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Northwestern University

Nature, Feb 07 2024, | https://doi.org/10.1038/s41586-024-07018-7 Naturally occurring T cell mutations enhance engineered T cell therapies

Julie Garcia ^1,2,14,15, Jay Daniels ^1,3,4,14,15, Yujin Lee ^3,4, Iowis Zhu ^1,2, Kathleen Cheng ^3,4, Qing Liu ^3,4, Daniel Goodman^1,2, Cassandra Burnett ^1,2, Calvin Law ^3,4, Chloë Thienpont¹, Josef Alavi ¹, Camillia Azimi ^1,2, Garrett Montgomery¹, Kole T. Roybal ^{1,2,5,6,7,8,9 ,*} & Jaehyuk Choi ^{3,4,10,11,12,13 ,*}

¹Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.
²Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
³Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁴Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
⁵Chan Zuckerberg Biohub, San Francisco, CA, USA.
⁶Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
⁷Department of Anesthesia, University of California, San Francisco, San Francisco, CA, USA.
⁸Gladstone-UCSF Institute for Genomic Immunology, San Francisco, CA, USA.
⁹UCSF Cell Design Institute, San Francisco, CA, USA.
¹⁰Center for Synthetic Biology, Northwestern University, Evanston, IL, USA.
¹¹Center for Human Immunobiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
¹²Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
¹³Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
¹⁴Present address: Moonlight Bio, Seattle, WA, USA.
¹⁵These authors contributed equally: Julie Garcia, Jay Daniels.

^*Corresponding authors: correspondence to Kole T. Roybal or Jaehyuk Choi

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 function. 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 lymphoma, 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.

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형식Research article
게재일2024년 02월 (BRIC 등록일 2024-02-12)
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