DR5 CAR-T cells target melanoma and suppress MDSCs with minimal toxicity

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Chimeric antigen receptor (CAR) T cell therapy faces challenges in solid tumors, including poor target specificity and immunosuppressive tumor microenvironments.
• Myeloid-derived suppressor cells (MDSCs) contribute to tumor immune evasion and are a potential therapeutic target.

Purpose of the Study:

• To investigate death receptor 5 (DR5) as a target for CAR T cell therapy in solid tumors.
• To engineer and evaluate DR5-specific CAR constructs for direct tumor killing and modulation of the tumor microenvironment.

Main Methods:

• Engineered agonistic DR5-specific CAR constructs.
• Evaluated CAR T cell activity in various solid tumor models (xenograft, syngeneic, patient-derived organoids, tissue slices).
• Assessed tumor killing, T cell viability, safety, and immune modulation (MDSC reduction, CD8+ T cell activity).

Main Results:

• DR5-specific CAR T cells demonstrated potent, DR5-dependent tumor cell killing across multiple models.
• Optimized CAR constructs maintained T cell viability while effectively eliminating tumors and MDSCs.
• In vivo studies showed reduced tumor growth, prolonged survival, and no detectable toxicity.
• Ex vivo analysis revealed CAR T cell infiltration, MDSC reduction, and enhanced CD8+ T cell activity in patient-derived tissues.

Conclusions:

• DR5-targeted CAR T cell therapy is a promising strategy for solid tumors, offering direct cytotoxicity and immune activation.
• This approach effectively targets both tumor cells and immunosuppressive MDSCs.
• The developed DR5 CAR T cell therapy exhibits a favorable safety profile and potential for clinical translation.