Human platelet lysate enhances in vivo activity of CAR-Vδ2 T cells by reducing cellular senescence and apoptosis

Feiyan Mo, Chiou Tsun Tsai, Rong Zheng, Chonghui Cheng, Helen E. Heslop, Malcolm K. Brenner, Maksim Mamonkin, Norihiro Watanabe

Research output: Contribution to journalArticlepeer-review

Abstract

Background aims: Vγ9Vδ2 T cells are an attractive cell platform for the off-the-shelf cancer immunotherapy as the result of their lack of alloreactivity and inherent multi-pronged cytotoxicity, which could be further amplified with chimeric antigen receptors (CARs). In this study, we sought to enhance the in vivo longevity of CAR-Vδ2 T cells by modulating ex vivo manufacturing conditions and selecting an optimal CAR costimulatory domain. Methods: Specifically, we compared the anti-tumor activity of Vδ2 T cells expressing anti-CD19 CARs with costimulatory endodomains derived from CD28, 4-1BB or CD27 and generated in either standard fetal bovine serum (FBS)- or human platelet lysate (HPL)-supplemented medium. Results: We found that HPL supported greater expansion of CAR-Vδ2 T cells with comparable in vitro cytotoxicity and cytokine secretion to FBS-expanded CAR-Vδ2 T cells. HPL-expanded CAR-Vδ2 T cells showed enhanced in vivo anti-tumor activity with longer T-cell persistence compared with FBS counterparts, with 4-1BB costimulated CAR showing the greatest activity. Mechanistically, HPL-expanded CAR Vδ2 T cells exhibited reduced apoptosis and senescence transcriptional pathways compared to FBS-expanded CAR-Vδ2 T cells and increased telomerase activity. Conclusions: This study supports enhancement of therapeutic potency of CAR-Vδ2 T cells through a manufacturing improvement.

Original languageEnglish (US)
JournalCytotherapy
DOIs
StateAccepted/In press - 2024

Keywords

  • Vδ2 T cells
  • apoptosis
  • cell senescence
  • chimeric antigen receptor
  • human platelet lysate
  • manufacture

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Genetics(clinical)
  • Cell Biology
  • Transplantation
  • Cancer Research

Fingerprint

Dive into the research topics of 'Human platelet lysate enhances in vivo activity of CAR-Vδ2 T cells by reducing cellular senescence and apoptosis'. Together they form a unique fingerprint.

Cite this