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

Zhiliang Bai, Bing Feng, Susan E. McClory, Beatriz Coutinho Oliveira, Caroline Diorio, Céline Gregoire, Bo Tao, Luojia Yang, Ziran Zhao, Lei Peng, Giacomo Sferruzza, Liqun Zhou, Xiaolei Zhou, Jessica Kerr, Alev Baysoy, Graham Su, Mingyu Yang, Pablo G. Camara, Sidi Chen, Li Tang (), Carl H. June (), J. Joseph Melenhorst (), Stephan A. Grupp () and Rong Fan ()
Additional contact information
Zhiliang Bai: Yale University
Bing Feng: École Polytechnique Fédérale de Lausanne (EPFL)
Susan E. McClory: Children’s Hospital of Philadelphia
Beatriz Coutinho Oliveira: Cleveland Clinic
Caroline Diorio: Children’s Hospital of Philadelphia
Céline Gregoire: Cleveland Clinic
Bo Tao: Yale University School of Medicine
Luojia Yang: Yale University School of Medicine
Ziran Zhao: Cleveland Clinic
Lei Peng: Yale University School of Medicine
Giacomo Sferruzza: Yale University School of Medicine
Liqun Zhou: Yale University School of Medicine
Xiaolei Zhou: École Polytechnique Fédérale de Lausanne (EPFL)
Jessica Kerr: Cleveland Clinic
Alev Baysoy: Yale University
Graham Su: Yale University
Mingyu Yang: Yale University
Pablo G. Camara: University of Pennsylvania
Sidi Chen: Yale University School of Medicine
Li Tang: École Polytechnique Fédérale de Lausanne (EPFL)
Carl H. June: University of Pennsylvania
J. Joseph Melenhorst: Cleveland Clinic
Stephan A. Grupp: Children’s Hospital of Philadelphia
Rong Fan: Yale University

Nature, 2024, vol. 634, issue 8034, 702-711

Abstract: Abstract 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 year4–6, 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 2high CAR T cell products demonstrated superior expansion and antitumour activity, particularly after leukaemia rechallenge. Restoring antitumour efficacy in type 2low 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.

Date: 2024
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DOI: 10.1038/s41586-024-07762-w

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