Organizer: IRB Barcelona
Date: Tuesday 4 May 2021, 17:00h
Title: Characterization of the neoepitope-specific T cell responses to cancer and genetic engineering of an antitumor immune response
Cancer immunotherapy has shown the relevance of the immune system in the fight against cancer. Understanding how the natural T cell responses unleashed by the treatment with immune checkpoint blockade (ICB) therapy eradicate solid tumors is essential to design the next-generation immunotherapies. Early studies have shown that neoepitopes derived from non-synonymous mutations are the primary target of T cell responses induced by ICB therapy. To characterize these responses, we generated hundreds of patient-specific capture reagents made of barcoded complexes of HLA-putative neoepitopes for the longitudinal analysis of blood and tumor samples. We showed that patients with response to therapy recurrently recognized a limited number of mutations through multiple T cells with diverse T-cell receptors (TCRs). Patients with no response recognized a similarly restricted number of mutations but lacked TCR polyclonality. TCRs from all cases, expressed in healthy donor PBMCs using non-viral T cell gene-editing methods, demonstrated specific neoantigen recognition and cytotoxicity to autologous melanoma cell lines. Therefore, we showed that effective PD-1 blockade therapy is mediated by polyclonal T cells recognizing a limited number of immunodominant mutations.
The success of ICB therapies relies on the ability of the patient to mount a potent immune response against the tumor. An alternative therapeutic strategy is the adoptive transfer of T cells genetically engineered to target the tumor, known as adoptive T cell therapy (ACT). The success of ACT for solid cancers is challenged, in part, by the lack of targets expressed at sufficient levels in the tumor. Tyrosinase-related protein-1 (TYRP-1) plays an essential role in melanin biosynthesis and is overexpressed in 30% of all melanoma lesions. TYRP-1 is localized intracellularly in the melanosomes. However, as a result of the fusion of the melanosomes with the plasma membrane, a small fraction of the cellular TYRP-1 is located on the cell surface and can be used as a Chimeric Antigen Receptor (CAR)-T cell target. We have developed a TYRP-1 CAR that leads to tumor cell growth inhibition and cytokine release upon co-culture with a panel of patient-derived and murine melanoma cell lines with high expression of TYRP-1. In vivo, this CAR-T cell therapy induces tumor growth control or elimination in immunocompromised mice bearing human tumors and in immunocompetent murine melanoma models. Our results show the relevance of the TYRP-1 expression on the cell surface as a widespread target for CAR-T cell therapy for melanoma patients. We are currently planning the clinical translation of this CAR-T cell therapy.
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