Abstract P005: GEN-011: A neoantigen-targeted peripheral blood-derived T cell therapy that has broad neoantigen specificity and high T cell purity while avoiding pro-tumor T cells

Abstract

Abstract Candidate adoptive T cell therapies (ACT), such as tumor infiltrating lymphocyte (TIL) treatments, have resulted in unprecedented and durable efficacy in clinical trials. Despite this, the manufacturing requires viable tumor resection, and TIL expansion conditions have the potential to promote T cell exhaustion. Moreover, a large proportion of patients do not respond to treatment, possibly due to exhaustion or to bystander T cells that are not tumor-specific present in the product candidates. In addition, we have shown that naturally occurring pro-tumor T cell responses to tumor-specific antigens we term Inhibigens™ are generated in nearly every subject with cancer; these T cells may be inadvertently expanded in the non-specific TIL manufacturing process. In animal models, Inhibigen-specific responses drive tumor hyperprogression. To avoid these pro-tumor T cells and improve upon ACT limitations, we are developing GEN-011, a neoantigen-targeted, peripheral T cell (NPT) therapy. GEN-011 is designed to contain primarily tumor-specific T cells with broad specificity and limited exhaustion, starting from easily accessible peripheral blood. Putatively beneficial neoantigen targets and deleterious pro-tumor Inhibigen targets are identified through measurement of cytokines in the assay supernatants of an in vitro ATLAS™ screen, in which each mutation identified in a patient's tumor is screened with the patient's own peripheral CD4+ and CD8+ T cells in a recall (overnight) assay, without algorithm prioritization. Next, the patient's peripheral T cells and monocyte-derived dendritic cells are incorporated into the PLANET™ manufacturing process where they are specifically stimulated with up to 30 ATLAS-verified neoantigens, avoiding Inhibigens, in a scalable, closed system. Development and engineering runs performed at scale show that the NPTs are up to 96% tumor-specific, with responses maintained for up to 89% of the intended neoantigen targets. They are non-exhausted effector and central memory T cells that express both proliferative and tissue homing markers. In addition to being highly polyfunctional, secreting multiple combinations of IFNγ, Granzyme B, TNFα, and MIP1α in response to specific neoantigens, they are also cytolytic in vitro and express memory-progenitor stem-like cell markers. The TITAN™ clinical trial evaluating GEN-011 NPTs is ongoing (NCT04596033). TiTAN is an open-label, multi-center Phase1/2a trial evaluating safety, tolerability, T cell persistence and proliferation, and clinical efficacy. The TiTAN clinical trial is testing two dosing regimens, a repeated lower dose regimen of GEN-011 without lymphodepletion and a single high dose administration of GEN-011 NPTs after lymphodepletion. Both groups will receive interleukin-2 after GEN-011 NPT dosing. By enriching healthy, broadly-specific neoantigen-targeted T cells and avoiding Inhibigens, the GEN-011 NPTs may represent an accessible and promising ACT for treating solid tumors. Citation Format: James Perry, Pranay D. Khare, Mercay Reuter, Daniel B. DeOliveira, Manish Jain, Colleen Winstead, Hubert Lam, Thomas Davis, Ray Stapleton, Jessica B. Flechtner. GEN-011: A neoantigen-targeted peripheral blood-derived T cell therapy that has broad neoantigen specificity and high T cell purity while avoiding pro-tumor T cells [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P005.