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Single-Cell RNA Analysis Reveals Cell-Intrinsic Functions of CAR T Cells Correlating with Response in a Phase II Study of Lymphoma Patients
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- Sarén, Tina (författare)
- Uppsala universitet,Cancerimmunterapi,Science for Life Laboratory, SciLifeLab,Department of Immunology, Genetics and Pathology, Uppsala University, Science for Life Laboratory, Uppsala, Sweden,Uppsala University
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- Ramachandran, Mohanraj, 1988- (författare)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Cancerimmunterapi,Vaskulärbiologi,Department of Immunology, Genetics and Pathology, Uppsala University, Science for Life Laboratory, Uppsala, Sweden,Uppsala University
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- Gammelgård, Gustav (författare)
- Uppsala universitet,Cancerimmunterapi,Science for Life Laboratory, SciLifeLab,Department of Immunology, Genetics and Pathology, Uppsala University, Science for Life Laboratory, Uppsala, Sweden,Uppsala University
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- American Association for Cancer Research Inc. 2023
- 2023
- Engelska.
- Ingår i: Clinical Cancer Research. - : American Association for Cancer Research Inc.. - 1078-0432 .- 1557-3265. ; 29:20, s. 4139-4152
- Tidskriftsartikel (refereegranskat)
Abstract
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- 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 ¼ 23) or leukemia (n ¼ 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 CD8þCAR-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 CD8þCAR-Ts in the infusion product. Conclusions: We identified cell-intrinsic characteristics of effector CD8þCAR-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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Nyckelord
- CD19 antigen; CD27 antigen; interleukin 2 receptor alpha; antigen expression; Article; B cell lymphoma; CD8+ T lymphocyte; cell subpopulation; chimeric antigen receptor immunotherapy; clinical article; clinical feature; clinical outcome; cohort analysis; controlled study; correlational study; cytokine production; cytotoxicity; disease association; ex vivo study; flow cytometry; gene cluster; genetic transcription; human; human cell; leukemia; phase 2 clinical trial; phenotype; RNA analysis; single cell analysis; treatment indication
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