(1) Junkuhn C (2) Schiele P (3) Walter AL (4) Hamm F (5) Obermayer B (6) Busch D (7) Stroux A (8) Frick M (9) Penack O (10) Damm F (11) Polansky J (12) Bullinger L (13) Künkele A (14) Frentsch M (15) Na IK

Journal for immunotherapy of cancer | Free PMC Article

Junkuhn et al. demonstrated the negative impact of chemotherapy on the quality of T cells for CAR T cell therapy in patients with B-cell non-Hodgkin’s lymphoma. Multiparameter flow cytometry and scRNAseq data identified a shift in T cell differentiation and an upregulation of exhaustion markers in post- compared to pre-chemotherapy T cells. Although these phenotypic differences diminished after CAR T cell production, CAR T cells derived from treatment-naive T cells exhibited superior cumulative killing efficacy in cytotoxicity assays, and maintained epigenetic features associated with clinical responses to therapy.

Contributed by Shishir Pant

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy depends on T cells that are genetically modified to recognize and attack cancer cells. Their effectiveness thus hinges on the functionality of a patient's own T cells. Since CAR T-cell therapy is currently only approved for advanced cancers after at least one line of chemotherapy, we evaluated the potential negative effects of prior exposure to chemotherapy on T-cell functionality. METHODS: We studied T cells of two B-cell non-Hodgkin's lymphoma patient cohorts, one collected before treatment (pre-therapy) and the other after one or more (median 3) lines of chemotherapy (post-therapy). Leveraging advanced multiparameter flow cytometry, single-cell RNA sequencing (scRNA-seq), whole-genome DNA methylation arrays and in vitro functionality testing of generated CAR T cells, we compared patient samples in their suitability for effective CAR T-cell therapy. RESULTS: We discovered significant modifications in T-cell subsets and their transcriptional profiles secondary to chemotherapy exposure. Our analysis revealed a discernible shift towards phenotypically more differentiated T cells and an upregulation of markers indicative of T-cell exhaustion. Additionally, scRNA-seq and DNA methylation analyses revealed gene expression and epigenetic changes associated with diminished functionality in post-therapy T cells. Cytotoxicity assays demonstrated superior killing efficacy of CAR T cells derived from treatment-na•ve patients compared with those with chemotherapy history. CONCLUSIONS: These findings corroborate that employing T cells collected prior to frontline chemotherapy could enhance the effectiveness of CAR T-cell therapy and improve patient outcomes.

Author Info: (1) Berlin Institute of Health at Charité, Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Berlin, Germany. BSIO Berlin School of Integrative Oncology, Ch

Author Info: (1) Berlin Institute of Health at Charité, Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Berlin, Germany. BSIO Berlin School of Integrative Oncology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. Department of Hematology, Oncology and Tumor Immunology, Charité University Hospital Berlin, Berlin, Germany. (2) Berlin Institute of Health at Charité, Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Berlin, Germany. Department of Hematology, Oncology and Tumor Immunology, Charité University Hospital Berlin, Berlin, Germany. (3) Berlin Institute of Health at Charité, Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Berlin, Germany. BSIO Berlin School of Integrative Oncology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. Department of Hematology, Oncology and Tumor Immunology, Charité University Hospital Berlin, Berlin, Germany. (4) Berlin Institute of Health at Charité, Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Berlin, Germany. (5) Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Core Unit Bioinformatics, Berlin, Germany. (6) Department of Hematology, Oncology and Tumor Immunology, Charité University Hospital Berlin, Berlin, Germany. (7) Institute for Biometrie and Clinical Epidemiology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. (8) Department of Hematology, Oncology and Tumor Immunology, Charité University Hospital Berlin, Berlin, Germany. (9) Department of Hematology, Oncology and Tumor Immunology, Charité University Hospital Berlin, Berlin, Germany. (10) Department of Hematology, Oncology and Tumor Immunology, Charité University Hospital Berlin, Berlin, Germany. German Cancer Consortium (DKTK), Berlin, Germany. (11) Berlin Institute of Health at Charité, Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Berlin, Germany. German Rheumatism Research Center (DRFZ), Immuno-Epigenetics, Berlin, Germany. (12) BSIO Berlin School of Integrative Oncology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. Department of Hematology, Oncology and Tumor Immunology, Charité University Hospital Berlin, Berlin, Germany. German Cancer Consortium (DKTK), Berlin, Germany. (13) BSIO Berlin School of Integrative Oncology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. German Cancer Consortium (DKTK), Berlin, Germany. Pediatric Oncology and Hematology, Charité Universitätsmedizin Berlin, Berlin, Germany. (14) Berlin Institute of Health at Charité, Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Berlin, Germany. Department of Hematology, Oncology and Tumor Immunology, Charité University Hospital Berlin, Berlin, Germany. (15) Berlin Institute of Health at Charité, Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Berlin, Germany il-kang.na@bih-charite.de. BSIO Berlin School of Integrative Oncology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. Department of Hematology, Oncology and Tumor Immunology, Charité University Hospital Berlin, Berlin, Germany. German Cancer Consortium (DKTK), Berlin, Germany.

Citation: J Immunother Cancer 2025 Apr 9 13: Epub04/09/2025

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/40210237

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