Abstract
Peritoneal carcinomatosis is a frequent metastatic condition in gastroesophageal cancer and is associated with poor prognosis and limited therapeutic options. Here, we establish clinically relevant mouse models of peritoneal carcinomatosis to evaluate the efficacy of a second-generation mesothelin-targeted chimeric antigen receptor (CAR) T-cell therapy. Our model recapitulates key clinical features, including ascites, bowel obstruction, and an immunosuppressive tumor microenvironment characterized by tumor-cell programmed death-ligand 1 expression and elevated TGF-β levels in ascites. To overcome T-cell exhaustion, we engineered a CAR T-cell construct (M28z1XXPD1DNR) that incorporates a programmed cell death protein-1 decoy receptor lacking the intracellular signaling domain, which enhances functional persistence. We demonstrate that intraperitoneal (regional) administration of CAR T cells at low doses achieves superior antitumor efficacy, longer survival, and sustained functional persistence, compared with intravenous (systemic) administration. Of note, intraperitoneal treatment also exhibits potency against distant disease sites. These findings provide a strong rationale for clinical translation; we are now conducting a clinical trial (NCT06623396) to evaluate intraperitoneal administration of M28z1XXPD1DNR CAR T cells in patients with gastroesophageal cancer peritoneal carcinomatosis.