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

doi:10.1016/j.jcyt.2024.03.006

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

Cytotherapy. 2024 Mar 12:S1465-3249(24)00095-1. doi: 10.1016/j.jcyt.2024.03.006. Online ahead of print.

Authors

Feiyan Mo¹, Chiou-Tsun Tsai², Rong Zheng³, Chonghui Cheng³, Helen E Heslop¹, Malcolm K Brenner¹, Maksim Mamonkin¹, Norihiro Watanabe⁴

Affiliations

¹ Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, Texas, USA; Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, USA.
² Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, Texas, USA.
³ Department of Molecular and Human Genetics, Lester & Sue Breast Center, Baylor College of Medicine, Houston, Texas, USA; Graduate Program in Integrative Molecular and Biomedical Sciences, Baylor College of Medicine, Houston, Texas, USA.
⁴ Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, Texas, USA. Electronic address: nwatanab@bcm.edu.

PMID: 38506769
DOI: 10.1016/j.jcyt.2024.03.006

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.

Keywords: Vδ2 T cells; apoptosis; cell senescence; chimeric antigen receptor; human platelet lysate; manufacture.

Abstract

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