GPC1 specific CAR-T cells eradicate established solid tumor without adverse effects and synergize with anti-PD-1 Ab

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Current mouse models for CAR T-cell therapy development face limitations in assessing on-target, off-tumor adverse effects for solid tumors.
• These limitations stem from antibody cross-reactivity issues and graft-versus-host disease in xenogeneic models.

Purpose of the Study:

• To evaluate the safety and antitumor efficacy of CAR T-cells targeting glypican-1 (GPC1) in solid tumors.
• To assess the utility of both xenogeneic and syngeneic mouse models for CAR T-cell therapy evaluation.

Main Methods:

• Generation of human and murine CAR T-cells targeting GPC1 using a novel anti-GPC1 antibody.
• Evaluation of antitumor effects in both xenogeneic and syngeneic mouse models.
• Assessment of CAR T-cell synergy with anti-PD-1 immunotherapy and investigation of antigen-spreading mechanisms.

Main Results:

• GPC1-specific CAR T-cells demonstrated significant antitumor activity in both xenogeneic (human CAR-T) and syngeneic (murine CAR-T) models.
• Murine CAR T-cells induced antigen-spreading, enhancing endogenous T-cell responses against other tumor antigens.
• Synergistic antitumor effects were observed when combining murine CAR T-cells with anti-PD-1 therapy, with no adverse events noted in syngeneic models.

Conclusions:

• Glypican-1 is a viable target for CAR T-cell therapy in solid tumors.
• Syngeneic models are crucial for comprehensive safety and efficacy evaluation of CAR T-cell therapies, including assessment of on-target, off-tumor effects and immune-mediated mechanisms.