A Case Study of Chimeric Antigen Receptor T Cell Function: Donor Therapeutic Differences in Activity and Modulation with Verteporfin

Chimeric antigen receptor (CAR) T cells have recently been demonstrated to extract and express cognate tumor antigens through trogocytosis. This process may contribute to tumor antigen escape, T cell exhaustion, and fratricide, which plays a central role in CAR dysfunction. We sought to evaluate the...

Full description

Saved in:
Bibliographic Details
Published in:Cancers 2023-02, Vol.15 (4), p.1085
Main Authors: Liang, Jiyong, Fang, Dexing, Gumin, Joy, Najem, Hinda, Sooreshjani, Moloud, Song, Renduo, Sabbagh, Aria, Kong, Ling-Yuan, Duffy, Joseph, Balyasnikova, Irina V, Pollack, Seth M, Puduvalli, Vinay K, Heimberger, Amy B
Format: Article
Language:English
Subjects:
Animal models
Antigen (tumor-associated)
Antigens
Autophagy
Brain cancer
Brain tumors
Care and treatment
Case studies
Cell culture
Cell death
Chimeric antigen receptors
Cytotoxicity
Dosage and administration
Flow cytometry
Glioma cells
Gliomas
Health aspects
Life sciences
Lymphocytes
Lymphocytes T
Manufacturers
PD-L1 protein
Plasma membranes
Software
Survival analysis
T cell receptors
T cells
Tumor cells
Verteporfin
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Chimeric antigen receptor (CAR) T cells have recently been demonstrated to extract and express cognate tumor antigens through trogocytosis. This process may contribute to tumor antigen escape, T cell exhaustion, and fratricide, which plays a central role in CAR dysfunction. We sought to evaluate the importance of this effect in epidermal growth factor receptor variant III (EGFRvIII) specific CAR T cells targeting glioma. EGFRvIII-specific CAR T cells were generated from various donors and analyzed for cytotoxicity, trogocytosis, and in vivo therapeutic activity against intracranial glioma. Tumor autophagy resulting from CAR T cell activity was evaluated in combination with an autophagy inducer (verteporfin) or inhibitor (bafilomycin A1). CAR T cell products derived from different donors induced markedly divergent levels of trogocytosis of tumor antigen as well as PD-L1 upon engaging target tumor cells correlating with variability in efficacy in mice. Pharmacological facilitation of CAR induced-autophagy with verteporfin inhibits trogocytic expression of tumor antigen on CARs and increases CAR persistence and efficacy in mice. These data propose CAR-induced autophagy as a mechanism counteracting CAR-induced trogocytosis and provide a new strategy to innovate high-performance CARs through pharmacological facilitation of T cell-induced tumor death.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers15041085