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

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 Bulk, Noel F. Miranda, Inge Jedema, John G. Haanen, Jeroen W. J. Heijst, Ton N. Schumacher, Carsten Linnemann and Gavin M. Bendle ()
Additional contact information
Thomas Kuilman: Neogene Therapeutics, A member of the AstraZeneca Group
Deborah S. Schrikkema: Neogene Therapeutics, A member of the AstraZeneca Group
Jules Gadiot: Neogene Therapeutics, A member of the AstraZeneca Group
Raquel Gomez-Eerland: Neogene Therapeutics, A member of the AstraZeneca Group
Laura Bies: Neogene Therapeutics, A member of the AstraZeneca Group
Julia Walker: Neogene Therapeutics, A member of the AstraZeneca Group
Robbert M. Spaapen: Neogene Therapeutics, A member of the AstraZeneca Group
Hanna Kok: Neogene Therapeutics, A member of the AstraZeneca Group
Demi Houg: Neogene Therapeutics, A member of the AstraZeneca Group
Milena Viyacheva: Neogene Therapeutics, A member of the AstraZeneca Group
Yvonne B. Claassen: Neogene Therapeutics, A member of the AstraZeneca Group
Manuel Saornil: Neogene Therapeutics, A member of the AstraZeneca Group
Oscar Krijgsman: Neogene Therapeutics, A member of the AstraZeneca Group
Bas Stringer: Neogene Therapeutics, A member of the AstraZeneca Group
Huiwen Ding: Neogene Therapeutics, A member of the AstraZeneca Group
Anou Geleijnse: Neogene Therapeutics, A member of the AstraZeneca Group
Anne C. Meinema: Neogene Therapeutics, A member of the AstraZeneca Group
Bianca Weissbrich: Neogene Therapeutics, A member of the AstraZeneca Group
Melissa Lancee: Neogene Therapeutics, A member of the AstraZeneca Group
Carmen G. Engele: Neogene Therapeutics, A member of the AstraZeneca Group
Marianna Sabatino: Neogene Therapeutics, A member of the AstraZeneca Group
Pei-Ling Chen: Moffitt Cancer Center
Kenneth Y. Tsai: Moffitt Cancer Center
James J. Mulé: Moffitt Cancer Center
Vernon K. Sondak: Moffitt Cancer Center
Jitske Bulk: Neogene Therapeutics, A member of the AstraZeneca Group
Noel F. Miranda: Leiden University Medical Center
Inge Jedema: The Netherlands Cancer Institute
John G. Haanen: The Netherlands Cancer Institute
Jeroen W. J. Heijst: Neogene Therapeutics, A member of the AstraZeneca Group
Ton N. Schumacher: The Netherlands Cancer Institute
Carsten Linnemann: Neogene Therapeutics, A member of the AstraZeneca Group
Gavin M. Bendle: Neogene Therapeutics, A member of the AstraZeneca Group

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-024-55420-6

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