Regional Immunotherapy for Peritoneal Carcinomatosis in Gastroesophageal Cancer: Emerging Strategies to Re-Condition a Maladaptive Tumor Environment

SIMPLE SUMMARY: Regional immunotherapy is a promising approach for treating peritoneal carcinomatosis gastric/gastroesophageal junction cancer (GC-PC) patients. This review explores the unique characteristics of GC-PC and peritoneal immune biology that make it a suitable target for immunotherapy. We discuss pre-clinical and clinical trials exploring a variety of potential immunomodulatory regional strategies designed to alter the peritoneal immune environment. Lastly, we present a blueprint for a future combinatorial strategy to leverage the peritoneal immune environment toward improved efficacy of regional cellular therapy, with the goal of creating durable local and systemic responses in GC-PC. ABSTRACT: Peritoneal carcinomatosis originating from gastric/gastroesophageal junction cancer (GC-PC) occurs in a defined subset of gastric cancer patients with unique clinical, pathologic, molecular and immunologic characteristics that create significant obstacles to effective treatment with modern therapy. Although systemic chemo- and immuno- therapy have yielded disappointing results in GC-PC, recent advances in the characterization of GC-PC and peritoneal immune biology present new opportunities for targeted therapeutics. In this review article, we discuss the distinct properties of GC-PC and the peritoneal immune environment as they pertain to current and investigative treatment strategies. We discuss pre-clinical studies and clinical trials relevant to the modulation of the peritoneal environment as a therapeutic intervention in GC-PC. Finally, we present a road map for future combinatorial strategies based on the conception of the peritoneal cavity as a bioreactor. Within this isolated compartment, prevailing immunosuppressive conditions can be altered through regional interventions toward an adaptive phenotype that would support the effectiveness of regionally delivered cellular therapy products. It is hoped that novel combination strategies would promote efficacy not only in the sequestered peritoneal environment, but also via migration into the circulation of tumor-reactive lymphocytes to produce durable systemic disease control, thereby improving oncologic outcome and quality of life in patients with GC-PC.