Human Platelet Lysate Enhances In Vivo Activity of Car-Vδ2 T Cells by Reducing Cellular Senescence and Apoptosis

Authors

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

Publication Date

8-1-2024

Journal

Cytotherapy

DOI

10.1016/j.jcyt.2024.03.006

PMID

38506769

PMCID

PMC11269029

PubMedCentral® Posted Date

8-1-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Humans, Apoptosis, Receptors, Chimeric Antigen, Animals, Cellular Senescence, Immunotherapy, Adoptive, Mice, Blood Platelets, T-Lymphocytes, Antigens, CD19, Cell Line, Tumor, CD28 Antigens, Xenograft Model Antitumor Assays, Tumor Necrosis Factor Receptor Superfamily, Member 9, Vδ2 T cells, chimeric antigen receptor, Manufacture, Human platelet lysate, apoptosis, cell senescence

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.

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