Naturally occurring T cell mutations enhance engineered T cell therapies

• Published in: Nature (London) Vol. 626; no. 7999; pp. 626 - 634
• Main Authors: Garcia, Julie, Daniels, Jay, Lee, Yujin, Zhu, Iowis, Cheng, Kathleen, Liu, Qing, Goodman, Daniel, Burnett, Cassandra, Law, Calvin, Thienpont, Chloë, Alavi, Josef, Azimi, Camillia, Montgomery, Garrett, Roybal, Kole T., Choi, Jaehyuk
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.02.2024; Nature Publishing Group
• Subjects: 13/31; 38/91; 42/40; 631/250/251; 631/67/69; 64/60; Anticancer properties; Antigens; Bcl-10 protein; Cancer; CARD Signaling Adaptor Proteins - genetics; CARD Signaling Adaptor Proteins - metabolism; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell culture; Cell therapy; Cloning; Cytokines - biosynthesis; Cytokines - immunology; Cytokines - metabolism; Effectiveness; Evolution; Evolution, Molecular; Gene fusion; Genes; Guanylate Cyclase - genetics; Guanylate Cyclase - metabolism; Hematology; Humanities and Social Sciences; Humans; Immunotherapy; Immunotherapy, Adoptive - methods; Kinases; Libraries; Lymphocytes; Lymphocytes T; Lymphoma, T-Cell, Cutaneous - genetics; Lymphoma, T-Cell, Cutaneous - immunology; Lymphoma, T-Cell, Cutaneous - pathology; Lymphoma, T-Cell, Cutaneous - therapy; multidisciplinary; Mutation; Neoplasms; Phosphatidylinositol 3-Kinases; Proteins; Science; Science (multidisciplinary); Signal Transduction - genetics; T cell receptors; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes - transplantation; Tumors
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-024-07018-7

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. A study examines the effects of mutations that occur naturally in T cell cancers, reporting that such mutations can potentially be exploited to increase the potency of T cell therapies.