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

Authors
  • Liang, Jiyong1, 2
  • Fang, Dexing1
  • Gumin, Joy1
  • Najem, Hinda3, 4
  • Sooreshjani, Moloud3, 4
  • Song, Renduo1
  • Sabbagh, Aria1
  • Kong, Ling-Yuan1
  • Duffy, Joseph3, 4
  • Balyasnikova, Irina V3, 4
  • Pollack, Seth M5
  • Puduvalli, Vinay K2
  • Heimberger, Amy B3, 4, 6
  • 1 Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 2 Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 3 Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
  • 4 Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
  • 5 Department of Cancer Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
  • 6 Department of Neurosurgery, Northwestern University, Simpson Querrey Biomedical Research Center, 303 E. Superior Street, 6-516, Chicago, IL 60611, USA.
Type
Published Article
Journal
Cancers
Publisher
MDPI AG
Publication Date
Feb 08, 2023
Volume
15
Issue
4
Identifiers
DOI: 10.3390/cancers15041085
PMID: 36831427
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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.

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