1. Natural TCRs targeting [KRAS.sup.G12V] display fine specificity and sensitivity to human solid tumors
- Author
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Bear, Adham S., Nadler, Rebecca B., O'Hara, Mark H., Stanton, Kelsey L., Xu, Chong, Saporito, Robert J., Rech, Andrew J., Baroja, Miren L., Blanchard, Tatiana, Elliott, Maxwell H., Ford, Michael J., Jones, Richard, Patel, Shivang, Brennan, Andrea, O'Neil, Zachary, Powell, Daniel J., Jr., Vonderheide, Robert H., Linette, Gerald P., and Carreno, Beatriz M.
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Oncology, Experimental ,T cells -- Receptors ,Gene mutations -- Research ,Antigen receptors, T cell -- Health aspects ,Cellular therapy -- Research ,Cancer vaccines -- Research ,Cancer -- Research ,Oncogenes -- Health aspects - Abstract
BACKGROUND. Neoantigens derived from [KRAS.sup.MUT] have been described, but the fine antigen specificity of T cell responses directed against these epitopes is poorly understood. Here, we explore [KRAS.sup.MUT] immunogenicity and the properties of 4 T cell receptors (TCRs) specific for [KRAS.sup.G12V] restricted to the HLA-A3 superfamily of class I alleles. METHODS. A phase 1 clinical vaccine trial targeting [KRAS.sup.MUT] was conducted. TCRs targeting [KRAS.sup.G12V] 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. RESULTS. Vaccination against [KRAS.sup.MUT] resulted in the priming of [CD8.sup.+] and [CD4.sup.+] T cell responses. [KRAS.sup.G12V] -specific natural (not affinity enhanced) TCRs exhibited exquisite specificity to mutated protein with no discernible reactivity against [KRAS.sup.WT]. 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.sup.+] T cells exhibited potent lytic activity against [KRAS.sup.G12V] cancers, while only HLA-A*11:01-restricted TCR-T [CD4.sup.+] T cells exhibited antitumor effector functions consistent with partial coreceptor dependence. All [KRAS.sup.G12V]-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. CONCLUSION. This study identifies [KRAS.sup.G12V]-specific TCRs with high therapeutic potential for the development of TCR-T cell therapies. TRIAL REGISTRATION. ClinicalTrials.gov NCT03592888. FUNDING. AACR SU2C/Lustgarten Foundation, Parker Institute for Cancer Immunotherapy, and NIH., Introduction T cell recognition of cancer antigens represents the end effector mechanism of successful cancer immunotherapy (1). Advances in the areas of T cell biology, gene engineering, and antigen identification [...]
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- 2024
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