Abstract IA06: Optimizing T-cell receptor gene therapy for cancer

Abstract

Abstract My lab is translating T-cell receptor (TCR)-engineered T-cell therapies for patients with solid and liquid tumors, working to understand relevant immune escape mechanisms and developing strategies to circumvent obstacles to clinical efficacy. To advance optimally safe and effective TCRs, we devised a system to identify the highest-affinity TCRs from the pooled peripheral repertoires of human leukocyte antigen (HLA)-matched donors, from which autoreactive clones had been removed by thymic selection. In the solid-tumor realm, we developed adoptive T-cell therapy for patients with Merkel cell carcinoma (MCC), a virus-driven cancer that is an ideal model to test TCR-based treatments targeting non-self epitopes. We treated patients using autologous Merkel cell polyomavirus (MCPy)-specific CD8+ T-cell lines and an immune checkpoint inhibitor. Dramatic tumor reductions were associated with dense infiltrates of activated T cells in two patients, but relapses occurred 22 and 18 months later. Single-cell RNA sequencing (scRNAseq) identified dynamic transcriptional suppression of the targeted HLAs, suggesting strong and specific immunologic pressure of therapeutic T cells. To address HLA downregulation as a tumor escape mechanism, we have initiated a trial utilizing a high-affinity HLA A*0201-restricted TCR to engineered autologous T cells, thus conferring a high-affinity TCR to all patients. As soon as safety is confirmed with this TCR alone, T cells carrying other MCPy-targeting TCR(s) with alternate HLA restrictions will be combined. Overall, revealing the in vivo escape mechanisms that undermine the efficacy of transgenic T-cell therapy in patients can inform significant improvements in the design of TCR-engineered immunotherapies. Citation Format: Aude G. Chapuis. Optimizing T-cell receptor gene therapy for cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA06.