Natural TCRs targeting KRASG12V display fine specificity and sensitivity to human solid tumors.

Autor:	Bear AS; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine., Nadler RB; The College of Arts and Sciences., O'Hara MH; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine.; Abramson Cancer Center, and., Stanton KL; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Xu C; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Saporito RJ; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Rech AJ; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Baroja ML; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Blanchard T; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Elliott MH; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Ford MJ; MSBioworks, Ann Arbor, Michigan, USA., Jones R; MSBioworks, Ann Arbor, Michigan, USA., Patel S; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Brennan A; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., O'Neil Z; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Powell DJ Jr; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Pathology and Laboratory Medicine and., Vonderheide RH; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine.; Abramson Cancer Center, and.; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Linette GP; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine.; Abramson Cancer Center, and.; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Carreno BM; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Department of Pathology and Laboratory Medicine and.; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2024 Sep 17; Vol. 134 (21). Date of Electronic Publication: 2024 Sep 17.
DOI:	10.1172/JCI175790
Abstrakt:	BACKGROUNDNeoantigens derived from KRASMUT have been described, but the fine antigen specificity of T cell responses directed against these epitopes is poorly understood. Here, we explore KRASMUT immunogenicity and the properties of 4 T cell receptors (TCRs) specific for KRASG12V restricted to the HLA-A3 superfamily of class I alleles.METHODSA phase 1 clinical vaccine trial targeting KRASMUT was conducted. TCRs targeting KRASG12V restricted to HLA-A*03:01 or HLA-A*11:01 were isolated from vaccinated patients or healthy individuals. A comprehensive analysis of TCR antigen specificity, affinity, crossreactivity, and CD8 coreceptor dependence was performed. TCR lytic activity was evaluated, and target antigen density was determined by quantitative immunopeptidomics.RESULTSVaccination against KRASMUT resulted in the priming of CD8+ and CD4+ T cell responses. KRASG12V -specific natural (not affinity enhanced) TCRs exhibited exquisite specificity to mutated protein with no discernible reactivity against KRASWT. TCR-recognition motifs were determined and used to identify and exclude crossreactivity to noncognate peptides derived from the human proteome. Both HLA-A*03:01 and HLA-A*11:01-restricted TCR-redirected CD8+ T cells exhibited potent lytic activity against KRASG12V cancers, while only HLA-A*11:01-restricted TCR-T CD4+ T cells exhibited antitumor effector functions consistent with partial coreceptor dependence. All KRASG12V-specific TCRs displayed high sensitivity for antigen as demonstrated by their ability to eliminate tumor cell lines expressing low levels of peptide/HLA (4.4 to 242) complexes per cell.CONCLUSIONThis study identifies KRASG12V-specific TCRs with high therapeutic potential for the development of TCR-T cell therapies.TRIAL REGISTRATIONClinicalTrials.gov NCT03592888.FUNDINGAACR SU2C/Lustgarten Foundation, Parker Institute for Cancer Immunotherapy, and NIH.
Databáze:	MEDLINE
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