%0 Journal Article
%A Immisch, Lena
%A Papafotiou, George
%A Gallarín Delgado, Nerea
%A Scheuplein, Vivian
%A Paschen, Annette
%A Blankenstein, Thomas
%A Willimsky, Gerald
%T Targeting the recurrent Rac1P29S neoepitope in melanoma with heterologous high-affinity T cell receptors.
%J Frontiers in immunology
%V 14
%@ 1664-3224
%C Lausanne
%I Frontiers Media
%M DKFZ-2023-00449
%P 1119498
%D 2023
%X Recurrent neoepitopes are cancer-specific antigens common among groups of patients and therefore ideal targets for adoptive T cell therapy. The neoepitope FSGEYIPTV carries the Rac1P29S amino acid change caused by a c.85C>T missense mutation, which is the third most common hotspot mutation in melanoma. Here, we isolated and characterized TCRs to target this HLA-A*02:01-binding neoepitope by adoptive T cell therapy. Peptide immunization elicited immune responses in transgenic mice expressing a diverse human TCR repertoire restricted to HLA-A*02:01, which enabled isolation of high-affinity TCRs. TCR-transduced T cells induced cytotoxicity against Rac1P29S expressing melanoma cells and we observed regression of Rac1P29S expressing tumors in vivo after adoptive T cell therapy (ATT). Here we found that a TCR raised against a heterologous mutation with higher peptide-MHC affinity (Rac2P29L) more efficiently targeted the common melanoma mutation Rac1P29S. Overall, our study provides evidence for the therapeutic potential of Rac1P29S-specific TCR-transduced T cells and reveal a novel strategy by generating more efficient TCRs by heterologous peptides.
%K Rho (Rho GTPase) (Other)
%K TCR gene therapy (Other)
%K humanized mouse models (Other)
%K melanoma (Other)
%K neoantigen (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:36875127
%2 pmc:PMC9978334
%R 10.3389/fimmu.2023.1119498
%U https://inrepo02.dkfz.de/record/274139