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| Item Type: | Article |
|---|---|
| Title: | Prior chemotherapy deteriorates T-cell quality for CAR T-cell therapy in B-cell non-Hodgkin's lymphoma |
| Creators Name: | Junkuhn, C., Schiele, P., Walter, A.L., Hamm, F., Obermayer, B., Busch, D., Stroux, A., Frick, M., Penack, O., Damm, F., Polansky, J., Bullinger, L., Künkele, A., Frentsch, M. and Na, I.K. |
| Abstract: | 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-naïve 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. |
| Keywords: | Adoptive Immunotherapy, B-Cell Lymphoma, Chimeric Antigen Receptors, DNA Methylation, T-Lymphocytes |
| Source: | Journal for ImmunoTherapy of Cancer |
| ISSN: | 2051-1426 |
| Publisher: | BMJ Publishing Group |
| Volume: | 13 |
| Number: | 4 |
| Page Range: | e010709 |
| Date: | April 2025 |
| Official Publication: | https://doi.org/10.1136/jitc-2024-010709 |
| PubMed: | View item in PubMed |
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