Enabling next-generation engineered TCR-T therapies based on high-throughput TCR discovery from diagnostic tumor biopsies

Enabling next-generation engineered TCR-T therapies based on high-throughput TCR discovery from diagnostic tumor biopsies

Abstract Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) can mediate tumor regression, including complete and durable responses, in a range of solid cancers, most notably in melanoma. However, its wider application and efficacy has been restricted by the limited accessibility, prolif...

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Main Authors: Thomas Kuilman, Deborah S. Schrikkema, Jules Gadiot, Raquel Gomez-Eerland, Laura Bies, Julia Walker, Robbert M. Spaapen, Hanna Kok, Demi Houg, Milena Viyacheva, Yvonne B. Claassen, Manuel Saornil, Oscar Krijgsman, Bas Stringer, Huiwen Ding, Anou Geleijnse, Anne C. Meinema, Bianca Weissbrich, Melissa Lancee, Carmen G. Engele, Marianna Sabatino, Pei-Ling Chen, Kenneth Y. Tsai, James J. Mulé, Vernon K. Sondak, Jitske van den Bulk, Noel F. de Miranda, Inge Jedema, John G. Haanen, Jeroen W. J. van Heijst, Ton N. Schumacher, Carsten Linnemann, Gavin M. Bendle
Format: Article
Language:English
Published: Nature Portfolio 2025-01-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-024-55420-6
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Summary:Abstract Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) can mediate tumor regression, including complete and durable responses, in a range of solid cancers, most notably in melanoma. However, its wider application and efficacy has been restricted by the limited accessibility, proliferative capacity and effector function of tumor-specific TIL. Here, we develop a platform for the efficient identification of tumor-specific TCR genes from diagnostic tumor biopsies, including core-needle biopsies frozen in a non-viable format, to enable engineered T cell therapy. Using a genetic screening approach that detects antigen-reactive TCRs with high sensitivity and specificity based on T cell activation, we show that high complexity TCR libraries can be efficiently screened against multiplexed antigen libraries to identify both HLA class I and II restricted TCRs. Through the identification of neoantigen-specific TCRs directly from melanoma as well as low tumor mutational burden microsatellite-stable colorectal carcinoma samples, we demonstrate the pan-cancer potential of this platform.
ISSN:2041-1723

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