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

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.

Keywords: carcinomatosis; gastric cancer; immunotherapy; peritoneal metastasis.

Figure 1

Regional immunotherapy in the peritoneal cavity. Emerging regional peritoneal options include intra-tumoral adjuvant injection, IP cytokine blockade, IP targeted therapy (monoclonal antibody or small molecule inhibitors), IP adoptive cellular therapy, and IP oncolytic viral or vaccine therapy and intra-tumoral injection. The ultimate goal of regional therapy is to generate and support a cytotoxic tumor-specific T-cell response in the peritoneal cavity. A combined or multimodal regional approach would stimulate TAA presentation by resident dendritic cells, promote an adaptive T_H1 response while minimizing immunosuppressive or tumor-promoting mediators, and deliver ACT, oncolytics, or vaccines via regional catheters. Drainage or effluent from the peritoneal cavity could serve as a fertile source of tumor-specific ACT products, as well as biomarkers for immune status and disease response. An adaptive regional immunotherapy response could then generate systemic anti-tumor activity in extraperitoneal sites of disease, while potentially sparing patients from the systemic toxicity of immunotherapy. Abbreviations: IP—intra-peritoneal, TAA—tumor-associated antigens; PAMPs—pathogen-associated molecular pathogens; DAMPs—damage-associated molecular pathogens; TH1—Type 1 T helper cells; DC—dendritic cells; EMT—epithelial-to-mesenchymal transition; ACT—adoptive cellular therapy; TIL—tumor-infiltrating lymphocytes; PK/PD—pharmacokinetics/pharmacodynamics.