학술논문
Naturally occurring T cell mutations enhance engineered T cell therapies.
Document Type
Academic Journal
Author
Garcia J; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.; Moonlight Bio, Seattle, WA, USA.; Daniels J; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.; Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; Moonlight Bio, Seattle, WA, USA.; Lee Y; Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; Zhu I; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.; Cheng K; Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; Liu Q; Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; Goodman D; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.; Burnett C; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.; Law C; Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.; Thienpont C; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.; Alavi J; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.; Azimi C; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.; Montgomery G; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.; Roybal KT; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA. kole.roybal@ucsf.edu.; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. kole.roybal@ucsf.edu.; Chan Zuckerberg Biohub, San Francisco, CA, USA. kole.roybal@ucsf.edu.; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. kole.roybal@ucsf.edu.; Department of Anesthesia, University of California, San Francisco, San Francisco, CA, USA. kole.roybal@ucsf.edu.; Gladstone-UCSF Institute for Genomic Immunology, San Francisco, CA, USA. kole.roybal@ucsf.edu.; UCSF Cell Design Institute, San Francisco, CA, USA. kole.roybal@ucsf.edu.; Choi J; Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. jaehyuk.choi@northwestern.edu.; Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. jaehyuk.choi@northwestern.edu.; Center for Synthetic Biology, Northwestern University, Evanston, IL, USA. jaehyuk.choi@northwestern.edu.; Center for Human Immunobiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. jaehyuk.choi@northwestern.edu.; Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. jaehyuk.choi@northwestern.edu.; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. jaehyuk.choi@northwestern.edu.
Source
Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE
Subject
Language
English
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 1 . 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 2 , 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.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)