Single-cell CAR T atlas reveals type 2 function in 8-year leukaemia remission

• 成果类型: Article
• 署名作者: Bai, Zhiliang; Feng, Bing; McClory, Susan E.; de Oliveira, Beatriz Coutinho; Diorio, Caroline; Gregoire, Celine; Tao, Bo; Yang, Luojia; Zhao, Ziran; Peng, Lei; Sferruzza, Giacomo; Zhou, Liqun; Zhou, Xiaolei; Kerr, Jessica; Baysoy, Alev; Su, Graham; Yang, Mingyu; Camara, Pablo G.; Chen, Sidi; Tang, Li; June, Carl H.; Melenhorst, J. Joseph; Grupp, Stephan A.; Fan, Rong
• 署名单位: Yale University; Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; Cleveland Clinic Foundation; Yale University; Yale University; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; Yale University; Yale University; Yale University; Yale New Haven Hospital
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4794
• DOI: 10.1038/s41586-024-07762-w
• 发表日期: 2024-10-17
• 页码: 702-+
• 关键词: exhaustion; promotes; PATHWAY; FAMILY; death

摘要

Despite a high response rate in chimeric antigen receptor (CAR) T cell therapy for acute lymphocytic leukaemia (ALL)(1-3), approximately 50% of patients relapse within the first year(4-6), representing an urgent question to address in the next stage of cellular immunotherapy. Here, to investigate the molecular determinants of ultralong CAR T cell persistence, we obtained a single-cell multi-omics atlas from 695,819 pre-infusion CAR T cells at the basal level or after CAR-specific stimulation from 82 paediatric patients with ALL enrolled in the first two CAR T ALL clinical trials and 6 healthy donors. We identified that elevated type 2 functionality in CAR T infusion products is significantly associated with patients maintaining a median B cell aplasia duration of 8.4 years. Analysis of ligand-receptor interactions revealed that type 2 cells regulate a dysfunctional subset to maintain whole-population homeostasis, and the addition of IL-4 during antigen-specific activation alleviates CAR T cell dysfunction while enhancing fitness at both transcriptomic and epigenomic levels. Serial proteomic profiling of sera after treatment revealed a higher level of circulating type 2 cytokines in 5-year or 8-year relapse- free responders. In a leukaemic mouse model, type 2(high) CAR T cell products demonstrated superior expansion and antitumour activity, particularly after leukaemia rechallenge. Restoring antitumour efficacy in type 2(low) CAR T cells was attainable by enhancing their type 2 functionality, either through incorporating IL- 4 into the manufacturing process or by priming manufactured CAR T products with IL-4 before infusion. Our findings provide insights into the mediators of durable CAR T therapy response and suggest potential therapeutic strategies to sustain long-term remission by boosting type 2 functionality in CAR T cells.