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

Area of Science:

• Immunotherapy
• Cancer Biology
• Cellular Mechanisms

Background:

• Chimeric antigen receptor (CAR) T cells can acquire tumor antigens via trogocytosis, potentially leading to CAR dysfunction.
• This trogocytosis may contribute to tumor escape, T cell exhaustion, and fratricide, impacting CAR T cell therapy efficacy.
• The role of trogocytosis in CAR T cell dysfunction, particularly in glioma targeting, requires further investigation.

Purpose of the Study:

• To evaluate the impact of trogocytosis on epidermal growth factor receptor variant III (EGFRvIII)-specific CAR T cells in glioma.
• To explore the relationship between CAR T cell-induced autophagy and trogocytosis.
• To identify strategies for enhancing CAR T cell performance by modulating these processes.

Main Methods:

• Generated EGFRvIII-specific CAR T cells from diverse donors and assessed their cytotoxicity and trogocytosis.
• Evaluated in vivo therapeutic efficacy against intracranial glioma models.
• Investigated the effects of an autophagy inducer (verteporfin) and inhibitor (bafilomycin A1) on CAR T cell activity and tumor autophagy.

Main Results:

• Significant variability in trogocytosis levels and PD-L1 expression was observed among CAR T cell products from different donors, correlating with therapeutic efficacy.
• Pharmacological induction of autophagy using verteporfin suppressed trogocytic antigen expression on CAR T cells.
• Verteporfin treatment enhanced CAR T cell persistence and improved therapeutic outcomes in preclinical glioma models.

Conclusions:

• CAR T cell-induced autophagy acts as a mechanism to counteract CAR-induced trogocytosis.
• Pharmacological modulation of autophagy presents a novel strategy to enhance CAR T cell function and efficacy.
• This approach offers a pathway to engineer more effective CAR T cell therapies for challenging cancers like glioma.