Language

English

Publication Date

4-9-2025

Journal

Journal for ImmunoTherapy of Cancer

DOI

10.1136/jitc-2024-010709

PMID

40210237

PMCID

PMC11987159

PubMedCentral® Posted Date

4-9-2025

PubMedCentral® Full Text Version

Post-print

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

Humans, Immunotherapy, Adoptive, T-Lymphocytes, Lymphoma, B-Cell, Receptors, Chimeric Antigen, DNA Methylation, Male, Female, Adoptive cell therapy - ACT, Chimeric antigen receptor - CAR, Lymphoma

Comments

This article has been corrected. See J Immunother Cancer. 2025 Jul 1;13(7):e010709corr1.

Published Open-Access

yes

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