CLDN18.2-targeting STAR-T cell therapy for pancreatic cancer: a strategy to minimize gastric off-tumor toxicity...

Area of Science:

• Immunotherapy
• Oncology
• Cellular Therapy

Background:

• Claudin18 isoform 2 (CLDN18.2) is a target in pancreatic cancer (PC) and present in gastric tissue.
• Chimeric antigen receptor T (CAR-T) cell therapy shows potential but carries risks of on-target, off-tumor (OTOT) toxicity due to CLDN18.2 expression in normal gastric mucosa.

Purpose of the Study:

• To develop and evaluate CLDN18.2-specific synthetic T cell receptor and antigen receptor T (STAR-T) cells as a safer alternative to CAR-T therapy for PC.
• To assess the in vitro and in vivo efficacy and safety profile of STAR-T cells compared to CAR-T cells.

Main Methods:

• Development of CLDN18.2-specific STAR-T cells.
• Comparative in vitro cytotoxicity assays between STAR-T and CAR-T cells.
• In vivo studies in animal models to evaluate antitumor effects and gastric safety.
• Clinical gastroscopy assessments in patients receiving STAR-T cell therapy.

Main Results:

• STAR-T and CAR-T cells exhibited comparable in vitro cytotoxicity.
• STAR-T cells demonstrated reduced in vivo gastric damage compared to CAR-T cells, despite slightly weaker antitumor effects.
• Clinical trials confirmed the gastric safety of STAR-T cell therapy and effective disease control.
• Incorporation of IL12β p40 subunit enhanced STAR-T cell function in preclinical studies.

Conclusions:

• CLDN18.2 STAR-T cell therapy represents a potentially safer alternative to CAR-T cell therapy for pancreatic cancer.
• Further clinical trials are warranted to validate the efficacy and safety of CLDN18.2 STAR-T cells.