[en] 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.
Disciplines :
Hematology Immunology & infectious disease
Author, co-author :
Bai, Zhiliang ✱; Department of Biomedical Engineering, Yale University, New Haven, CT, USA
Feng, Bing ✱; Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland ; Institute of Materials Science & Engineering, EPFL, Lausanne, Switzerland
McClory, Susan E; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA ; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
de Oliveira, Beatriz Coutinho; Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
Diorio, Caroline; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA ; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA
GREGOIRE, Céline ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'hématologie clinique ; Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
Tao, Bo ; Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
Yang, Luojia; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
Zhao, Ziran; Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
Peng, Lei; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
Sferruzza, Giacomo; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
Zhou, Liqun; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
Zhou, Xiaolei; Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland ; Institute of Materials Science & Engineering, EPFL, Lausanne, Switzerland
Kerr, Jessica; Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
Baysoy, Alev; Department of Biomedical Engineering, Yale University, New Haven, CT, USA
Su, Graham; Department of Biomedical Engineering, Yale University, New Haven, CT, USA
Yang, Mingyu; Department of Biomedical Engineering, Yale University, New Haven, CT, USA
Camara, Pablo G; Department of Genetics and Institute for Biomedical Informatics, University of Pennsylvania, Philadelphia, PA, USA
Chen, Sidi ; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
Tang, Li ; Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. li.tang@epfl.ch ; Institute of Materials Science & Engineering, EPFL, Lausanne, Switzerland. li.tang@epfl.ch
June, Carl H ; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. cjune@upenn.edu ; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. cjune@upenn.edu ; Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. cjune@upenn.edu
Melenhorst, J Joseph ; Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. melenhj@ccf.org
Grupp, Stephan A ; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA. grupp@chop.edu ; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA. grupp@chop.edu
Fan, Rong ; Department of Biomedical Engineering, Yale University, New Haven, CT, USA. rong.fan@yale.edu ; Department of Pathology, Yale University School of Medicine, New Haven, CT, USA. rong.fan@yale.edu ; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA. rong.fan@yale.edu ; Human and Translational Immunology, Yale University School of Medicine, New Haven, CT, USA. rong.fan@yale.edu ; Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA. rong.fan@yale.edu
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