Intraperitoneal CF33-hNIS combined with PD-L1 blockade eradicates gastric cancer peritoneal metastases and prevents recurrence via durable T cell memory

BACKGROUND: Peritoneal metastasis (PM) from gastric cancer (GC) is associated with poor prognosis and limited treatment options. We investigated a novel peritoneal-targeted therapy using CF33-human sodium iodide symporter (hNIS), a chimeric orthopoxvirus, combined with anti-PD-L1 immune checkpoint blockade in an immunocompetent mouse model of GCPM. METHODS: T cell subsets in the peritoneal cavity and tumor microenvironment. Mice that showed complete tumor regression (CTR) were rechallenged with ACKPY3944 cells to assess memory T cell responses. RESULTS: plaque-forming units) combined with IP anti-PD-L1 (Combo 2) with 75% CTR. Notably, mice with CTR rejected tumor rechallenge, exhibiting significantly elevated effector and central memory T cell populations in the peritoneal cavity and spleen. IP CF33-hNIS demonstrates robust anti-tumor efficacy against GCPM, particularly when combined with IP anti-PD-L1 in the high-dose Combo 2 regimen. CONCLUSIONS: These findings support a simplified, high-dose IP treatment strategy to overcome immune resistance in GCPM and provide a strong rationale for future clinical evaluation.