학술논문
Single-Cell RNA Analysis Reveals Cell-Intrinsic Functions of CAR T Cells Correlating with Response in a Phase II Study of Lymphoma Patients.
Document Type
Academic Journal
Author
Sarén T; Department of Immunology, Genetics and Pathology, Uppsala University, Science for Life Laboratory, Uppsala, Sweden.; Ramachandran M; Department of Immunology, Genetics and Pathology, Uppsala University, Science for Life Laboratory, Uppsala, Sweden.; Gammelgård G; Department of Immunology, Genetics and Pathology, Uppsala University, Science for Life Laboratory, Uppsala, Sweden.; Lövgren T; Department of Immunology, Genetics and Pathology, Uppsala University, Science for Life Laboratory, Uppsala, Sweden.; Mirabello C; IFM Bioinformatics, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Linköping University, Linköping, Sweden.; Björklund ÅK; Department of Life Sciences, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Chalmers University of Technology, Göteborg, Sweden.; Wikström K; VECURA, Karolinska University Hospital Huddinge, Stockholm, Sweden.; Hashemi J; Department of Immunology, Genetics and Pathology, Uppsala University, Science for Life Laboratory, Uppsala, Sweden.; Freyhult E; Department of Medical Sciences, Uppsala University, Uppsala, Sweden.; Ahlström H; Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.; Antaros Medical AB, Mölndal, Sweden.; Amini RM; Department of Immunology, Genetics and Pathology, Uppsala University, Science for Life Laboratory, Uppsala, Sweden.; Hagberg H; Department of Immunology, Genetics and Pathology, Uppsala University, Science for Life Laboratory, Uppsala, Sweden.; Loskog A; Department of Immunology, Genetics and Pathology, Uppsala University, Science for Life Laboratory, Uppsala, Sweden.; Lokon Pharma AB, Uppsala, Sweden.; Enblad G; Department of Immunology, Genetics and Pathology, Uppsala University, Science for Life Laboratory, Uppsala, Sweden.; Essand M; Department of Immunology, Genetics and Pathology, Uppsala University, Science for Life Laboratory, Uppsala, Sweden.
Source
Publisher: The Association Country of Publication: United States NLM ID: 9502500 Publication Model: Print Cited Medium: Internet ISSN: 1557-3265 (Electronic) Linking ISSN: 10780432 NLM ISO Abbreviation: Clin Cancer Res Subsets: MEDLINE
Subject
Language
English
Abstract
Purpose: Although CD19 chimeric antigen receptor T cells (CAR-T) therapy has shown remarkable success in B-cell malignancies, a substantial fraction of patients do not obtain a long-term clinical response. This could be influenced by the quality of the individual CAR-T infusion product. To shed some light on this, clinical outcome was correlated to characteristics of CAR-T infusion products.
Patients and Methods: In this phase II study, patients with B-cell lymphoma (n = 23) or leukemia (n = 1) received one or two infusions of third-generation CD19-directed CAR-Ts (2 × 108/m2). The clinical trial was registered at clinicaltrials.gov: NCT03068416. We investigated the transcriptional profile of individual CD19 CAR-T infusion products using targeted single-cell RNA sequencing and multicolor flow cytometry.
Results: Two CAR-T infusions were not better than one in the settings used in this study. As for the CAR-T infusion products, we found that effector-like CD8+CAR-Ts with a high polyfunctionality, high cytotoxic and cytokine production profile, and low dysfunctional signature were associated with clinical response. An extended ex vivo expansion time during CAR-T manufacturing negatively influenced the proportion of effector CD8+CAR-Ts in the infusion product.
Conclusions: We identified cell-intrinsic characteristics of effector CD8+CAR-Ts correlating with response that could be used as an indicator for clinical outcome. The results in the study also serve as a guide to CAR-T manufacturing practices.
(©2023 The Authors; Published by the American Association for Cancer Research.)
Patients and Methods: In this phase II study, patients with B-cell lymphoma (n = 23) or leukemia (n = 1) received one or two infusions of third-generation CD19-directed CAR-Ts (2 × 108/m2). The clinical trial was registered at clinicaltrials.gov: NCT03068416. We investigated the transcriptional profile of individual CD19 CAR-T infusion products using targeted single-cell RNA sequencing and multicolor flow cytometry.
Results: Two CAR-T infusions were not better than one in the settings used in this study. As for the CAR-T infusion products, we found that effector-like CD8+CAR-Ts with a high polyfunctionality, high cytotoxic and cytokine production profile, and low dysfunctional signature were associated with clinical response. An extended ex vivo expansion time during CAR-T manufacturing negatively influenced the proportion of effector CD8+CAR-Ts in the infusion product.
Conclusions: We identified cell-intrinsic characteristics of effector CD8+CAR-Ts correlating with response that could be used as an indicator for clinical outcome. The results in the study also serve as a guide to CAR-T manufacturing practices.
(©2023 The Authors; Published by the American Association for Cancer Research.)