Naturally occurring T cell mutations enhance engineered T cell therapies

Julie Garcia, Jay Daniels, Yujin Lee, Iowis Zhu, Kathleen Cheng, Qing Liu, Daniel Goodman, Cassandra Burnett, Calvin Law, Chloë Thienpont, Josef Alavi, Camillia Azimi, Garrett Montgomery, Kole T. Roybal () and Jaehyuk Choi ()
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Julie Garcia: University of California, San Francisco
Jay Daniels: University of California, San Francisco
Yujin Lee: Northwestern University Feinberg School of Medicine
Iowis Zhu: University of California, San Francisco
Kathleen Cheng: Northwestern University Feinberg School of Medicine
Qing Liu: Northwestern University Feinberg School of Medicine
Daniel Goodman: University of California, San Francisco
Cassandra Burnett: University of California, San Francisco
Calvin Law: Northwestern University Feinberg School of Medicine
Chloë Thienpont: University of California, San Francisco
Josef Alavi: University of California, San Francisco
Camillia Azimi: University of California, San Francisco
Garrett Montgomery: University of California, San Francisco
Kole T. Roybal: University of California, San Francisco
Jaehyuk Choi: Northwestern University Feinberg School of Medicine

Nature, 2024, vol. 626, issue 7999, 626-634

Abstract: Abstract Adoptive T cell therapies have produced exceptional responses in a subset of patients with cancer. However, therapeutic efficacy can be hindered by poor T cell persistence and function1. In human T cell cancers, evolution of the disease positively selects for mutations that improve fitness of T cells in challenging situations analogous to those faced by therapeutic T cells. Therefore, we reasoned that these mutations could be co-opted to improve T cell therapies. Here we systematically screened the effects of 71 mutations from T cell neoplasms on T cell signalling, cytokine production and in vivo persistence in tumours. We identify a gene fusion, CARD11–PIK3R3, found in a CD4+ cutaneous T cell lymphoma2, that augments CARD11–BCL10–MALT1 complex signalling and anti-tumour efficacy of therapeutic T cells in several immunotherapy-refractory models in an antigen-dependent manner. Underscoring its potential to be deployed safely, CARD11–PIK3R3-expressing cells were followed up to 418 days after T cell transfer in vivo without evidence of malignant transformation. Collectively, our results indicate that exploiting naturally occurring mutations represents a promising approach to explore the extremes of T cell biology and discover how solutions derived from evolution of malignant T cells can improve a broad range of T cell therapies.

Date: 2024
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DOI: 10.1038/s41586-024-07018-7

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