细胞外囊泡蛋白监测并干扰靶向 CLDN18.2 的 CAR-T 细胞和抗体治疗胃肠道肿瘤

Claudin 18. 2 (CLDN18. 2)-targeted CAR-T cell and antibody therapies show promise against gastrointestinal cancers, but biomarkers predictive of long-term benefit and therapeutic sensitization strategies are needed.

Here we show that proteins carried by circulating extracellular vesicles (EVs) can reflect and influence the efficacy of CLDN18. 2-targeted therapies. By profiling serial plasma samples of patients from the CT041-CG4006 trial (CLDN18. 2- CAR-T-therapy) or the GLOW trial (Zolbetuximab), we identified EV-associated CLDN18. 2, PD1 and PD-L2 as therapeutic markers and integrated them into a signature (CPP-score) for better predictive robustness.

Mechanistically, specific EV-proteins exhaust CAR-T cells, neutralize CLDN18. 2-targeted-antibodies, activate immunosuppressive IL-6-expressing cancer-associated fibroblasts, and alter the TH1/TH2 balance, thereby reshaping the tumor microenvironment and interfere with CLDN18. 2-targeted therapies.

Strategies including combining anti-PD1 antibody or CAF inhibitor, CLDN18. 2-CAR-T plus CLDN18. 2-antibody, and depleting plasma EVs, can sensitize CLDN18. 2-CAR-T/antibody by countermeasuring EV-proteins' therapeutic interferences. Collectively, our work provides potential options to monitor and improve CLDN18. 2-targeted therapies in clinical practice.