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 K. L. Walker, Robbert M. Spaapen, Hanna Kok, Demi Houg, Milena Viyacheva, Yvonne 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.C.C. de Miranda, Inge Jedema, John B.A.G. Haanen, Jeroen W. J. van Heijst, Ton N. Schumacher, Carsten Linnemann, Gavin Bendle
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. Kuilman et al. established a functional genetic screening platform for the efficient identification of tumor-specific TCRs. It is compatible with routine diagnostic tumor biopsies and can be applied in fully individualized TCR-T cell therapy.