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

autophagy chimeric antigen receptor T cells epidermal growth factor receptor variant III glioblastoma phagocytosis trogocytosis

Journal

Cancers
ISSN: 2072-6694
Titre abrégé: Cancers (Basel)
Pays: Switzerland
ID NLM: 101526829

Informations de publication

Date de publication:
08 Feb 2023
Historique:
received: 02 11 2022
revised: 20 01 2023
accepted: 03 02 2023
entrez: 25 2 2023
pubmed: 26 2 2023
medline: 26 2 2023
Statut: epublish

Résumé

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.

Sections du résumé

BACKGROUND BACKGROUND
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.
METHODS METHODS
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).
RESULTS RESULTS
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.
CONCLUSION CONCLUSIONS
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.

Identifiants

DOI: 10.3390/cancers15041085 PMID: 36831427 PMC: PMC9953964
pubmed: 36831427
pii: cancers15041085
doi: 10.3390/cancers15041085
pmc: PMC9953964
pii:
doi:

Types de publication

Journal Article

Langues

eng

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Auteurs

Jiyong Liang (J)

Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Dexing Fang (D)

Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Joy Gumin (J)

Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Hinda Najem (H)

Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
ORCID: 0000-0003-4432-9708

Moloud Sooreshjani (M)

Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.

Renduo Song (R)

Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Aria Sabbagh (A)

Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Ling-Yuan Kong (LY)

Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Joseph Duffy (J)

Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.

Irina V Balyasnikova (IV)

Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.

Seth M Pollack (SM)

Department of Cancer Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
ORCID: 0000-0002-2466-0607

Vinay K Puduvalli (VK)

Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Amy B Heimberger (AB)

Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Department of Neurosurgery, Northwestern University, Simpson Querrey Biomedical Research Center, 303 E. Superior Street, 6-516, Chicago, IL 60611, USA.
ORCID: 0000-0002-9970-8695

Classifications MeSH