Abstract 26: An HLA-class II restricted HPV18 E7 specific TCR cloned from a long-term surviving cervical cancer patient

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Abstract T cell receptor (TCR)-engineered T cell therapy is a promising approach for the treatment of solid malignancy, with multiple clinical trials reporting impressive responses using affinity-matured TCRs. However, artificially mutated TCRs can increase the risk of off-target toxicities due to unexpected cross-reactions, which limits the overall safety of this approach. To tackle this challenge, we have developed a novel strategy for cloning tumor-specific endogenous therapeutic TCRs from long-term surviving patients who have responded to immunotherapy. Specifically, we have identified a TCR (10F04) that is specific to human papillomavirus type 18 (HPV18) E784-98 and restricted to human leukocyte antigen (HLA) class II molecular DRA/DRB1*09:01 from the peripheral blood of a patient with HPV-positive metastatic cervical cancer who received multiple antigens stimulating cellular therapy (MASCT) and exhibited sustained T-cell immunological responses. Upon transduction into human T cells, the 10F04 TCR demonstrated robust antitumor activity in both in vitro and in vivo models. Notably, the TCR effectively redirected both CD4 and CD8 T cells to specifically recognize tumor cells and induced multiple cytokine secretion along with durable antitumor activity. Importantly, no cross-reactivity was detected in toxicity studies. As a result, this TCR is currently being investigated in a phase I clinical trial for treating HPV18-positive cancers (NCT05787535). The first-in-human infusion had been just completed. No severe adverse event had been observed, while an early proliferation of TCR-T was detected several days after infusion. Our approach of cloning tumor-specific and safe endogenous therapeutic TCRs from long-term surviving patients offers a promising strategy for developing safe and effective TCR-engineered T-cell therapies for solid tumors. These findings provide important insights into the potential of HLA class II-restricted TCR-T therapy as a novel cancer treatment modality. Citation Format: Jianting Long, Xihe Chen, Shudan Ou, Minjun Ma, Junjun Chu, Yanyan Han. An HLA-class II restricted HPV18 E7 specific TCR cloned from a long-term surviving cervical cancer patient [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 26.

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