Abstract B041: Non-clinical Development of T-Plex Component TSC-203-A0201: A TCR-T Cell Therapy Directed to an HLA-A*02:01-Restricted PRAME Epitope for the Treatment of Solid Tumors

Abstract

Abstract Introduction: T-Plex is an autologous T cell receptor (TCR)-T cell therapy product for the treatment of solid tumors. T-Plex consists of two to three TCR-T cell components selected from TScan’s ImmunoBank, a repository of therapeutic TCRs each recognizing a different tumor-restricted antigen presented by an HLA class I molecule. By combining components from the ImmunoBank, a multiplex TCR-T product is customized to match the target and HLA expression pattern of a patient’s tumor. Every component of T-Plex is engineered using a transposon-based vector encoding the therapeutic TCR, CD8α and CD8β co-receptors, a CD34 epitope tag, a dominant-negative TGFβRII (DN-TGFβRII), and a mutated form of dihydrofolate reductase (DHFRdm). TSC-203-A0201 is a new component of the ImmunoBank designed to recognize an HLA-A*02:01-restricted epitope derived from the cancer-testis antigen PRAME, which is frequently overexpressed in solid tumors but is absent in healthy tissues, except testis. Methods: TScan’s proprietary ReceptorScan platform was used to identify a potent naturally occurring TCR recognizing an HLA-A*02:01-restricted PRAME epitope. The PRAME-specific TCR was then used to build TSC-203-A0201. TSC-203-A0201 TCR-T cells were engineered using a full-scale representative workflow for the planned clinical manufacturing process and were used to investigate the in vitro pharmacology and safety of TSC-203-A0201. The specificity of TSC-203-A0201 for the HLA-A*02:01-restricted PRAME epitope was tested, and target-dependent cytotoxicity, proliferation and cytokine secretion were evaluated in vitro and in vivo. Resistance to TGFβ, conferred by expression of DN-TGFβRII, was evaluated by assessing resistance to TGFβ-mediated suppression of target-dependent IFN-γ secretion. Further, SafetyScan was used to investigate allo-and off-target reactivity. In addition, the reactivity of TSC-203-A0201 TCR-T cells to a panel of 60 healthy HLA-A*02:01-positive human primary and iPSC-derived cells isolated from tissues that are traditionally assessed in toxicology studies was evaluated. Results: TSC-203-A0201 TCR-T cells displayed selective and potent target-dependent engagement, with secretion of inflammatory cytokines, proliferation of both engineered CD4+ and CD8+ T cells, and cytotoxicity. Moreover, TSC-203-A0201 TCR-T cells displayed anti-tumor activity against Hs 695T xenografts in mice. Target-dependent IFN-γ production was maintained in the presence of physiological levels of TGFβ. Further, TSC-203-A0201 displayed alloreactivity to only two of the 110 most common class I HLAs in the US population. Although three putative off-targets were identified in the SafetyScan screen, TSC-203-A0201 showed no off-tumor reactivity to normal primary or iPSC-derived cells. Conclusions: TSC-203-A0201 exhibits high specificity and potency with limited alloreactivity and no projected off-target reactivity. Based on these results, TSC-203-A0201 has been cleared by the FDA for clinical development and has been incorporated in the T-Plex Phase 1 clinical trial master protocol. Citation Format: Nivya Sharma. Non-clinical Development of T-Plex Component TSC-203-A0201: A TCR-T Cell Therapy Directed to an HLA-A*02:01-Restricted PRAME Epitope for the Treatment of Solid Tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B041.