CD22 TCR-engineered T cells exert antileukemia cytotoxicity without causing inflammatory responses

Area of Science:

• Immunotherapy
• Oncology
• Cellular Therapy

Background:

• Chimeric antigen receptor (CAR) T cells are effective against B cell malignancies.
• CAR-T therapies can cause inflammatory toxicities like cytokine release syndrome (CRS).
• T cell receptor (TCR)-engineered T cells rarely cause CRS.

Purpose of the Study:

• To compare the inflammatory potential of CAR-T and TCR-T cells targeting the same antigen.
• To investigate how receptor type influences inflammatory responses in a model system.
• To evaluate the therapeutic efficacy and safety profiles of CD22 CAR-T and CD22 TCR-T cells.

Main Methods:

• Discovery of a CD22-specific TCR.
• Comparison of CD22 CAR-T cells and CD22 TCR-T cells in a preclinical model.
• Assessment of antileukemia activity in xenografts.
• Analysis of inflammatory pathway upregulation in response to antigen engagement.

Main Results:

• Both CD22 CAR-T and CD22 TCR-T cells eradicated leukemia in xenografts.
• Only CD22 CAR-T cells induced dose-dependent systemic inflammation.
• CAR-T cells showed disproportionate upregulation of inflammatory pathways compared to TCR-T cells.
• CAR-T cells did not show concordant augmentation of cytotoxicity pathways upon antigen engagement.

Conclusions:

• Differences in receptor type (CAR vs. TCR) significantly impact inflammatory responses.
• CAR-T cells elicit greater systemic inflammation than TCR-T cells, even when targeting the same antigen.
• TCR-engineered T cells may offer a safer alternative for cancer immunotherapy due to reduced inflammatory potential.