Naturally occurring T cell mutations enhance engineered T cell therapies

• 成果类型: Article
• 署名作者: Garcia, Julie; Daniels, Jay; Lee, Yujin; Zhu, Iowis; Cheng, Kathleen; Liu, Qing; Goodman, Daniel; Burnett, Cassandra; Law, Calvin; Thienpont, Chloe; Alavi, Josef; Azimi, Camillia; Montgomery, Garrett; Roybal, Kole T.; Choi, Jaehyuk
• 署名单位: University of California System; University of California San Francisco; Northwestern University; Feinberg School of Medicine; Northwestern University; Feinberg School of Medicine; Chan Zuckerberg Initiative (CZI); University of California System; University of California San Francisco; UCSF Medical Center; UCSF Helen Diller Family Comprehensive Cancer Center; University of California System; University of California San Francisco; Northwestern University; Northwestern University; Feinberg School of Medicine; Northwestern University; Feinberg School of Medicine; Northwestern University; Feinberg School of Medicine; Robert H. Lurie Comprehensive Cancer Center; Ann & Robert H. Lurie Children's Hospital of Chicago
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5951
• DOI: 10.1038/s41586-024-07018-7
• 发表日期: 2024-02-15
• 关键词: identification; exhaustion; antigen; nfat

摘要

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. 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.