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• W4308375788 abstract "<h3>Background</h3> The primary target of T-cell responses to cancer cells are peptides derived from non-synonymous mutations presented by HLA. However, the large diversity of HLA alleles and restricted availability of clinical samples has limited the study of the antigenic determinants recognized by T cells (termed neoepitopes) at the scale needed for a landscape analysis of antitumor immune responses in patients. <h3>Methods</h3> We applied a newly developed technology to perform a longitudinal landscape analysis of the neoepitope-specific T cells in peripheral blood and tumor from 11 patients with metastatic melanoma, 7 with response (R) or 4 with no response (NR) to immune checkpoint blockade (ICB) immunotherapy. Briefly, based on the computational prediction of patient-specific putative neoepitopes, hundreds of capture reagents were made consisting of the patient HLA class I subtypes loaded with the corresponding predicted neoepitope; neoepitope-specific T cells were then isolated, and the TCR alpha and beta sequenced. The tumor reactivity of the isolated neoepitope-specific TCRs (neoTCR) was assessed upon co-culture of autologous melanoma cell lines from each patient with primary human T cells expressing the neoTCRs generated using a CRISPR-based non-viral precision genome engineering to replace the endogenous TCRs. <h3>Results</h3> The tumor mutation burden ranged between 2562 and 54 and 297 to 31 for patients with R and NR, respectively. We screened an average of 157 (range 243 to 17) predicted neoepitope-HLA per patient across their 6 HLA molecules, and isolated neoTCRs in all 11 patients. The number of mutations targeted ranged between 13 and 1. We assessed tumor reactivity in samples from 3 R and 3 NR; 39 of the 64 neoTCRs demonstrated specific recognition and cytotoxicity to patient-matched melanoma cell lines. Multiple T cells with different neoTCRs (T cell clonotypes) recognized a limited number of mutations in 7 patients with R (average of 31 different neoTCR clonotypes per patient). These T cell specificities were recurrently detected at different time points in blood and tumors. Samples from 4 patients with NR also demonstrated neoepitope-specific T cell responses in blood and tumor to a similarly restricted number of mutations but lacked TCR polyclonality (average 3 neoTCR clonotypes per patient) and were not recurrently detected in sequential samples. <h3>Conclusions</h3> Effective ICB therapy is associated with polyclonal neoepitope-specific T cell responses in the tumor and blood that recognize a limited number of immunodominant mutations and are recurrently recognized over time. <h3>Ethics Approval</h3> Patients with metastatic melanoma were selected as they signed an informed consent to collect PBMC and tumour biopsies while receiving therapy with anti-PD-1 therapy alone or in combination with other drugs. Biopsies and blood samples were collected under the University of California, Los Angeles (UCLA) Institutional Review Board approvals 11–003254." @default.
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• W4308375788 date "2022-11-01" @default.
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• W4308375788 title "123 Landscape analysis of the neoepitope-specific T cell responses in patients with and without clinical benefit from immune checkpoint blockade therapy" @default.
• W4308375788 doi "https://doi.org/10.1136/jitc-2022-sitc2022.0123" @default.
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