Treating solid tumors with TCR-based chimeric antigen receptor targeting extra domain B-containing fibronectin

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Chimeric antigen receptor (CAR) T-cell therapy faces challenges in solid tumors due to the suppressive tumor microenvironment (TME).
• Extra domain B (EDB)-fibronectin is an oncofetal antigen present on tumor neovasculature and cancer cells, identified as a potential T-cell therapy target.
• Existing CAR T-cells show limited in vivo efficacy against solid tumors.

Purpose of the Study:

• To develop and evaluate redirected TCR-CAR T cells (rTCR-CAR) targeting EDB-fibronectin to overcome TME suppression.
• To investigate the efficacy of rTCR-CAR T cells in solid tumor treatment.
• To compare rTCR-CAR T cells with traditional CAR T-cell designs.

Main Methods:

• Generated EDB-targeting CAR by fusing single-chain variable fragment to CD3ε, creating rTCR-CAR.
• Studied EDB-targeting T cells using human primary T cells and Jurkat cells.
• Characterized differences in signaling, immune synapse formation, and T-cell exhaustion compared to traditional CAR T cells.
• Assessed in vitro cytotoxicity and in vivo therapeutic efficacy using xenograft models.

Main Results:

• rTCR-CAR T cells exhibited superior in vivo efficacy compared to traditional CAR T cells in xenograft models.
• Significant reduction in tumor vessel density and tumor growth inhibition were observed.
• rTCR-CAR T cells formed superior immune synapse structures upon binding to EDB-fibronectin.
• Activation via EDB-fibronectin led to increased in vivo expansion of rTCR-CAR T cells with low basal activation.

Conclusions:

• rTCR-CAR T cells targeting EDB-fibronectin show significant potential as an anticancer therapeutic.
• These engineered T cells possess both antiangiogenic and cytotoxic activities, bypassing suppressive TMEs.
• This single therapeutic agent offers potential for sustained control of solid tumors.