Item 1. Business.
Overview
We are a clinical-stage biopharmaceutical company focused on developing an innovative cell therapy pipeline of autologous tumor infiltrating lymphocyte, or TIL, therapies for the treatment of patients with cancer. We have assembled an accomplished team with a successful track record in the development, manufacture, regulatory approval and commercialization of multiple cell therapies. Using our optimized and scalable manufacturing process, we are advancing our lead TIL product candidate, ITIL-168, for the treatment of advanced melanoma. Based on the clinical results from a compassionate use program with a TIL product that was manufactured using a prior version of the ITIL-168 manufacturing process, we submitted an investigational new drug application, or IND, to the U.S. Food and Drug Administration, or the FDA, and were authorized to initiate a Phase 2 trial in late 2021 with expected topline safety and efficacy data in 2023, which we believe could support a biologics license application, or BLA submission. We plan to initiate a Phase-1 trial of ITIL-168 in additional indications with unmet medical need, including cutaneous squamous cell carcinoma, or CSCC, non-small cell lung cancer, or NSCLC, head and neck squamous cell carcinoma, or HNSCC, and cervical cancer, in 2022. ITIL-168 will be manufactured in our company-operated in-house manufacturing facilities for both our clinical trials and commercial sales, if approved.
We are also developing a novel class of genetically engineered TIL therapies using our Co-Stimulatory Antigen Receptor, or CoStAR, platform. These modified TILs still rely on their native, patient-specific T cell receptors, or TCRs, to bind to tumor neoantigens, but have been enhanced to express novel CoStAR molecules, which bind to shared tumor-associated antigens and provide potent costimulation to T cells within the tumor microenvironment. We believe that the ability of CoStAR to augment the activation of TILs upon native TCR-mediated recognition of tumor neoantigens has the potential to bring TIL therapy to patients with cancer types that have been historically resistant to immunotherapy. We anticipate filing an investigational new drug, or IND, application for our lead CoStAR-TIL product candidate, ITIL-306, in 2022.
We believe the critical advantage of TIL therapy over other cell therapies relates to the intrinsic and diverse anti-tumor reactivity of TILs. Unlike most cell therapies in development for solid tumors, which only recognize a single target antigen shared across a diverse patient population, TILs are polyclonal and therefore have the ability to recognize the broad set of antigens unique to each patient. This comprehensive polyclonality helps overcome a major limitation of cell therapies, such as CAR-Ts and TCR-Ts, by providing the requisite diversity to match the marked heterogeneity of solid tumors.
The successful use of TIL therapy to treat solid tumors was first published in 1988 by Steven A. Rosenberg, M.D., Ph.D., and his colleagues from the National Cancer Institute, or NCI, who demonstrated remissions in patients with advanced melanoma who had been treated with TILs. Since these initial reports, clinical studies of TILs have expanded significantly. In a study published in Annals of Oncology in 2019, U. Dafni and colleagues conducted a meta-analysis of clinical trials of TIL therapies published between 1988 and 2016, which reported an overall remission rate, or ORR, of 41% and a complete remission, or CR, rate of 12% in 410 heavily pretreated patients with metastatic melanoma. As shown below, in patients for whom detailed follow-up was available, the CRs were found to be remarkably durable, with only one of 28 patients experiencing disease recurrence.
TIL Therapy Demonstrated Durable CRs
in Patients with Melanoma in Clinical Trials Between 1988 and 2016
In addition to melanoma, TIL therapy has also demonstrated efficacy in multiple other solid tumors, including NSCLC, HNSCC, and cervical cancer. However, despite these compelling clinical results, TIL therapy has largely been limited to the academic or compassionate use settings due to the lack of an industrialized and scalable process for the manufacture of these products.
By leveraging our team’s experience, we are executing on our plan to efficiently launch in-house capabilities of manufacturing, process development, clinical operations, regulatory strategy and research and development. We have created a robust, reproducible process to generate well-characterized and commercially viable TIL product candidates that we believe will provide patients with long-term therapeutic benefit.
Our Strengths
Our goal is to become the leader in the design, manufacture and delivery of TIL therapies to patients with cancer. We believe the following strengths will enable us to achieve this goal:
Highly experienced team. Our senior management team and a large fraction of our operational staff have extensive experience in cell therapy, with many having participated in the design and execution of the clinical development, manufacture and regulatory approval of Yescarta and Tecartus at Kite Pharma/Gilead, as well as the development of other clinical-stage cell therapy product candidates. In addition, our team and scientific advisors have a track record of successfully leading the technology discovery, process development, GMP manufacturing and clinical operations functions at other cell therapy companies.
Robust clinical development experience with TILs. Members of our team have been generating and improving TIL therapy for over a decade, and a TIL product manufactured by us has been used in the treatment of patients with refractory melanoma through a compassionate use program at the Christie Hospital in Manchester, United Kingdom,
which is the largest single-site cancer center in Europe. In the 21 patients treated through the compassionate use program using a TIL product that was manufactured using a prior version of the ITIL-168 manufacturing process, we observed a CR in four patients (19%) and a partial remission, or PR, in 10 patients (48%), resulting in an ORR of 67%. In addition, four patients reported SD, resulting in a disease control rate, or DCR, of 86%. Ten of the 21 patients have died from complications arising from disease progression. The results from the compassionate use program do not provide a guarantee that ITIL-168 will be deemed to be safe or effective for the treatment of melanoma or additional indications, and extensive clinical testing and regulatory approval will be required before ITIL-168 can be commercially marketed for the treatment of melanoma. Based on these results, together with our development and manufacturing expertise, we intend to transform TIL therapy into what we believe will be a scalable, convenient and effective option for patients with cancer.
Optimized and scalable manufacturing process. We have developed a manufacturing process customized for autologous TIL therapies to maximize manufacturing success rate and potential for clinical efficacy beyond current practices. To ensure product quality and consistency, we have chosen to maintain full control of the entire manufacturing process, from the procurement of tumor samples through the shipping of the final product, without any outsourcing of core manufacturing process or quality control testing steps. Our process includes the optimized cryopreservation of both the digested tumor at the beginning to preserve cell viability and potency and the final product at the end to provide increased shelf life. Importantly, our cryopreservation process also provides significant scheduling flexibility for physicians and patients.
Company-operated in-house manufacturing facilities. We believe we are well positioned to execute on our clinical development plans and serve the U.S. and European markets with our existing and planned infrastructure. We have invested and plan to continue to invest in our manufacturing capabilities on two continents, with one facility in the United States in Tarzana, California for both clinical and commercial manufacturing and another in Manchester, United Kingdom for clinical manufacturing. By controlling and operating our manufacturing facilities on two continents, we believe we have the unique ability to more efficiently implement continuous improvements into our operations and to readily provide therapies to patients across a broad geography. With planned capacity across both of our facilities, we expect to have sufficient doses for all our clinical trials, as well as to meet the initial commercial demand of ITIL-168, if approved.
Strong capitalization. Since 2019, we have financed our operations with $719.0 million in net proceeds raised in our initial public offering and private placements of convertible preferred stock to date. This funding has enabled us to assemble a team with experience across the entire spectrum of cell therapy development, including clinical development and operations, regulatory submissions, process engineering, quality analytics, manufacturing and strategic commercialization planning.
Our Pipeline
We are building an innovative pipeline of optimized TIL product candidates, including both unmodified and genetically engineered TILs, for the treatment of patients with cancer. We own worldwide rights to all our product candidates. Our current pipeline is summarized in the diagram below.
Our lead product candidate, ITIL-168, is an autologous TIL therapy that we are initially developing for the treatment of PD-1-inhibitor relapsed or refractory advanced melanoma. We are utilizing an optimized and scalable manufacturing process that we believe will differentiate the profile of ITIL-168 from other cell therapies, including other TIL therapies. Our process for ITIL-168 manufacturing begins with the complete digestion of the tumor tissue, which releases all TILs from the tumor microenvironment and enables cryopreservation of the digested tumor at the beginning of the process to preserve cell viability and potency. Additionally, we cryopreserve the final product to provide increased shelf life. Our cryopreservation process at both the beginning and end of the manufacturing process provides significant scheduling flexibility for physicians and patients.
We have generated preliminary safety and efficacy data in advanced melanoma in the context of a compassionate use program in the United Kingdom, using a TIL product that was produced with a prior version of the ITIL-168 manufacturing process. Twenty-one patients with stage IV metastatic cutaneous melanoma were treated in this compassionate use program between 2011 and 2019. Treatment led to an ORR of 67%, including four patients (19%) who achieved CR and ten patients (48%) who achieved a PR. The DCR, which included patients with CR, PR or SD, was 86%. Based on these clinical results and our discussions with the FDA, we submitted IND for ITIL-168 and were authorized to initiate a Phase 2 trial in late 2021 with expected topline safety and efficacy data in 2023, which we believe could support a BLA submission. Additionally, in 2022, we intend to initiate Phase 1 trials of ITIL-168 in tumor types where evidence of immune cell recognition and elimination of cancer cells has been observed, such as CSCC, NSCLC, HNSCC and cervical cancer.
We are also developing genetically engineered TIL product candidates modified with CoStAR to augment the activation of TILs in the tumor microenvironment. In preclinical studies, CoStAR+ T cells demonstrated markedly increased activity as compared to normal T cells, including enhanced cytokine expression and proliferative capacity. CoStAR’s modular architecture can be adapted to potentially target any cell surface antigen, which will allow us to develop additional CoStAR-TIL product candidates that enhance TIL function in multiple solid tumors.
Our lead CoStAR-TIL product candidate, ITIL-306, expresses a CoStAR molecule designed to recognize folate receptor alpha, or FOLR1, a tumor-associated antigen that is expressed on numerous solid tumors, including ovarian cancer, uterine cancer, NSCLC and renal cancer. We believe that ITIL-306 has the potential to increase anti-tumor activity due to its ability to improve proliferation and enhance cytokine secretion while retaining the specificity and polyclonality of TILs. We intend to submit an IND for ITIL-306 in 2022 and initiate a Phase 1 trial in 2022 to evaluate safety, feasibility and preliminary efficacy in multiple tumor types.