites were amended in 2019 and 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 process.

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 quarterly fixed fees payable for each of the dedicated manufacturing suites range from $1.2 million to $2.7 million depending on the production capacity level targeted.

The terms of the related statements of work for the first and second dedicated manufacturing suites currently extend to May 2020 and June 2021, respectively.

Personalized Patient Product

In September 2017, we entered into an agreement with TrakCel Ltd., or TrakCel, to build a scheduling and logistics software tool that automates the supply chain for our TIL therapy products.

The TrakCel software will electronically link us with our clinical sites, CMOs and couriers to schedule and track TIL therapies for each patient.

The TrakCel software is also intended to help manage capacity utilization and throughput and will provide efficiencies in the delivery of TIL treatment.

The TrakCel software is also designed to ensure chain of identity for each patient’s product.

Because our product candidates are specifically manufactured for each individual patient, we will be required to maintain a chain of identity with respect to the patient’s tumor as it moves from the patient to the manufacturing facility, through the manufacturing process, and back to the patient.

We continue to explore optimized scheduling and logistics software tools useful in the commercialization of our TIL therapies, including tools from vendors other than TrakCel.

Orphan Drug Designation

During 2015, we received an orphan-drug designation for lifileucel in the United States to treat malignant melanoma stages IIB-IV.

If approved, this designation provides seven years of market exclusivity in the United States, subject to certain limited exceptions.

However, the orphan drug designation does not convey any advantage in, or shorten the duration of, the regulatory review or approval process.

During 2018, we received an orphan drug designation from the FDA for LN-145 for the treatment of cervical cancer with a tumor size of greater than 2 cm in diameter.

Fast Track Designation

Orphan Drug Designations

During 2015, we received an Orphan Drug Designation, or ODD, for lifileucel in the U.S.

to treat malignant melanoma stages IIB-IV.

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

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

The benefits and limitations of ODD are described in more detail elsewhere in this Annual Report on Form 10-K.

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.

Fast Track Designations

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

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

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

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.

Regenerative Medicine Advanced Therapy Designation

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

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

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

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

Under this designation,

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

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

Breakthrough Therapy Designation

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

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

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

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

BTD also allows the sponsor to file sections of the BLA on an ongoing basis for rolling review where the FDA may consider beginning review portions of a marketing application before the full submission is complete.

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

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

Commercialization Plan

We currently have limited sales, marketing or commercial product distribution capabilities and as a company we have no experience in commercializing a cell therapy products.

We are in the process of building our U.S.

commercial and medical affairs infrastructure and intend to build our own global commercialization capabilities over time in certain geographies for our TIL product candidates including lifileucel for metastatic melanoma and LN-145 for metastatic cervical cancer.

Melanoma is a common type of skin cancer, accounting for approximately 96,000 patients diagnosed and 7,230 deaths each year in the United States according to SEER as of 2019.

In cervical cancer approximately 13,000 women were diagnosed and approximately 4,300 cervical cancer-related deaths occurred in the United States in 2019.

If any of our TIL product candidates are approved, we expect to commercialize those products in the United States with an experienced sales, marketing, payer access and distribution organization including a national specialty oncology sales force.

We currently have limited sales, marketing or commercial product distribution capabilities and as a company we have no experience in commercializing cell therapy products.

We are continuing to build our U.S.

If any of our TIL product candidates are approved, we expect to commercialize those products in the U.S.

with an experienced sales, marketing, payer access and distribution organization including a national specialty oncology sales force.

We have started and continue to build a dedicated team of medical affairs professionals to help educate health professionals about our TIL therapy and to assist in any training necessary for individual centers to administer our therapy.

Outside the United States, we are in the process of defining our regulatory and commercial strategy.

Outside the U.S., we are in the process of defining our regulatory and commercial strategy.

As additional product candidates advance through our pipeline, our commercial plans will evolve as we consider elements such as the market potential.

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● building a patient-centric organization

To date, in the United States lifileucel has been administered in 23 centers and LN-145 for cervical cancer has been administered in 19 centers.

We anticipate that centers with prior TIL experience will be the initial targets for launch upon approval.

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.

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 also plan to rely on regulatory protection afforded through orphan drug designations, available regulatory exclusivities and patent term extensions where available.

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.

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

We have engaged in the development of our own patent portfolio based on internal research and development activities in 2018.

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

Our patent portfolio includes nine recently-granted U.S.

patents related to our Gen 2 TIL manufacturing process.

We expect to further develop our own patent portfolio as a strategic focus in 2020.

We expect to further develop our patent portfolio as a strategic focus in 2021.

We have developed our own patent portfolio based on internal research and development activities.

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.

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

We anticipate that the terms of these patents related to Gen 2 manufacturing processes will extend to January 2038, not including any patent term extensions or adjustments that may be available.

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

frozen tumor-based TIL technologies;

remnant TIL and digest TIL compositions, methods and processes;

methods of treatment of a broad range of cancers using TIL therapies;

methods of manufacturing TIL, MIL, and PBL therapies;

the use of costimulatory molecules in TIL therapy and manufacturing;

stable and transient genetically-modified TIL therapies;

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

TIL selection technologies;

and methods of treating patient subpopulations.

Research, Development and License Agreements

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 preclinical collaborations with MDACC and Ohio State University.

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 United States 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.

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.

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.

National Institutes of Health and the National Cancer Institute

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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 HPV-associated cancers.

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.

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

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 the Company 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.

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.

Exclusive Patent License Agreement Related to TIL Selection

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

Under the Exclusive Patent License Agreement, the Company 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 United States, and the first commercial sale of a licensed product or process in any foreign country.

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.

Lee Moffitt Cancer Center

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

Lee Moffitt Cancer Center, or Moffitt.

At the same time, we have entered into a clinical grant agreement with Moffitt 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.

Lee Moffitt Cancer Center, or 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 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.

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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 United States, Europe and Japan and in other countries designated by us in agreement with Moffitt.

We entered into a license agreement with Moffitt effective as of May 7, 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 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.

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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.

PolyBioCept Exclusive and Co-Exclusive License Agreement

On September 14, 2016, we entered into an exclusive and co-exclusive license Agreement, or the PolyBioCept Agreement, with PolyBioCept, AB, or PolyBioCept, a corporation organized under the laws of Sweden.

Under the PolyBioCept Agreement, we received the exclusive right and license to PolyBioCept’s intellectual property to develop, manufacture, market and genetically engineer TIL produced by expansion, selection and enrichment using a proprietary cytokine cocktail.

We also received a co-exclusive license (with PolyBioCept) to develop, manufacture and market genetically engineered TIL under the same intellectual property.

The licenses were for use in all cancers and were worldwide in scope, with the exception that the uses in melanoma are not included for certain countries of the former Soviet Union.

On June 13, 2019, we terminated the PolyBioCept Agreement.

Anderson Cancer Center

Strategic Alliance Agreement

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.

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The SAA’s term shall continue in effect until the later of the fourth anniversary of the SAA or the completion or termination of the research and receipt by us of all deliverables due from MDACC thereunder.

In May 2017, the Company made a prepayment of $1.4 million under this agreement.

In December 2015, we entered into a collaboration agreement, the MedImmune Agreement, with MedImmune, the global biologics research and development arm of AstraZeneca, to conduct clinical and preclinical research immuno-oncology.

Under the MedImmune Agreement, we funded and sought to conduct at least one clinical trial combining MedImmune's PD-L1 inhibitor, durvalumab with TIL for treatment of patients.

MedImmune supplied durvalumab for the clinical trials.

On April 3, 2019, the Company and MedImmune announced that the study was closed because of a changing treatment landscape and a lack of enrollment, and the collaboration agreement was terminated as of April 1, 2019.

In November 2016, the Company entered into a three-year manufacturing and services agreement, or MSA, with WuXi pursuant to which WuXi agreed to provide manufacturing and other services.

Under the agreement, the Company entered into two statements of work for two cGMP manufacturing suites to be established and operated by WuXi for the Company.

The statements of work for each of the suites were amended in 2019 and 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 the Company 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 May 2020 and June 2021, respectively.

In June 2018, we entered into a preclinical research collaboration with Cellectis to investigate TALEN for genetic editing in conjunction with TIL therapy.

In January 2020, we entered into a license agreement with Cellectis to use the TALEN technology to genetically edit TIL (see Subsequent Events).

In May 2017, we made a prepayment of $1.4 million under this agreement.

In light of the disease caused by the novel coronavirus, SARS-CoV-2, which was declared a public health emergency on January 31, 2020, under section 319 of the Public Health Service Act (42 U.S.C.

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.

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.

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.

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 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.

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

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We anticipate that we will face possibly increasing competition as new drugs and therapies enter the market and advanced technologies become available.

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, Immetacyte, WindMIL Therapeutics, Seattle Genetics, and others.

We also may compete with therapies based on genetically engineered T cells rendered reactive against tumor-associated antigens prior to their administration to patients.

Genetically engineered T cells are being pursued by several companies, including Adaptimmune, Bristol-Myers Squibb’s through its acquisition of Celgene, Gilead Sciences, Novartis and others.

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.

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 compounds currently under development.

In 2019, Idera Pharmaceuticals reported results from an ongoing Phase 3 clinical trial of the TLR9 agonist IMO-2125 in combination with ipilimumab indicating an ORR of 18% in 49 melanoma patients who had previously received anti-PD-1 therapy.

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.

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, and Roche.

Immunotherapy is also being pursued by several biotechnology companies as well as by large-cap pharmaceutical companies.

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

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

We cannot predict whether other types of immunotherapies may be enhanced and show greater efficacy.

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The FDA and other regulatory authorities at federal, state, and local levels, as well as in foreign countries, extensively regulate, among other things, the research, development, testing, manufacture, quality control, import, export, safety, effectiveness, labeling, packaging, storage, distribution, record keeping, approval, advertising, promotion, marketing, post-approval monitoring, and post-approval reporting of biologics such as those we are developing.

We, along with our third-party contractors, will be required to

navigate the various preclinical, clinical and commercial approval and post-approval requirements of the governing regulatory agencies of the countries in which we wish to conduct studies or seek approval or licensure of our product candidates.

We, along with our third-party contractors, will be required to navigate the various preclinical, clinical and commercial approval and post-approval requirements of the governing regulatory agencies of the countries in which we wish to conduct studies or seek approval or licensure of our product candidates.

The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local, and foreign statutes and regulations require the expenditure of substantial time and financial resources.

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Failure to comply with regulatory requirements may result in significant regulatory actions.

Such actions may include refusal to approve pending applications, license suspension or revocation, withdrawal of an approval, imposition of a clinical hold or termination of clinical trials, warning letters, untitled letters, cyber letters, modification of promotional materials or labeling, provision of corrective information, imposition of post-market requirements including the need for additional testing, imposition of distribution or other restrictions under a Risk Evaluation and Mitigation Strategy, or REMS, product recalls, product seizures or detentions, refusal to allow imports or exports, total or partial suspension of production or distribution, FDA debarment, injunctions, fines, consent decrees, corporate integrity agreements, debarment from receiving government contracts and new orders under existing contracts, exclusion from participation in federal and state healthcare programs, restitution, disgorgement, or civil or criminal penalties, including fines and imprisonment, and adverse publicity, among other adverse consequences.

The process required by the FDA before biologic product candidates may be marketed in the United States generally involves the following:

Such actions may include refusal to approve pending applications, license suspension or revocation, withdrawal of an approval, imposition of a clinical hold or termination of clinical trials, warning letters, untitled letters, modification of promotional materials or labeling, provision of corrective information, imposition of post-market requirements including the need for additional testing, imposition of distribution or other restrictions under a Risk Evaluation and Mitigation Strategy, or REMS, product recalls, product seizures or detentions, refusal to allow imports or exports, total or partial suspension of production or distribution, FDA debarment, injunctions, fines, consent decrees, corporate integrity agreements, debarment from receiving government contracts and new orders under existing contracts, exclusion from participation in federal and state healthcare programs, restitution, disgorgement, or civil or criminal penalties, including fines and imprisonment, and adverse publicity, among other adverse consequences.

The process required by the FDA before biologic product candidates may be marketed in the U.S.

generally involves the following:

● completion of preclinical laboratory tests and animal studies performed in accordance with the FDA’s current Good Laboratory Practices, or GLP, regulation, as well as manufacturing development and formulation studies;

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

● 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 United States, which must be updated periodically when changes are made.

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.

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

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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.

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Phase 1, Phase 2 and Phase 3, and Phase 4 testing, if applicable, may not be completed successfully within a specified period, if at all, and there can be no assurance that the data collected will support FDA approval or licensure of the product.

Concurrent with clinical trials,

companies may complete additional animal studies and develop additional information about the biological characteristics of the product candidate and must finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.

Concurrent with clinical trials, companies may complete additional animal studies and develop additional information about the biological characteristics of the product candidate and must finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.

The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, must develop methods for testing the identity, strength, quality and purity of the final product, or for biologics, the safety, purity and potency.

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The manufacture of investigational biologics for the conduct of human clinical trials is subject to cGMP requirements.

Investigational biologics and active ingredients imported into the United States are also subject to regulation by the FDA relating to their labeling and distribution.

Further, the export of investigational products outside of the United States is subject to regulatory requirements of the importing country as well as U.S.

Investigational biologics and active ingredients imported into the U.S.

are also subject to regulation by the FDA relating to their labeling and distribution.

Further, the export of investigational products outside of the U.S.

is subject to regulatory requirements of the importing country as well as U.S.

export requirements under the FDCA.

Additional United States and foreign laws and regulations may also be applicable to the handling, import, export, and transportation of biological materials, including tissue samples.

Additional U.S.

and foreign laws and regulations may also be applicable to the handling, import, export, and transportation of biological materials, including tissue samples.

During the development of a new therapeutic, a sponsor may be able to request a Special Protocol Assessment, or SPA, the purpose of which is to reach an agreement with the FDA on the Phase 3 clinical trial protocol design and analysis that will form the primary basis of product approval and an efficacy claim, as well as preclinical carcinogenicity trials and stability studies.

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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.

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.

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.

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

The submission of a BLA requires payment of a substantial user fee to the FDA, under the

Prescription Drug User Fee Act, and the sponsor of an approved BLA is also subject to annual program fees.

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

These fees are typically increased annually.

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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:

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A sponsor may seek approval of its product candidate under programs designed to accelerate the FDA’s review and approval of new drugs and biological products that meet certain criteria.

Specifically, new drugs and biological products are eligible for Fast Track designation if they are intended to treat a serious or life-threatening condition and demonstrate the potential to address unmet medical

needs for the condition.

For a Fast Track designation, the FDA may consider sections of the BLA for review on a rolling basis before the complete application is submitted if relevant criteria are met.

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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 sponsor;

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

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.

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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 the RMAT designation for metastatic melanoma.

In 2019 the FDA granted Fast Track designation and Breakthrough Therapy Designation for LN-145 for metastatic cervical cancer.

During 2015, we received an orphan drug designation for lifileucel in the United States to treat malignant melanoma stages IIB-IV.

We plan to seek orphan drug designation for some or all 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 orphan-drug designation from the FDA for LN-145 for the treatment of cervical cancer with a tumor size of greater than 2cm in diameter.

Under the Orphan Drug Act, the FDA may grant orphan drug designation 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 United States, or a patient population greater than 200,000 individuals in the United States and when there is no reasonable expectation that the cost of developing and making available the drug or biologic in the United States will be recovered from sales in the United States for that drug or biologic.

Additionally, sponsors must present a plausible hypothesis for clinical superiority to obtain orphan drug designation if there is a product already approved by the FDA that is intended for the same indication and that is considered by the FDA to be the same product as the already approved product.

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.

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

will be recovered from sales in the U.S.

for that drug or biologic.

Additionally, sponsors must present a plausible hypothesis for clinical superiority to obtain ODD if there is a product already approved by the FDA that is intended for the same indication and that is considered by the FDA to be the same product as the already approved product.

This hypothesis for clinical superiority must be demonstrated to obtain orphan exclusivity.

Orphan drug designation must be requested before submitting a BLA.

After the FDA grants orphan drug designation, the generic identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA.

If a product that has orphan drug designation subsequently receives the first FDA approval for a particular active ingredient for the disease for which it has such designation, the product is entitled to orphan product exclusivity, which means that the FDA may not approve any other applications, including a full BLA, to market the same biologic, as sameness is defined in the FDA’s regulations, for the same indication for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with orphan drug exclusivity or if the FDA finds that the holder of the orphan drug exclusivity has not shown that it can assure the availability of sufficient quantities of the orphan drug to meet the needs of patients with the disease or condition for which the drug was designated.

ODD must be requested before submitting a BLA.

After the FDA grants ODD, the generic identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA.

If a product that has ODD subsequently receives the first FDA approval for a particular active ingredient for the disease for which it has such designation, the product is entitled to orphan product exclusivity, which means that the FDA may not approve any other applications, including a full BLA, to market the same biologic, as sameness is defined in the FDA’s regulations, for the same indication for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with orphan drug exclusivity or if the FDA finds that the holder of the orphan drug exclusivity has not shown that it can assure the availability of sufficient quantities of the orphan drug to meet the needs of patients with the disease or condition for which the drug was designated.

Orphan drug exclusivity does not prevent the FDA from approving a different drug or biologic for the same disease or condition, or the same drug or biologic for a different disease or condition.

Among the other benefits of orphan drug designation are tax credits for certain research, opportunities for certain research grant funding, and a waiver of the BLA application fees.

Among the other benefits of ODD are tax credits for certain research, opportunities for certain research grant funding, and a waiver of the BLA application fees.

The tax credit, however, was recently limited through Congress’s tax reform efforts.

Despite these benefits, the orphan drug designation does not convey any advantage in, or shorten the duration of, the regulatory review or approval process.

Despite these benefits, the ODD does not convey any advantage in, or shorten the duration of, the regulatory review or approval process.

A designated orphan drug may not receive orphan drug exclusivity if it is approved for a use that is broader than the indication for which it received orphan designation.

In addition, orphan drug exclusive marketing rights in the United States may be lost if the FDA later determines that the request for designation was materially defective or if the manufacturer is unable to assure sufficient quantities of the product to meet the needs of patients with the rare disease or condition.

In addition, orphan drug exclusive marketing rights in the U.S.

may be lost if the FDA later determines that the request for designation was materially defective or if the manufacturer is unable to assure sufficient quantities of the product to meet the needs of patients with the rare disease or condition.

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

While the FDA may eventually license products, as further described below, that are biosimilar to any of our product candidates that are approved, our products may receive periods of regulatory exclusivity, in addition to orphan drug exclusivity for those products with orphan drug designations, providing additional protection from certain forms of competition.

While under the Biologics Price Competition and Innovation Act of 2009, or BPCIA, the FDA may eventually license products, as further described below, that are biosimilar to any of our product candidates that are approved, our products may receive periods of regulatory exclusivity, in addition to orphan drug exclusivity for those products with ODDs, providing additional protection from certain forms of competition.

For instance, our products may receive 12 years of reference product exclusivity that begins running at the time of first licensure.

During this time, the FDA may not make an approval of a biosimilar product effective and may not accept a biosimilar application for four years from the date of licensure.

During this 12-year time period, the FDA may not make an approval of a biosimilar product effective and may not accept a biosimilar application until after four years from the date of first licensure.

However, certain changes and supplements to an approved BLA, and subsequent applications filed by the same sponsor, manufacturer, licensor, predecessor in interest, or other related entity do not qualify for the exclusivity period.

The PHSA also includes provisions to protect reference products that have patent protection.

The biosimilar product sponsor and reference product sponsor may, but are not required to, exchange certain patent and product information for the purpose of determining whether there should be a legal patent challenge.

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

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

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

The biosimilar applicant may also be able to bring an action for declaratory judgment concerning the patent.

The Biologics Price Competition and Innovation Act, or BPCIA, created an abbreviated approval pathway for biological products shown to be highly similar to or interchangeable with an FDA-licensed reference biological product.

Accordingly, if we receive FDA

licensure, we may face competition from biosimilar products.

The biosimilar applicant may also be able to bring an action for declaratory judgment concerning the patent under certain circumstances.

The BPCIA created an abbreviated approval pathway for biological products shown to be highly similar to or interchangeable with an FDA-licensed reference biological product.

Accordingly, if we receive FDA licensure, we may face competition from biosimilar products.

Biosimilarity sufficient to reference a prior FDA-approved product requires a high similarity to the reference product notwithstanding minor differences in clinically inactive components, and no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency.

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Pediatric Exclusivity and Patent Term Extension

Pediatric exclusivity is another type of non-patent marketing exclusivity in the United States and, if granted, provides for the attachment of an additional six months of marketing protection to the term of any existing regulatory exclusivity.

This six-month exclusivity may be granted if a sponsor submits pediatric data that fairly respond to a written request from the FDA for such data.

Pediatric exclusivity is another type of non-patent marketing exclusivity in the U.S.

and, if granted, provides for the attachment of an additional six months of marketing protection to the term of any existing regulatory exclusivity.

Under the Best Pharmaceuticals for Children Act, a six-month exclusivity may be granted if a sponsor submits pediatric data that fairly respond to a written request from the FDA for such data.

The data do not need to show the product to be effective in the pediatric population studied;

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If reports of requested pediatric studies are submitted to and accepted by the FDA, whatever regulatory periods of exclusivity that already cover the product are extended by six months.

Pediatric exclusivity is thus an “add-on” exclusivity and is unique in this regard among the various regulatory exclusivities provided by FDA.

The FDA can also require pediatric studies of a drug submitted in a new drug application if the FDA determines that the product is likely to be used in a substantial number of pediatric patients, or if the product would provide a meaningful benefit in the pediatric population over existing treatments.

This requirement may be waived in certain circumstances, for example, where the indication does not occur or is not highly prevent in the pediatric population.

If approved, biologics may also be eligible for periods of U.S.

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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 with the FDA and certain state agencies that list their products, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP and other 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.

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

In addition, changes to the manufacturing process are strictly regulated, and depending on the significance of the change, may require

prior FDA approval or notification before being implemented.

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

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

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

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

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

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

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

Further, the DSCSA limits the distribution of prescription pharmaceutical products and imposes requirements to ensure overall accountability and security in the drug supply chain.

As of November 27, 2018, product identifier information, an aspect of the product tracing scheme, is required.

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

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

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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 United States and between states.

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.

After a BLA is approved, the product may also be subject to official lot release as a condition of approval.

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Other Healthcare Laws and Compliance Requirements

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 United States, 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 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.

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The term "remuneration"

includes kickbacks, bribes or rebates and also has been

broadly interpreted to include anything of value, including, for example, gifts, discounts, waivers of payment, ownership interest and providing anything at less than its fair market value.

includes kickbacks, bribes or rebates and also has been broadly interpreted to include anything of value, including, for example, gifts, discounts, waivers of payment, ownership interest and providing anything at less than its fair market value.

Additionally, the intent standard under the federal AKS provides that a person or entity need not have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

In addition, a claim including items or services resulting from a violation of the federal AKS constitutes a false or fraudulent claim for purposes of the federal civil False Claims Act.

There are a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution or other regulatory sanctions.

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Our practices may not in all cases meet all the criteria for protection under a statutory exception or regulatory safe harbor.

Additionally, the intent standard under the federal AKS was amended by the Patient Protection Affordable Care Act of 2010, as amended by the Health Care and Education Reconciliation Act of 2010, which is collectively referred to as the Affordable Care Act, or ACA, to a stricter standard such that a person or entity no longer needs to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

In addition, the ACA codified case law that a claim including items or services resulting from a violation of the federal AKS constitutes a false or fraudulent claim for purposes of the federal civil False Claims Act.

The safe harbors are subject to change through legislative and regulatory action, and we may decide to adjust our business practices or be subject to heightened scrutiny as a result.

The civil monetary penalties statute imposes penalties against any person or entity who, among other things, is determined to have presented or caused to be presented a claim for payment, or approval to a federal healthcare program that the person knows or should know is for an item or service that was not provided as claimed or is false or fraudulent.

The FCA imposes liability on persons who, among other things, knowingly present or cause to be presented false or fraudulent claims for payment to, or approval by the federal government knowingly making or using, or causing to be made or used a false statement or record material to a claim to the federal government, or avoiding, decreasing or concealing an obligation to pay money to the federal government.

As a result of a modification made by the Fraud Enforcement and Recovery Act of 2009, a claim includes "any request or demand"

for money or property presented to the federal government.

A claim includes "any request or demand"

for money or property presented directly or indirectly to the federal government.

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.

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In addition, federal AKS violations (which may be alleged based on certain marketing practices, including allegations of off-label promotion) implicate the FCA.

The compliance and enforcement landscape, and related risk, is informed by government litigation and settlement precedent, Advisory Opinions, and Special Fraud Alerts.

Our approach to compliance may evolve over time in light of these types of developments.

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 United States 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.

Activities that violate the FCPA, even if they occur wholly outside the United States, can result in criminal and civil fines, imprisonment, disgorgement, oversight, and debarment from government contracts.

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

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.

Activities that violate the FCPA, even if they occur wholly outside the U.S., can result in criminal and civil fines, imprisonment, disgorgement, oversight, and debarment from securing government contracts.

We cannot assure you that our internal control policies and procedures will protect us from reckless or negligent acts committed by our employees, future distributors, partners, collaborators or agents.

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The Medicaid Drug Rebate statute requires manufacturers to calculate and report price points, which are used to determine Medicaid rebate payments shared between the states and the federal government and Medicaid payment rates for the drug.

For drugs paid under Medicare Part B, manufacturers must also calculate and

report their Average Sales Price or ASP, which is used to determine the Medicare Part B payment rate for the drug.

Drugs that are approved under a Biologic License Application, or BLA, or a New Drug Application, or NDA, including 505(b)(2) drugs, are subject to an additional inflation penalty which can substantially increase rebate payments.

For drugs paid under Medicare Part B, manufacturers must also calculate and report their Average Sales Price or ASP, which is used to determine the Medicare Part B payment rate for the drug.

Drugs that are approved under a BLA or a New Drug Application, or NDA, including 505(b)(2) drugs, are subject to an additional inflation penalty which can substantially increase rebate payments.

In addition, for BLA and NDA drugs, the Veterans Health Care Act, or VHCA, requires manufacturers to calculate and report to the Veterans Administration, or VA, a different price called the Non‑Federal Average Manufacturing Price, which is used to determine the maximum price that can be charged to certain federal agencies, referred to as the Federal Ceiling Price, or FCP.

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In addition, the VHCA requires manufacturers participating in Medicaid to agree to provide different mandatory discounts to certain Public Health Service grantees and other safety net hospitals and clinics.

The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which imposes criminal and civil 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.

The ACA amended the intent requirement of certain of these criminal statutes under HIPAA so that a person or entity no longer needs 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 regulation by both the federal government and the states in which we conduct our business.

HIPAA, as amended by the Health Information Technology and Clinical Health Act, or HITECH, and their respective implementing regulations, including the final omnibus rule published on January 25, 2013, imposes specific requirements relating to the privacy, security and transmission of individually identifiable health information.

Among other things, HITECH makes HIPAA’s privacy and security standards directly applicable to “business associates,” defined as a person or entity that performs certain functions or activities that involve the use or disclosure of protected health information in connection with providing a service for or on behalf of, or provide services to, a covered entity.

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.

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.

While we would not be a “covered entity” under HIPAA, it is possible that we may enter into a service or business arrangement that would cause us to serve as a “business associates,” defined as a person or entity that performs certain functions or activities that involve the use or disclosure of protected health information in connection with providing a service for or on behalf of, or provide services to, a covered entity.

HITECH also increased the civil and criminal penalties that may be imposed against covered entities, business associates and possibly other persons, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorney’s fees and costs associated with pursuing federal civil actions.

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The Department of Health and Human Services Office of Civil Rights, or the OCR, has increased its focus on compliance and continues to train state attorneys general for enforcement purposes.

The OCR has increased both its efforts to audit HIPAA compliance and its level of enforcement, with one recent penalty exceeding $5 million.

Even for entities that are not deemed “covered entities” or “business associates” under HIPAA, according to the United States Federal Trade Commission, or the FTC, failing to take appropriate steps to keep consumers’ personal information secure constitutes unfair acts or practices in or affecting commerce in violation of Section 5(a) of the Federal Trade Commission Act, or the FTCA, 15 USC § 45(a).

Even for entities that are not deemed “covered entities” or “business associates” under HIPAA, according to the U.S.

Federal Trade Commission, or the FTC, failing to take appropriate steps to keep consumers’ personal information secure constitutes unfair acts or practices in or affecting commerce in violation of Section 5(a) of the Federal Trade Commission Act, or the FTCA, 15 USC § 45(a).

The FTC expects a company's data security measures to be reasonable and appropriate in light of the sensitivity and volume of consumer information it holds, the size and complexity of its business, and the cost of available tools to improve security and reduce vulnerabilities.

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The FTC's guidance for appropriately securing consumers' personal information is similar to what is required by the HIPAA Security Rule.

In addition to the laws discussed above, we may see more stringent state and federal privacy legislation in 2021 and beyond, as the increased cyber-attacks during the pandemic have heightened attention data privacy and security in the U.S.

and other jurisdictions.

We cannot predict where new legislation might arise, the scope of such legislation, or the potential impact to our business and operations.

Payments made to physicians and other healthcare providers, and other financial interests, have been the subject of a range of federal and state laws.

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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.

In the future, the reporting and transparency requirements for payments and transfers of value will be extend (based on 2018 legislation) beyond physicians to physician assistants, nurse practitioners, and other mid-level HCPs, (with reporting requirements going into effect in 2022 for payments made in 2021).

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.

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.

Analogous state laws and regulations, such as state anti-kickback and false claims laws, and other state laws addressing the pharmaceutical and healthcare industries, which may apply to items or services reimbursed by any third-party payor, including commercial insurers, and in some cases may apply regardless of payor, i.e.

even if reimbursement is not available.

Some state laws require pharmaceutical companies to comply with the pharmaceutical industry's voluntary compliance guidelines (the PhRMA Code) and the relevant compliance program guidance promulgated by the federal government (HHS-OIG) 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 legislation – the California Consumer Privacy Act, or CCPA, – which went into effect on January 1, 2020.

The CCPA, among other things, creates new data privacy obligations for covered companies and provides new privacy rights to California residents, including the right to opt out of certain disclosures of their information.

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.

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.

Companies must still comply with the CCPA during the ramp up period before CPRA goes into effect.

The CCPA and CPRA, among other things, create new data privacy obligations for covered companies and provides new privacy rights to California residents, including the right to opt out of certain disclosures of their information.

The CCPA also created a private right of action with statutory damages for certain data breaches, thereby potentially increasing risks associated with a data breach.

It remains unclear what, if any, additional modifications will be made to the CPRA by the California legislature or how it will be interpreted.

Therefore, the effects of the CCPA and CPRA are significant and will likely require us to modify our data processing practices, and may cause us to incur substantial costs and expenses to comply.

To the extent that any of our products are sold in a foreign country, we may be subject to similar foreign laws and regulations, which may include, for instance, applicable post-marketing requirements, including safety surveillance, anti‑fraud and abuse laws, and implementation of corporate compliance programs and reporting of payments or transfers of value to HCPs.

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The product candidates that we develop may not be considered cost-effective.

It is time consuming and expensive for us to seek coverage

and reimbursement from third-party payors.

It is time consuming and expensive for us to seek coverage and reimbursement from third-party payors.

Moreover, a payor’s decision to provide coverage for a drug product does not imply that an adequate reimbursement rate will be approved, especially for product candidates such as ours, which are used in the inpatient setting, usually resulting in no separate reimbursement for pharmaceuticals.

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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.

Government laws and regulations also establish price controls on prescription drugs purchased by government agencies that provide health care and certain federally funded hospital outpatient departments and clinics.

In the United States, private health insurers and other third-party payors often provide reimbursement for products and services based on the level at which the government provides reimbursement through the Medicare or Medicaid programs for such products and services.

In the U.S., private health insurers and other third-party payors often provide reimbursement for products and services based on the level at which the government provides reimbursement through the Medicare or Medicaid programs for such products and services.

These restrictions and limitations influence the purchase of healthcare services and products.

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Further, some stakeholders have recently questioned whether the market price of prescription drugs may be inflated by virtue of the built-in cost imparted by the government rebate model, often negotiated indirectly in exchange for a coverage determination or formulary placement where relevant.

In the United States, the European Union, and other potentially significant markets for our product candidates, government authorities and private third-party payors are increasingly attempting to limit or regulate the price of medical products and services, particularly for new and innovative products and therapies, which often has resulted in average selling prices lower than they would otherwise be.

In the U.S., the European Union, and other potentially significant markets for our product candidates, government authorities and private third-party payors are increasingly attempting to limit or regulate the price of medical products and services, particularly for new and innovative products and therapies, which often has resulted in average selling prices lower than they would otherwise be.

Manufacturers frequently must rebate a portion of the prescription price to the third‑party payors as a condition of coverage, which can greatly reduce realization on the sale.

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Achieving favorable CMS coverage and reimbursement is usually a significant gating issue for successful introduction of a new product, because Medicare and Medicaid can represent a sizeable share of the market and because private payors often rely on the lead of the governmental payors in rendering coverage and reimbursement determinations.

Further, the increased emphasis on managed healthcare in the United States and on country and regional pricing and reimbursement controls in the European Union will likely put additional pressure on product pricing, reimbursement, and utilization, which may adversely affect our future product sales and results of operations.

Further, the increased emphasis on managed healthcare in the U.S.

and on country and regional pricing and reimbursement controls in the European Union will likely put additional pressure on product pricing, reimbursement, and utilization, which may adversely affect our future product sales and results of operations.

These pressures can arise from rules and practices of managed care groups, competition within therapeutic classes, availability of generic equivalents, judicial decisions and governmental laws and regulations related to Medicare, Medicaid, and healthcare reform, pharmaceutical coverage and reimbursement policies, and pricing in general.

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A payor’s decision to provide coverage for a drug product does not imply that an adequate reimbursement rate will be approved.

Adequate third-party reimbursement may not be available to ensure

acceptance and use of our products and product candidates or enable us to maintain price levels sufficient to realize an appropriate return on our investment in drug development.

Adequate third-party reimbursement may not be available to ensure acceptance and use of our products and product candidates or enable us to maintain price levels sufficient to realize an appropriate return on our investment in drug development.

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

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Healthcare Reform

The United States and some foreign jurisdictions are considering or have enacted a number of legislative and regulatory proposals to change the healthcare system in ways that could affect our ability to sell our products profitably.

Among policy makers and payors in the United States 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 United States, the pharmaceutical industry has been a particular focus of these efforts and has been significantly affected by major federal and state legislative initiatives.

and some foreign jurisdictions are considering or have enacted a number of legislative and regulatory proposals to change the healthcare system in ways that could affect our ability to sell our products profitably.

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.

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.

In addition, other legislative and regulatory changes have been proposed and adopted since the ACA was enacted.

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Although hospital trade associations filed a lawsuit challenging the regulation, the final rule is now in effect.

These new laws may result in additional reductions in Medicare and other healthcare funding, which could have a material adverse effect on customers for our product candidates, if approved, and, accordingly, our financial operations.

In recent years, there have been and continue to be proposals by the federal government, state governments, regulators, and third-party payors to control these costs and, more generally, to reform the U.S.

health care system.

Certain of these proposals could limit the prices we are able to charge for our products or the amounts of reimbursement available for our products.

These laws and future laws may result in additional reductions in Medicare and other healthcare funding, which could have a material adverse effect on customers for our product candidates, if approved, and, accordingly, our financial operations.

Any reduction in reimbursement from Medicare or other government-funded programs may result in a similar reduction in payments from private payors.

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Foreign Regulation

In addition to regulations in the United States, we will be subject to a variety of foreign regulations governing clinical trials and commercial sales and distribution of our products to the extent we choose to develop or sell any products outside of the United States.

In addition to regulations in the U.S., we will be subject to a variety of foreign regulations governing clinical trials and commercial sales and distribution of our products to the extent we choose to develop or sell any products outside of the U.S.

The approval process varies from country to country and the time may be longer or shorter than that required to obtain FDA approval.

The requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement vary greatly from country to country.

In the EU, member states require both regulatory clearances by the national competent authority and a favorable ethics committee opinion prior to the commencement of a clinical trial.

In the EU and the United Kingdom, member states require both regulatory clearances by the national competent authority and a favorable ethics committee opinion prior to the commencement of a clinical trial.

Under the EU regulatory systems, marketing authorization applications may be submitted under either a centralized or decentralized procedure.

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By law, a company can only start to market a medicine once it has received a marketing authorization.

Employees and Human Capital Management

As of December 31, 2020, we had 241 employees, 176 of whom were engaged in research and development activities and 65 of whom were engaged in general and administrative support activities.

None of our employees are subject to a collective bargaining agreement.

Our employees are highly skilled, and many hold advanced degrees.

Most of our employees have experience with the development of cell therapies.

We consider our relationship with our employees to be good.

Our future performance depends significantly upon the continued service of our key scientific, technical and senior management personnel.

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.

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.

We have taken proactive, aggressive action throughout the COVID-19 pandemic to protect the health and safety of our employees.

We expect to continue to implement these measures until we determine that the COVID-19 pandemic is adequately contained for purposes of our business.

We may take further actions, in compliance with all appropriate government regulations, that we determine to be in the best interest of our employees.

Available Information

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

What changed 10-K

Item 1. Business