Iovance Biotherapeutics Stock

Iovance Biotherapeutics, Inc. (Iovance) operates as a commercial-stage biopharmaceutical company.

The company is pioneering a transformational approach to treating cancer by harnessing the human immune system's ability to recognize and destroy diverse cancer cells using therapies personalized for each patient. The company's intention is to be the global leader in innovating, developing and delivering tumor infiltrating lymphocyte, or TIL, cell therapies for patients with solid tumor cancers. With the recent approval of the company's biologics license application, or BLA, the company is executing the U.S. launch of Amtagvi (lifileucel), the first product within the company's autologous TIL cell therapy platform, while also marketing Proleukin (aldesleukin), an interleukin-2, or IL-2, product used in the Amtagvi treatment regimen. Amtagvi is a tumor-derived autologous T cell immunotherapy indicated for the treatment of adult patients with unresectable or metastatic melanoma previously treated with a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor. This indication is approved under accelerated approval based on an endpoint of overall response rate, or ORR. Continued approval for this indication may be contingent upon verification and description of clinical benefit in future confirmatory trials. Amtagvi is the first and the only one-time, individualized T cell therapy to receive FDA approval for a solid tumor cancer. Amtagvi and Proleukin are part of a treatment regimen that also includes lymphodepletion.

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

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

The company's development pipeline includes multicenter trials of TIL cell therapies in additional treatment settings for solid tumor cancers. The company is investigating TIL monotherapies for patients with later stage disease who were previously treated with standard of care therapies and TIL combinations with standard of care therapies to potentially improve outcomes in patients who are earlier in their disease. These trials include two ongoing registrational trials to support a supplementary BLA, or sBLA, of the company's TIL cell therapies in frontline advanced melanoma and in advanced non-small cell lung cancer following standard of care chemo-immunotherapy. The company is also developing next generation therapies using TIL, such as genetically modified TIL cell therapy.

Strategy

The company's strategies are to be the global leader in innovating, developing and delivering TIL cell therapy; successfully commercialize the company's lead product Amtagvi for the treatment of post-anti-PD-1 advanced melanoma; and prepare for commercial manufacturing to meet forecasted demand.

The U.S. Commercial Launch of the First TIL Cell Therapy in Advanced Melanoma

Amtagvi

Amtagvi (lifileucel) was approved by the FDA on February 16, 2024 for the treatment of adult patients with unresectable or metastatic melanoma previously treated with a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF inhibitor with or without MEK inhibitor. The approval is based on safety and efficacy results from the C-144-01 clinical trial, a global, multicenter trial investigating Amtagvi in patients with advanced melanoma previously treated with anti-PD-1 therapy and targeted therapy, where applicable. Amtagvi demonstrated deep and durable responses. The primary efficacy analysis set included 73 patients from Cohort 4 who received the recommended Amtagvi dose from an approved manufacturing facility. Among the 73 patients, 31.5% achieved an objective response by Response Evaluation Criteria in Solid Tumors, or RECIST 1.1, with a median duration of response not reached at 18.6 months follow-up; 43.5% of responses had a duration greater than 12 months. Additionally, the supporting pooled efficacy set included a total of 153 patients from Cohort 4 and Cohort 2. Among the 153 patients, 31.4% achieved an objective response by RECIST 1.1 with a median duration of response not reached at 21.5 months follow-up; 54.2% of responses had a duration greater than 12 months. The company completed the BLA submission in March 2023, which the FDA accepted in May 2023 for Priority Review. Based on the unmet need in post-anti-PD-1 advanced melanoma, as well as initial clinical data, Amtagvi previously received a Regenerative Medicine Advanced Therapy, or RMAT, designation from the FDA in 2018.

Amtagvi has a boxed warning for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment. Warnings and precautions include treatment-related mortality, prolonged severe cytopenia, internal organ hemorrhage, severe infection, cardiac disorder, respiratory failure, acute renal failure, and hypersensitivity reactions.

Amtagvi is manufactured using a proprietary process to collect and multiply a patient's unique T cells from a portion of their tumor. Amtagvi returns billions of the patient's T cells back to the body to fight cancer. ATCs will administer Amtagvi to patients as part of a treatment regimen that includes lymphodepletion and a short course of high-dose Proleukin (aldesleukin).

Proleukin

In May 2023, the company acquired the worldwide rights to Proleukin(aldesleukin) as well as the manufacturing, supply, and commercialization income generated from such rights and associated operations from Clinigen Holdings Limited, Clinigen Healthcare Limited, and Clinigen, Inc, which the company refers to collectively as Clinigen. Ownership of Proleukin provides an additional revenue source, allows Iovance to secure its supply chain and logistics surrounding TIL cell therapy administration, and lowers cost of goods and clinical trial expenses for Proleukin used with TIL cell therapies.

Proleukin is an IL-2 product used in the Amtagvi treatment regimen. Proleukin has also received regulatory approvals for the treatment of adults with metastatic melanoma and metastatic renal cell carcinoma in the United States. Proleukin is also licensed in multiple countries around the world for the treatment of patients with metastatic renal cell carcinoma and/or metastatic melanoma.

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

TIL cell therapy is a T cell-based immunotherapy technology platform that leverages patient-specific cells to recognize and attack diverse cancer cells that are unique to each patient. Unlike other cell therapies that act on a single or small number of shared antigen targets common to certain tumors, the company's individualized T cell therapy are polyclonal or designed to target a variety of neoantigens that are unique to the patient or tumor. This polyclonal cell therapy is potentially applicable to many solid tumor cancers, where the majority of immune targets are patient-specific. The company's TIL cell therapy platform and manufacturing process have been initially validated through the FDA approval of Amtagvi.

The company has investigated TIL cell therapy in global, multicenter clinical trials in advanced melanoma, cervical cancer, non-small cell lung cancer, or NSCLC, and head and neck squamous cell carcinoma, or HNSCC. Through ongoing academic collaborations, as well as government and other partners, the company is investigating the next frontier for TIL cell therapy in other tumor types and treatment settings.

Frontline Advanced Melanoma: In frontline advanced melanoma patients who are naïve to anti-PD-1 therapy, the company is investigating lifileucel in combination with pembrolizumab in the Phase 3 TILVANCE-301 clinical trial. TILVANCE-301 is a randomized Phase 3 clinical trial intended to support registration in advanced frontline melanoma, as well as to serve as a confirmatory trial for full approval in post-anti-PD-1 advanced melanoma. TILVANCE-301 is expected to enroll approximately 670 patients and features dual primary endpoints of ORR and progression free survival, or PFS, by a blinded independent review committee.

Non-Small Cell Lung Cancer: In NSCLC, the company is investigating LN-145 TIL cell therapy in two clinical trials in NSCLC patient populations with significant unmet need. IOV-LUN-202 is a registrational clinical trial of LN-145 in advanced NSCLC patients who have progressed following chemotherapy and anti-PD-1 therapy. The IOV-COM-202 trial in solid tumors also includes cohorts of NSCLC patients treated with LN-145 monotherapy and combination therapy.

Gynecological Cancers: The company is planning to initiate a clinical trial for lifileucel TIL cell therapy in endometrial cancer to potentially address the unmet need for patients previously treated with anti-PD-1 therapy. The company is also exploring lifileucel in advanced cervical cancer in the C-145-04 multicenter Phase 2 clinical trial.

Next Generation TIL Cell Therapy: The company's first genetically modified, PD-1 inactivated TIL cell therapy, IOV-4001, entered a first-in-human Phase 1/2 clinical trial, IOV-GM1-201, in 2022 in patients with previously treated advanced melanoma and NSCLC. IOV-4001 utilizes the gene-editing TALEN technology, licensed from Cellectis S.A., or Cellectis, to inactivate the gene coding for the programmed cell death protein-1, or PD-1.

Additional Solid Tumor Cancers: Iovance TIL cell therapy has been investigated in additional solid tumor cancers in Iovance-and-investigator-sponsored clinical trials. LN-145 was evaluated as a monotherapy and in combination with pembrolizumab in the Phase 2 C-145-03 and IOV-COM-202 clinical trials in multiple patient cohorts with metastatic HNSCC. Indications studied in investigator sponsored clinical trials supported by Iovance include soft tissue sarcoma, osteosarcoma, pancreatic and colorectal cancer, platinum resistant ovarian cancer, anaplastic thyroid cancer and triple negative breast cancer.

Intellectual Property

The company established leadership within the field of TIL cell therapy by building and augmenting a leading intellectual property portfolio developed internally and licensed from third parties. The company owns more than 60 U.S. patents related to TIL cell therapy, including patents directed to compositions and methods of treatment in a broad range of cancers. Pending patent applications and granted patents cover the fields of TIL cell therapy, genetically edited TIL cell therapy, selected TIL cell therapy, small core or biopsy TIL cell therapy, fresh or frozen tumor digest-derived TIL cell therapy, TIL and ICI combination therapy, marrow infiltrating lymphocytes, or MIL therapy, and PBL therapy. The company also licenses rights to a broad range of technologies related to the company's platforms.

Iovance-Sponsored Clinical Trials

Frontline Advanced Melanoma

Following the accelerated approval of Amtagvi, the company's confirmatory trial is designed to support a registrational path for lifileucel in combination with pembrolizumab in frontline advanced melanoma, as well as full U.S. approval for Amtagvi, which has received an accelerated U.S. approval in its initial indication in post-anti-PD-1 advanced melanoma.

During the second quarter of 2023, the first patient was randomized in TILVANCE-301 in patients with unresectable or metastatic melanoma who have had no prior therapy for metastatic or unresectable disease. TILVANCE-301 is a Phase 3 multicenter, open-label, randomized, parallel group, treatment clinical trial that will randomize approximately 670 patients to investigate lifileucel in combination with pembrolizumab in the experimental arm compared with pembrolizumab monotherapy in the control arm. In the experimental arm, a tumor sample is procured from each patient for lifileucel manufacturing using the Gen 2 process. Patients receive pembrolizumab prior to and after the lifileucel regimen until disease progression. In the control arm, pembrolizumab monotherapy is given every six weeks until disease progression, with an optional crossover to lifileucel monotherapy upon confirmed progressive disease verified by a blinded independent review committee, or BIRC, and if patients meet eligibility criteria.

In 2022, the company reached agreement with the FDA on the TILVANCE-301 clinical trial design, including dual primary endpoints of ORR to support accelerated approval and PFS to support full approval of lifileucel in frontline advanced melanoma. The dual primary endpoints will be assessed by a BIRC using RECIST 1.1.

The company's strategy in frontline melanoma is supported by clinical results from the ongoing Cohort 1A of the company's IOV-COM-202 clinical trial, as well as prior published NCI data for TIL monotherapy in anti-PD-1 naïve melanoma patients. In January 2023, the company disclosed that updated efficacy and safety results from nearly 20 patients treated in Cohort 1A remain consistent with previously reported Cohort 1A data and continue to support the company's strategy in frontline advanced melanoma.

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

LN-145 for Advanced, or Metastatic or Unresectable NSCLC

The company is developing its TIL cell therapy, LN-145, alone and in combination with approved therapies to treat advanced NSCLC in the IOV-LUN-202 and IOV-COM-202 clinical trials.

IOV-LUN-202 Registrational Trial

IOV-LUN-202 is a single-arm, registrational trial investigating LN-145 in patients who have progressed on or after chemotherapy and anti-PD-1 therapy for advanced (unresectable or metastatic) NSCLC without epidermal growth factor receptor, or EGFR, ROS proto-oncogene receptor tyrosine kinase, or ROS, anaplastic lymphoma kinase, or ALK, genomic mutations and had received at least one line of an FDA-approved targeted therapy if indicated by other actionable tumor mutations. IOV-LUN-202 includes two registrational patient cohorts (Cohorts 1 and 2) and two exploratory patient cohorts (Cohort 3 and 4). The programmed death-ligand 1, or PD-L1, tumor proportion score, or TPS, in patients at the time they started frontline therapy was less than one percent or unknown in patients in Cohort 1 and greater than or equal to one percent in patients in Cohort 2. In Cohort 3, TIL is extracted from core biopsy and manufactured using the company's Gen 3 process. In Cohort 4, patients undergo surgical resection for TIL manufacturing prior to disease progression. Based on the regulatory discussions and positive regulatory feedback received by the FDA regarding the design of the IOV-LUN-202 trial, the company plans to enroll a total of approximately 120 patients into the registrational Cohorts 1 and 2 of the IOV-LUN-202 trial.

In July 2023, the company announced a preliminary analysis of the IOV-LUN-202 trial from 23 NSCLC patients treated with LN-145. An objective response rate of 26.1% per RECIST 1.1 was observed in six patients, with one complete response and five partial responses, and a disease control rate of 82.6%. While still early on study, the median duration of response, or DOR, was not reached. The DOR ranged from 1.4+ months to 9.8+ months. Treatment-emergent adverse events were consistent with the underlying disease and known adverse event profiles of non-myeloablative lymphodepletion and interleukin-2. The company also reported additional ongoing responses, and duration of response greater than six months for 71% of the confirmed responders in the trial, in an updated analysis from November of 2023.

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

The opportunity for TIL cell therapy in NSCLC is also supported by clinical results for LN-145 in heavily pre-treated patients with NSCLC (Cohort 3B) in the company's IOV-COM-202 trial in solid tumors. At the Society for Immunotherapy of Cancer, or SITC, in November 2021, the company reported Cohort 3B results from 28 patients who had progressed on or after prior immune checkpoint inhibitor, or ICI, therapy, including patients with oncogene-driven tumors who received prior tyrosine kinase inhibitor, or TKI, therapy. The ORR was 21.4% per RECIST 1.1, including one complete response and five partial responses. The complete response remained ongoing at 37 months following treatment in a subsequent data extract from November of 2022. All Cohort 3B patients had received prior anti-PD-1/-L1 therapy, and all six responding patients had also received prior chemotherapy. The TEAE profile was consistent with the underlying disease and known adverse event profiles of non-myeloablative lymphodepletion and IL-2.

On December 22, 2023, the FDA placed a partial clinical hold on the IOV-LUN-202 trial in response to a reported Grade 5 (fatal) serious adverse event, or SAE, potentially related to the non-myeloablative lymphodepletion pre-conditioning regimen. The company has paused enrollment and the LN-145 treatment regimen for new patients in IOV-LUN-202 during the clinical hold. Patients previously treated with LN-145 in the IOV-LUN-202 trial continue to be monitored and followed according to the trial protocol. While enrollment is paused due to an FDA-imposed clinical hold, enrollment is expected to be completed in 2025. The company is working closely with the FDA to safely resume enrollment in the IOV-LUN-202 trial as soon as possible in 2024.

Frontline NSCLC Development and Regulatory Strategy

The company is preparing to meet with the FDA in 2024 to discuss a randomized confirmatory trial of LN-145 in frontline advanced NSCLC patients. This confirmatory trial in frontline advanced NSCLC is expected to be well underway at the time of a potential approval of LN-145 in advanced post-anti-PD-1 NSCLC. The company's intention is to improve frontline NSCLC therapy by adding TIL cell therapy to standard of care pembrolizumab maintenance therapy, administered after completion of the initial chemo-immunotherapy. This approach is supported by initial results from Cohort 3A in the IOV-COM-202 trial in solid tumors. Cohort 3A is evaluating LN-145 in combination with pembrolizumab in patients who have not received prior immunotherapy, including ICIs.

In September 2023, the company reported preliminary Cohort 3A data in an oral presentation at the International Association for the Study of Lung Cancer, or IASLC, 2023 World Conference on Lung Cancer. The confirmed ORR per RECIST 1.1 was 58.3% in twelve treatment-naïve or post-chemotherapy patients with EGFR wild-type disease, regardless of PD-L1 status. Duration of responses of 15.4+, 10.2 +, 7.1, 6.9, 6.9+, 4.6, and 3.7 months were observed in seven patients, and three of these responses remained ongoing. Safety was consistent with other studies of Iovance TIL cell therapies in combination with pembrolizumab. Study enrollment remains ongoing.

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

Gynecological Cancers

The company plans to begin a Phase 2 trial of lifileucel in post-anti-PD-1 and post-chemotherapy advanced endometrial cancer, including mismatch repair, or MMR, deficient and MMR proficient patient populations in the first half of 2024. Based on the TIL mechanism of action, the benefit of TIL cell therapy is likely to extend across patients with tumors that are MMR mechanism deficient and proficient.

The potential for TIL cell therapy in gynecological cancers is also supported by the company's clinical data for lifileucel alone and in combination with pembrolizumab in advanced cervical cancer. C-145-04 is a Phase 2, multicenter pivotal clinical trial that included patient previously treated with chemotherapy (Cohort 1), previously treated with chemo and ICIs (Cohort 2), and patients who had not received prior systemic therapy (Cohort 3). Cohorts 1 and 2 received lifileucel monotherapy and Cohort 3 received lifileucel in combination with pembrolizumab. Initial results from the C-145-04 clinical trial were reported at the American Society of Clinical Oncology in June 2019 and the SITC in November 2021.

Following the company's assessment of the current treatment landscape in gynecological cancers, the company is prioritizing endometrial cancer over cervical cancer. The C-145-04 clinical trial is expected to close during 2024. The company plans to continue to explore the use of TIL cell therapies in cervical cancer, including using genetically modified TIL products and using TIL products in combination with anti-PD-1/PD-L1 blocking antibody therapies in frontline cervical cancer, with the goal of returning to clinical development in the future.

IOV-4001 for Advanced Melanoma and NSCLC

The company has a worldwide exclusive license from Cellectis that enables the company to use certain TALEN technology addressing multiple gene targets in several cancer indications, to develop genetically edited and potentially more potent TIL cell therapies. The company's lead genetically modified TIL cell therapy, IOV-4001, utilizes this TALEN technology to inactivate the gene coding for PD-1. The company is investigating the safety and efficacy of IOV-4001 in IOV-GM1-201, a multicenter, first-in-human Phase 1/2 clinical trial in two patient cohorts. Cohort 1 includes patients with advanced melanoma, who were previously treated with anti-PD-1/PD-L1 blocking antibody therapy, and in those patients with BRAF mutations, after BRAF/MEK inhibitor therapy. In Cohort 2, the company is investigating IOV-4001 in patients with metastatic NSCLC who have received no more than three prior lines of therapy, with or without oncogene driver mutations. The company treated the first patient with IOV-4001 in the third quarter of 2022 and the Phase 1 safety portion of the clinical trial is ongoing.

Additional Clinical Trials

The company previously investigated the potential for TIL cell therapy in metastatic HNSCC. The Phase 2 C-145-03 trial investigated LN-145 as monotherapy, using various manufacturing processes. The trial began in June 2017 and closed in January 2021 after reaching its pre-specified enrollment target. The company also investigated LN-145 in combination with pembrolizumab in patients with HNSCC who are naïve to anti-PD-1 therapy in IOV-COM-202 Cohort 2A. The results from Cohort 2A are supportive of the company's strategies to develop TIL cell therapy in combination with pembrolizumab in earlier treatment settings for solid tumor cancers.

The company has also explored the potential for polyclonal T cell immunotherapies in blood cancers. A first-in-human clinical trial, IOV-CLL-01, evaluated the safety and efficacy of IOV-2001, the company's polyclonal PBL therapy, in patients with relapsed or refractory chronic lymphocytic leukemia, or CLL, and small lymphocytic lymphoma, or SLL.

Next-Generation TIL Cell Therapy Product Candidates

The company's next-generation technology platforms are designed to optimize outcomes with TIL cell therapy across three key initiatives: genetic modifications, potency, and new treatment regimens.

Genetic modifications: The company is pursuing several targets for genetic modification that utilize the gene-editing TALEN platform licensed from the clinical-stage biotechnology company, Cellectis. Single- and multiple- knockouts may further harness the immune system response to cancer and potentially increase the potency of TIL cell therapy. Preclinical development is also ongoing with cytokine-tethered TIL products and additional TIL products and TIL-cell lines using transient and stable gene insertion and inactivation, which may expand and activate TIL to achieve better efficacy while avoiding systemic side effects of cytokines.

Potency: The company is exploring potential approaches to increase potency of the final TIL product through sorting and selection of specific TIL, such CD39/69 double-negative TIL, and the use of certain inhibitors or other reagents in TIL expansion cultures. The company has also manufactured and investigated patient cohorts treated with TIL candidate, LN-145-S1, manufactured from TIL selected for PD-1 expression.

New treatment regimens: The company is exploring potential improvements to the TIL treatment regimen. IND-enabling studies are investigating IOV-3001, an antibody cytokine-engrafted protein, or IL-2 analog, which the company licensed from Novartis Pharma AG. in 2020.

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

WuXi Advanced Therapies, Inc.

Manufacturing and Services Agreements

In November 2016, the company entered into a three-year manufacturing services agreement, or the First WuXi MSA, with WuXi, pursuant to which WuXi agreed to provide manufacturing and other services, which has since been amended and assigned to the company's subsidiary Iovance Biotherapeutics Manufacturing LLC. Under the First Wuxi MSA, the company entered into two statements of work for two cGMP manufacturing suites to be operated by WuXi for the company. The terms of one of these statements of work were extended to December 2022.

In October 2022, Iovance Biotherapeutics Manufacturing LLC entered into an additional three-year MSA, or the Second WuXi MSA, with WuXi and its parent company WuXi Apptec, Co. Ltd. The Second WuXi MSA and its related statement of work superseded the statement of work under the First WuXi MSA with respect to commercial, clinical manufacturing and related testing services for the two existing manufacturing suites. Both suites are expected to be capable of use for the commercial manufacture of the company's products.

National Institutes of Health and the National Cancer Institute

Cooperative Research and Development Agreement

In August 2011, the company signed a five-year Cooperative Research and Development Agreement, or CRADA, with the NCI to work on the development of adoptive cell immunotherapies in multiple solid tumor types, including unmodified TIL as a stand-alone therapy or in combination, improved methods for the generation and selection of TIL cell therapy with anti-tumor reactivity and strategies for more potent TILs. The CRADA was amended in 2015 and 2016, to, among other things, extend the term of the CRADA through August 2021, include new indications, such as bladder, lung, triple-negative breast, and Human Papilloma Virus, or HPV, associated cancers and modify the focus on the development of unmodified TIL as a stand-alone therapy or in combination. The parties have continued the development of improved methods for the generation and selection of TIL with anti-tumor reactivity in metastatic melanoma, bladder, lung, breast, and HPV-associated cancers.

In August 2021, a third amendment extended the term of the CRADA by three years to August 2024, among other things. The research plan in this third amendment includes the evaluation in clinical trials of strategies for the development of more potent TILs, such as selection of CD39/69 double negative cells and the use of certain inhibitors or other reagents in TIL expansion cultures.

Pursuant to the terms of the CRADA, as amended, the company is required to make quarterly payments of $0.5 million to the NCI for support of research activities. To the extent the company licenses patent rights relating to a TIL-based product candidate, the company will be responsible for all patent-related expenses and fees, past and future. In addition, the company may be required to supply certain test articles, including TIL, grown and processed under cGMP conditions, suitable for use in clinical trials. The company or the NCI may unilaterally terminate the CRADA for any reason or for no reason, at any time, by providing written notice at least 60 days before the desired termination date.

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

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

The company entered into an Exclusive Patent License Agreement, or the Patent License Agreement, with the NIH, in 2011, which was amended in 2015. Pursuant to the Patent License Agreement, as amended, the NIH granted the company 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.

In May 2021, the company entered into an Amended and Restated Patent License Agreement with NIH, which included the grant of additional exclusive, worldwide patent rights in the indications to interleukin-15 and interleukin-21 cytokine-tethered TIL technology, and expanded the non-exclusive, worldwide field of use to all cancers. Effective August 1, 2022, the company entered into a Second Amended and Restated Patent License Agreement with NIH to include additional exclusive, worldwide patent rights to TIL products expressing interleukin-12, expanded rights to TIL selection technologies previously licensed under the Exclusive Patent License Agreement below, and additional non-exclusive, worldwide patent rights to certain technologies related to enhancing TIL potency.

Exclusive Patent License Agreement Related to TIL Selection

In February 2015, the company entered into an exclusive patent license agreement, or the Exclusive Patent License Agreement, with the NIH under which the company received an exclusive worldwide license under the selected TIL patents. This license was superseded and replaced by the Second Amended and Restated Patent License Agreement.

H. Lee Moffitt Cancer Center

Research Collaboration and Clinical Grant Agreement

In June 2020, the company entered into a Sponsored Research Agreement with Moffitt, with a term that ends either upon completion of the research thereunder or on July 1, 2022, whichever is sooner. In August 2023, this agreement was extended until September 2023. In December 2023, this agreement was extended until the later of November 30, 2024 or a mutually agreed determination of the completion of the Sponsored Research Agreement.

In December 2016, the company entered into a clinical grant agreement with Moffitt to support an ongoing clinical trial at Moffitt that combines TIL cell therapy with nivolumab for the treatment of patients with metastatic melanoma. In June 2017, the company entered into a second clinical grant agreement with Moffitt to support a new clinical trial at Moffitt that combines TIL cell therapy with nivolumab for the treatment of patients with non-small cell lung cancer, under which the company obtained a non-exclusive, royalty-free license to any new Moffitt inventions made in the performance of the agreement. Under both clinical grant agreements with Moffit, the company has non-exclusive rights to clinical data arising from the respective clinical trials, which are now concluded.

Exclusive License Agreements

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

The company entered into a license agreement with Moffitt, or the First Moffitt License, effective as of June 28, 2014, under which the company received a worldwide license to Moffitt's rights to patent-pending technologies related to methods for improving TIL for adoptive cell therapy using TLR agonists. Unless earlier terminated, the term of the license extends until the earlier of the expiration of the last issued patent related to the licensed technology or 20 years after the effective date of the license agreement.

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

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

The University of Texas M.D. Anderson Cancer Center, or MDACC

Strategic Alliance Agreement

In April 2017, the company entered into a Strategic Alliance Agreement, or the SAA, with MDACC, under which the company and MDACC agreed to conduct clinical and preclinical research studies. The company has also been granted certain rights to clinical data generated by MDACC outside of the clinical trials to be performed under the SAA. 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 the company of all deliverables due from MDACC thereunder.

Cellectis S.A.

Research Collaboration and Exclusive Worldwide License Agreement

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

Novartis Pharma AG

License Agreement

In January 2020, the company obtained a license from Novartis Pharma AG, or Novartis, to develop and commercialize an antibody cytokine engrafted protein, which the company refers to as IOV-3001. Under the agreement, the company has paid an upfront payment to Novartis and may pay future milestones related to initiation of patient dosing in various phases of clinical development for IOV-3001 and approval of the product in the U.S., the European Union, or EU, and Japan. Novartis is also entitled to low-to-mid single digit percentage royalties from commercial sales of the product.

Boehringer Ingelheim Biopharmaceuticals GmbH

In May 2023, as part of the completion of the acquisition of the worldwide rights to Proleukin, the company inherited a manufacturing and supply agreement from Clinigen with Boehringer Ingelheim Biopharmaceuticals GmbH, or BI, pursuant to which BI will carry out the processing, manufacturing and supply of Proleukin in unlabeled vials. The term of this agreement is through October 2025, with automatic renewals for a period of two years unless terminated as permitted by the contract. Under this agreement, the company must purchase a minimum number of vials each calendar year at fixed prices determined by vial batch size.

Intellectual Property

The company has established a leading intellectual property portfolio developed internally and licensed from third parties. The company owns more than 60 U.S. patents related to TIL cell therapy, including patents directed to compositions and methods of treatment in a broad range of cancers, such as U.S. Patent Nos. 10,130,659; 10,166,257; 10,272,113; 10,363,273; 10,398,734; 10,420,799; 10,463,697; 10,517,894; 10,537,595; 10,639,330; 10,646,517; 10,653,723; 10,695,372; 10,894,063; 10,905,718; 10,918,666; 10,925,900; 10,933,094; 10,946,044; 10,946,045; 10,953,046; 10,953,047; 11,007,225; 11,007,226; 11,013,770; 11,026,974; 11,040,070; 11,052,115; 11,052,116; 11,058,728; 11,083,752; 11,123,371; 11,141,438; 11,168,303; 11,168,304; 11,179,419; 11,202,803; 11,202,804; 11,220,670; 11,241,456; 11,254,913; 11,266,694; 11,273,180; 11,273,181; 11,291,687; 11,304,979; 11,304,980; 11,311,578; 11,337,998; 11,344,579; 11,344,580; 11,344,581; 11,351,197; 11,351,198; 11,351,199; 11,364,266; 11,369,637; 11,384,337; 11,433,097; 11,517,592; 11,529,372 ; 11,541,077; 11,713,446; 11,819,517; and 11,866,688. More than 40 of these patents are related to the company's Gen 2 TIL manufacturing processes and have terms that the company anticipates will extend to January 2038, not including any patent term extensions or adjustments that may be available. The company's owned and licensed intellectual property portfolio also includes patents and patent applications relating to TIL, marrow infiltrating lymphocytes, or MIL, and peripheral blood lymphocyte, or PBL, therapies; frozen tumor-based TIL technologies; remnant TIL and digest TIL compositions, methods and processes; methods of manufacturing TIL, MIL, and PBL therapies; the use of costimulatory and T cell modulating molecules in TIL cell therapy and manufacturing; stable and transient genetically-modified TIL cell therapies, including genetic knockouts of immune checkpoints; cytokine-tethered TIL cell therapies; methods of using ICIs in combination with TIL cell therapies; TIL selection technologies; and methods of treating patient subpopulations.

Government Regulations

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 the company is developing.

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

The company's 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.

Research and Development

During 2023, the company incurred $344.1 million of research and development expenses.

History

The company was founded in 2007. It was incorporated in the state of Nevada in 2007. The company was formerly known as Genesis Biopharma, Inc. and changed its name to Lion Biotechnologies, Inc. in 2013. Further, the company changed its name to Iovance Biotherapeutics, Inc. in 2017.