Dual-targeting CD133/PD-L1 CAR-T plus αPD-1 overcomes immunosuppressive microenvironment and enhanced by radiation...

Area of Science:

• Immunotherapy
• Oncology
• Cellular Therapy

Background:

• Solid tumors require innovative chimeric antigen receptor (CAR) T-cell strategies for improved therapeutic outcomes.
• Existing CAR T-cell therapies face challenges in solid tumor microenvironments.

Purpose of the Study:

• To develop and evaluate a novel dual-targeting CAR T-cell therapy for CD133-positive tumors.
• To assess the efficacy of combining this dual-targeting CAR T-cell therapy with PD-1 blockade and radiation pre-conditioning.

Main Methods:

• Development of a dual-targeting CAR T-cell therapy combining alphaPDL1.CD28 and alphaCD133 CAR constructs.
• Assessment of CAR T-cell activation, cytotoxic function, and in vivo antitumor efficacy in mouse models.
• Evaluation of combination therapy including PD-1 blockade and radiation pre-conditioning.

Main Results:

• The dual-targeting CAR T-cells demonstrated enhanced activation and cytotoxic function against CD133+ tumors.
• Combination with PD-1 blockade prolonged therapeutic efficacy by disrupting inhibitory signals.
• Radiation pre-conditioning (10 Gy or 4 Gy) maximized antitumor effects, leading to complete tumor regression.
• Radiation induced a tissue-resident memory CAR T-cell phenotype (CXCR6+, CD103+), potentially interacting with irradiation-induced E-cadherin on tumor cells.

Conclusions:

• A novel dual-targeting CD133/PD-L1 CAR T-cell therapy was successfully developed.
• A triple combination of dual-targeting CAR T-cells, PD-1 blockade, and radiation shows significant therapeutic potential for solid tumors.
• Radiation pre-conditioning can induce a potent anti-tumor immune response mediated by tissue-resident memory CAR T-cells.