AR6 - Intraperitoneal CMP-001, A Novel Immunotherapy for Treating Peritoneal Carcinomatosis of Gastrointestinal and Pancreaticobiliary Cancers

Background: Peritoneal metastasis is common in gastrointestinal and pancreaticobiliary cancers. Current treatment and life expectancy of patients with peritoneal carcinomatosis (PC) are limited. CMP-001, a virus-like particle composed of Qbeta bacteriophage capsid protein encapsulating a Toll-Like Receptor 9 agonist CpG-A oligodeoxynucleotide, activates plasmacytoid dendritic cells (pDC) and triggers interferon alpha (IFNa) release, leading to a cascade of anti-tumor immune response.

Methods: To evaluate the ability of CMP-001 for triggering immune response in patients with PC, an ex vivo model was established. Malignant ascites or peritoneal lavage fluids were collected from patients with PC. Immune profiles of isolated cells were obtained using flow cytometry. Peritoneal cells were stimulated by CMP-001 and IFNa release was quantified by ELISA. To evaluate the anti-tumor response in vivo, murine PC models were generated using mouse cancer cell lines (Panc2 and MC38) and treated with intraperitoneal (ip) CMP-001 or saline on days 5, 9 and 13 after tumor challenge. Kaplan Meier method was used for survival analysis. Necropsy and immunophenotyping of peritoneal tumor microenvironment were performed on day 26.

Results: pDC was found in 1.0% (0.1-3.9%, N=15) of the isolated peritoneal cells. Ex vivo CMP-001 stimulation of the peritoneal cells released on average 1 ng/ml IFNa (1.8-4700 pg/ml, N=9). IFNa concentration was directly proportional to %pDC present in the peritoneal cell mixture (r=0.8, p=0.012). In murine PC models, ip CMP-001 treatment elicited a robust anti-tumor immune response including an increase in chemokines (RANTES, MIP1a, MIP1b), proinflammatory cytokines (IFNgamma, IL6, IL12), and peritoneal/tumor immune infiltrates (CD4+/CD8+ T cells and NK cells). This immune response led to an improved survival in both Panc2 (median: 35 vs. 28 days) and MC38 (median: 57 vs. 35 days) PC models (P<0.05).

Conclusion: CMP-001 is a novel immunotherapeutic agent currently on clinical trial for advanced melanoma resistant to immune checkpoint inhibition with impressive treatment response. Our preclinical data suggest CMP-001 can be used to treat patients with PC. Clinical development of CMP-001 in PC is under discussion.