Abstract A37: Engineering armored TCR-modified T cells to enhance anti-tumor efficacy

Abstract

Clinical trials utilizing T cells genetically engineered to express a tumor-targeted T-cell receptor (TCR) illustrate the promise of this therapy in treating cancer patients. However, there are obstacles that must be overcome to improve the efficacy of TCR gene therapy. Two separate signals are needed to completely activate T cells and drive T-cell proliferation and differentiation. Co-stimulatory molecules present on the surface of cancer cells can become downregulated as an escape mechanism, thus depriving the T cells of complete activation and leading to T-cell apoptosis or anergy. This project aims to armor tumor-associated antigen-specific T cells with proinflammatory cytokines, specifically IL-12 and IL-18. We hypothesize that this genetic modification will provide an alternate form of co-stimulation that will augment antitumor efficacy. Tumor-associated antigen specific pmel-1 T cells transduced with retroviral constructs were shown to be more functional through increased secretion of IFNγ when co-cultured with antigen-positive tumor cells. Additionally, the armored pmel T cells were able to significantly enhance lysis of the B16F10 melanoma cell line in vitro. Subsequently, the in vivo efficacy of the armored T cells was assessed in a syngeneic, immune-competent B16F10 melanoma mouse model. The armored pmel T cells were confirmed to significantly delay the B16F10 tumor progression and enhance the survival of these mice in comparison to control pmel T cells. These results provide future insight into applying the concept of armored TCR T cells to a therapeutically relevant human tumor target to enhance TCR-modified T-cell antitumor responses. Citation Format: Dylan J. Drakes, Sarwish Rafiq, Terence Purdon, Renier Brentjens. Engineering armored TCR-modified T cells to enhance anti-tumor efficacy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A37.