Prior chemotherapy deteriorates T-cell quality for CAR T-cell therapy in B-cell non-Hodgkin's lymphoma.

in Journal for immunotherapy of cancer by Charlotte Junkuhn, Phillip Schiele, Anna Luzie Walter, Frederik Hamm, Benedikt Obermayer, David Busch, Andrea Stroux, Mareike Frick, Olaf Penack, Frederik Damm, Julia Polansky, Lars Bullinger, Annette Künkele, Marco Frentsch, Il-Kang Na

TLDR

  • The study found that chemotherapy exposure can modify T-cell subsets and reduce their functionality, suggesting that using treatment-naïve T cells may improve CAR T-cell therapy outcomes.

Abstract

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. 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. 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. 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.

Overview

  • The study evaluated the potential negative effects of prior chemotherapy exposure on T-cell functionality for CAR T-cell therapy.
  • The researchers compared T-cell subsets and transcriptional profiles of two patient cohorts: one collected before treatment (pre-therapy) and the other after one or more lines of chemotherapy (post-therapy).
  • The primary objective was to assess the suitability of patient samples for effective CAR T-cell therapy and identify potential differences in T-cell functionality between the two cohorts.

Comparative Analysis & Findings

  • The study discovered significant modifications in T-cell subsets and transcriptional profiles secondary to chemotherapy exposure, including a shift towards phenotypically more differentiated T cells and upregulation of markers indicative of T-cell exhaustion.
  • Single-cell RNA sequencing (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.

Implications and Future Directions

  • The findings suggest that employing T cells collected prior to frontline chemotherapy could enhance the effectiveness of CAR T-cell therapy and improve patient outcomes.
  • Future studies should address the limitations of the current study, such as the small sample size and the need for larger, more diverse patient cohorts.
  • Novel approaches, such as in vitro reprogramming of T cells or small molecule inhibitors of T-cell exhaustion, could be explored to overcome the negative effects of chemotherapy on T-cell functionality.
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