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 is innovating, developing, and delivering tumor infiltrating lymphocyte, or TIL, cell therapies for patients with solid tumor cancers. The company is executing the U.S. launch...
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 is innovating, developing, and delivering tumor infiltrating lymphocyte, or TIL, cell therapies for patients with solid tumor cancers. The company is executing the U.S. launch of Amtagvi (lifileucel), the first product within its autologous TIL cell therapy platform, while also marketing Proleukin (aldesleukin), an interleukin-2, or IL-2, product used in the Amtagvi treatment regimen and in other applications. Amtagvi is the first and the only one-time, individualized T cell therapy to receive FDA approval for a solid tumor cancer. 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 was approved in February 2024 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 and Proleukin are part of a treatment regimen that also includes lymphodepletion.
The company’s multi-center trials, novel TIL cell therapy products, manufacturing processes, facilities, and bioanalytical platforms have transformed TIL cell therapy into a commercially viable treatment, which thousands of patients with cancer can access.
The company manufactures Amtagvi and its investigational TIL cell therapies using centralized, scalable, and proprietary manufacturing processes, which rejuvenate and multiply polyclonal T cells unique to each patient into the billions, and yield a cryopreserved, individualized therapy. Amtagvi is manufactured for commercial use at its manufacturing facility, the Iovance Cell Therapy Center, or the iCTC, and by a contract manufacturing organization, or CMO.
The company’s development pipeline includes multicenter trials of TIL cell therapies in additional treatment settings and indications for solid tumor cancers. To potentially improve outcomes for patients, the company is investigating TIL monotherapies for patients previously treated with standard of care therapies and TIL cell therapy in combination with standard of care therapies for patients in earlier treatment settings. The company is conducting two ongoing registrational trials to support a supplementary BLA, or sBLA, of lifileucel in frontline advanced melanoma and in advanced non-small cell lung cancer, or NSCLC, following standard of care chemo-immunotherapy. The company is also developing next-generation therapies, such as genetically modified TIL cell therapy and next-generation cytokines for use in the TIL cell therapy regimen.
Strategy
The company's strategies are to be the global leader in innovating, developing, and delivering TIL cell therapy, and to successfully commercialize the company's lead product Amtagvi for the treatment of post-anti-PD-1 advanced melanoma in the U.S.
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 a 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. The company completed the Biologics Licensing Application, or BLA, submission in March 2023, which the FDA accepted in May 2023 for Priority Review.
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. Amtagvi is administered to patients as part of a treatment regimen that includes lymphodepletion and a short course of high-dose Proleukin (aldesleukin).
Proleukin
Proleukin (aldesleukin) is an IL-2 product used in the Amtagvi treatment regimen and manufacturing process, as well as in other commercial, clinical, manufacturing, and research settings, which provides additional revenue. In May 2023, the company acquired the worldwide rights to Proleukin, 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 are referred to collectively as Clinigen. Ownership of Proleukin provides an additional revenue source, secures its Proleukin supply chain, lowers cost of goods, and reduces clinical trial expenses for Proleukin used with its TIL cell therapies.
Proleukin has received regulatory approvals for the treatment of adults with metastatic melanoma and metastatic renal cell carcinoma in the U.S. Proleukin is also licensed in multiple countries around the world for the treatment of patients with metastatic renal cell carcinoma and/or metastatic melanoma. The company also sells aldesleukin for clinical trial use and for use in the manufacturing of various cell and gene therapies to numerous third-party clients.
TIL Cell Therapy Clinical Development in Advanced, Metastatic or Unresectable Solid Tumor Cancers
The company’s TIL cell therapy platform and manufacturing process have been initially validated through the FDA approval of Amtagvi. 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 therapies are polyclonal to target a variety of neoantigens that are unique to the patient and tumor.
The company has investigated TIL cell therapy in global, multicenter clinical trials in advanced melanoma, gynecological cancers, 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 patients with frontline advanced melanoma not previously treated with anti-PD-1 therapy, the company is investigating lifileucel in combination with pembrolizumab in TILVANCE-301, a global randomized Phase 3 clinical trial intended to support registration in advanced frontline melanoma, as well as to serve as a confirmatory trial to support 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, assessed by a blinded independent review committee. The company also added Cohort 1D to its IOV-COM-202 trial to investigate lifileucel in combination with relatlimab and nivolumab in frontline advanced melanoma patients.
Advanced Non-Small Cell Lung Cancer: In NSCLC, the company is investigating lifileucel in two clinical trials in NSCLC patient populations with significant unmet need. IOV-LUN-202 is a registrational clinical trial of lifileucel in advanced NSCLC patients who have progressed following chemotherapy and anti-PD-1 therapy. The IOV-COM-202 trial in solid tumors includes cohorts of NSCLC patients treated with lifileucel monotherapy and combination therapy. The company added Cohorts 3D and 3E to its IOV-COM-202 trial to investigate lifileucel in combination with pembrolizumab and chemotherapy in frontline advanced NSCLC patients.
Advanced Endometrial Cancer: The company initiated a clinical trial, IOV-END-201, in the second quarter of 2024 for lifileucel in endometrial cancer to potentially address the unmet need for patients previously treated with platinum-based chemotherapy and anti-PD-1 therapy regardless of mismatch repair.
Next Generation TIL Cell Therapy: The company’s first genetically modified TIL cell therapy, IOV-4001, is being investigated in the multi-center Phase 2 efficacy portion of a first-in-human clinical trial, IOV-GM1-201, in previously treated patients with advanced melanoma or NSCLC. IOV-4001 utilizes the gene-editing TALEN technology, licensed from the clinical-stage biotechnology company, Cellectis S.A., or Cellectis, to inactivate the gene coding for PD-1. A second next-generation TIL cell therapy, IOV-5001, is in Investigational New Drug, or IND, enabling studies. IOV-5001 is a genetically engineered, inducible, and tethered interleukin-12 TIL cell therapy designed to enhance TIL efficacy while optimizing safety.
Next Generation IL-2: A Phase 1/2 clinical trial is underway to investigate IOV-3001, a second-generation, modified interleukin-2 analog, for use in the TIL therapy treatment regimen. Preclinical studies of IOV-3001 demonstrated the potential for improved safety with strong effector T cell expansion.
Additional Solid Tumor Cancers: Iovance TIL cell therapy has been investigated in additional solid tumor cancers in Iovance- and investigator-sponsored clinical trials. Lifileucel 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 cohorts of patients with metastatic HNSCC, and in patients with advanced cervical cancer in the C-145-04 multicenter Phase 2 clinical trial. 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, non-melanoma skin cancer, and triple-negative breast cancer.
Next-Generation TIL 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: In addition to IOV-4001, the company is pursuing several targets for genetic modification that utilize the gene-editing TALEN platform licensed from Cellectis. Single- and multiple-knockouts may further harness the immune system's response to cancer and potentially increase the potency of TIL cell therapy. Preclinical development is ongoing with additional TIL products and TIL-cell lines using transient and stable gene inactivation, which may expand and activate TIL to achieve better efficacy while avoiding systemic side effects.
Cytokine-Tethered TIL Therapy: The company’s genetically engineered, inducible, and tethered IL-12 TIL cell therapy, designated IOV-5001, is in IND-enabling studies. In preclinical studies, IOV-5001 augmented anti-tumor activity in vitro, and a clinical trial of a prior generation IL-12 TIL therapy at the NCI showed improved efficacy. A pre-IND meeting is planned with the FDA to discuss IOV-5001 in the first quarter of 2025, and then an IND application submission in 2026.
New treatment regimens: The company is exploring potential improvements to the TIL treatment regimen. The company is investigating IOV-3001, a second-generation, modified IL-2 analog, which it licensed from Novartis Pharma AG in 2020. The company submitted an IND application for a phase 1/2 clinical trial of IOV-3001 for use in the TIL therapy treatment regimen in the third quarter of 2024, which was accepted in the fourth quarter of 2024. Results from non-human primate and IND-enabling studies of IOV-3001 were presented at the American Society of Clinical Oncology’s 2024 Annual Meeting and demonstrate the potential for improved safety with strong effector T cell expansion.
Intellectual Property
The company owns more than 250 granted or allowed U.S. and international patents and patent applications pertaining to Amtagvi and other TIL-related technologies that are expected to provide Amtagvi with exclusivity into 2042. More than 75 U.S. patents are 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 peripheral blood lymphocyte, or PBL, therapy. The company also licenses rights to a broad range of technologies related to its platforms.
Iovance-Sponsored Clinical Trials
Frontline Advanced Melanoma
Melanoma is a common type of skin cancer, accounting for an estimated 100,640 patients diagnosed and 8,290 deaths in 2024 in the U.S., according to the Surveillance, Epidemiology and End Results program, or SEER, program. Following the accelerated approval of Amtagvi, the company’s confirmatory trial, TILVANCE-301, is designed to support a registrational path for lifileucel in combination with pembrolizumab in frontline advanced melanoma, as well as to support 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.
TILVANCE-301 is a Phase 3 multicenter, open-label, randomized, parallel-group treatment clinical trial that will randomize approximately 670 patients with unresectable or metastatic melanoma who have had no prior therapy for metastatic or unresectable disease to investigate lifileucel in combination with pembrolizumab in the experimental arm compared with pembrolizumab monotherapy in the control arm. Patients in the experimental arm 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.
The company reached an 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 its IOV-COM-202 clinical trial, as well as prior published NCI data for TIL monotherapy in anti-PD-1 naïve melanoma patients. As of the most recent detailed Cohort 1A clinical data update in May 2024, the company observed a 65% ORR in twenty-three patients per RECIST 1.1. Fifteen patients had a confirmed objective response, including seven complete responses and eight partial responses. Nearly all responders had ongoing responses, and eight responders had a duration of response of more than one year at the time of the data cut. The treatment-emergent adverse event, or TEAE, profile was consistent with the underlying advanced disease and the known adverse event profiles of pembrolizumab, lymphodepletion, and IL-2 regimens.
The company’s strategy is also supported by several NCI trials of TIL cell therapy that were conducted prior to the approval of anti-PD-1 therapies.
Lifileucel for Advanced, or Metastatic or Unresectable NSCLC
The company is developing lifileucel 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 lifileucel 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 (Cohorts 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 lifileucel. 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 2023.
The opportunity for TIL cell therapy in NSCLC is also supported by clinical results for lifileucel in heavily pre-treated patients with NSCLC in Cohort 3B of 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. In March 2024, the FDA lifted its partial clinical hold and the company resumed enrollment in the IOV-LUN-202 trial.
A separate patient cohort, Cohort 3C, in IOV-COM-202 is investigating lifileucel in combination with ipilimumab or nivolumab in patients who previously received only a prior line of approved systemic ICI monotherapy.
Frontline NSCLC Development and Regulatory Strategy
In frontline NSCLC, the company’s goal is to improve the current standard of care pembrolizumab maintenance therapy by administering TIL after completion of the initial chemo-immunotherapy. This approach is supported by initial results from Cohort 3A in the IOV-COM-202 trial, which is evaluating lifileucel in combination with pembrolizumab in patients who have not received prior immunotherapy, including ICIs, and will be further investigated in the IOV-COM-202 trial in two new cohorts, 3D and 3E.
In November 2024, the company reported updated preliminary results from Cohort 3A in the IOV-COM-202 trial at the Society for Immunotherapy of Cancer Annual Meeting, which continue to demonstrate robust response rates and durability for lifileucel in combination with pembrolizumab in NSCLC patients who were not previously treated with immune checkpoint inhibitor therapy. A confirmed objective response was observed in 9 of 14 EGFR wild-type patients, or 64.3%, including 6 of 11 patients, or 54.5%, who also had difficult-to-treat PD-L1 negative disease. Median duration of response was not reached at a median study follow-up of 26.5 months. This data supports the opening of a new cohort, 3D, in the IOV-COM-202 trial to investigate lifileucel plus pembrolizumab following chemotherapy as part of frontline therapy for patients with EGFR wild-type NSCLC, representing the majority of patients with an unmet medical need in this setting.
Gynecological Cancers
The company began 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, which evaluated lifileucel monotherapy in patients previously treated with chemotherapy or previously treated with chemotherapy and ICIs, lifileucel in combination with pembrolizumab in Cohort 3 included patients who had not received prior systemic therapy.
Following an assessment of the treatment landscape in gynecological cancers, the company is prioritizing endometrial cancer over cervical cancer. 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 it 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 completed.
Additional Clinical Trials
The company previously investigated the potential for TIL cell therapy in metastatic HNSCC. The Phase 2 C-145-03 trial investigated lifileucel 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 lifileucel 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.
Research, Development, Manufacturing, and License Agreements for TIL Cell Therapy
WuXi Advanced Therapies, Inc.
Manufacturing and Services Agreements
Since November 2016, the company entered into various manufacturing services agreements with WuXi Advanced Therapies, Inc., and its parent company WuXi Apptec, Co. Ltd, or collectively, WuXi, pursuant to which WuXi agreed to provide manufacturing and other services for two cGMP manufacturing suites for commercial, clinical manufacturing, and related testing services. Both suites are 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 has been amended since then to, among other things, extend the term of the CRADA, 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 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.
In July 2024, the company and the NCI entered into a fourth amendment to the CRADA to extend its term by an additional five years to August 2029. The fourth amendment also includes collaboration on preclinical and clinical development of enhanced tumor-reactive TIL products for the treatment of a broad range of common epithelial cancers.
Pursuant to the terms of the CRADA, as amended, the company was required to make quarterly payments of $0.5 million to the NCI for support of research activities through the end of 2024. Commencing in 2025, the company is required to make quarterly payments of $0.9 million to the NCI for the support of research activities through the end of the CRADA’s term. 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, relating to the TIL-based product candidate. 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 entered into an Exclusive Patent License Agreement, or the Patent License Agreement, 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, in 2011, as 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. In August 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, or the SRA, with the H. Lee Moffitt Cancer Center, or Moffitt, with a term that ends either upon completion of the research thereunder or on July 1, 2022, whichever is sooner. The SRA was then extended numerous times, most recently to May 31, 2025.
The University of Texas M.D. Anderson Cancer Center
Strategic Alliance Agreement
In April 2017, the company entered into a Strategic Alliance Agreement, or the SAA, with the University of Texas M.D. Anderson Cancer Center, or 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. On March 28, 2024, the company entered into the first amendment to the SAA, under which the company and MDACC agreed to conduct additional preclinical research studies.
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. Financial terms of the license include annual license payments and development, regulatory, and sales milestone payments from the company to Cellectis, as well as royalty payments based on net sales of TALEN modified TIL products.
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 the 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.
In May 2023, as part of the completion of the acquisition of the worldwide rights to Proleukin, or the Acquisition, the company inherited two historical asset purchase agreements, one historical master cell bank license and working cell bank transfer agreement, and one historical license agreement from Clinigen with Novartis AG, Novartis Pharma AG, and Novartis Vaccines and Diagnostics, Inc., pursuant to which, among other things.
Boehringer Ingelheim Biopharmaceuticals GmbH
In May 2023, as part of the Acquisition, 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 currently owns more than 75 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; 11,857,573; 11,865,140; 11,866,688; 11,939,596; 11,969,444; 11,975,028; 11,981,921; 12,023,355; 12,024,718; 12,031,157; 12,104,172; 12,121,541; 12,159,700; 12,170,134; 12,188,048; and 12,194,061. 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 October 2037 or 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.
The company is required to register certain clinical trials and post the results of certain completed clinical trials on a government-sponsored database, ClinicalTrials.gov, within specified timeframes, and also to certify to the U.S. Food and Drug Administration, or the FDA, its compliance with these requirements when the company makes FDA submissions.
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 laws and regulations, such as the federal Anti-Kickback Statute, or AKS; the civil monetary penalties statute, or the CMP Law; the Foreign Corrupt Practices Act, or the FCPA; the False Claims Act, or the FCA; the Veterans Health Care Act, or the VHCA; physician payment transparency laws; privacy and security laws; and other federal, state, and local laws similar to the foregoing.
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.
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