Phase I Trial Combining Chemokine-Targeting with Loco-Regional Chemoimmunotherapy for Recurrent, Platinum-Sensitive Ovarian Cancer Shows Induction of CXCR3 Ligands and Markers of Type 1 Immunity

Purpose: Increased prevalence of cytotoxic T lymphocytes (CTL) in the tumor microenvironment (TME) predicts positive outcomes in patients with epithelial ovarian cancer (EOC), where-as the regulatory T cells (Treg) predict poor outcomes. Guided by the synergistic activity of TLR3 ligands, IFN alpha, and COX-2 block-ers in selectively enhancing CTL-attractants but suppressing Treg-attractants, we tested a novel intraperitoneal chemoimmu-notherapy combination (CITC), to assess its tolerability and TME-modulatory impact in patients with recurrent EOC. Patients andMethods: Twelve patients were enrolled in phase I portion of the trial NCT02432378, and treated with intraperitoneal cisplatin, intraperitoneal rintatolimod (dsRNA, TLR3 ligand), and oral celecoxib (COX-2 blocker). Patients in cohorts 2, 3, and 4 also received intraperitoneal IFN alpha at 2, 6, and 18 million units (MU), respectively. Primary objectives were to evaluate safety, identify phase 2 recommended dose (P2RD), and characterize changes in the immune TME. Peritoneal resident cells and intraperitoneal wash fluid were profiled via NanoString and Meso Scale Discovery (MSD) multiplex assay, respectively. Results: The P2RD of IFN alpha was 6 MU. Median progression-free survival and overall survival were 8.4 and 30 months, respectively. Longitudinal sampling of the peritoneal cavity via intraperitoneal washes demonstrated local upregulation of IFN-stimulated genes (ISG), including CTL-attracting chemokines (CXCL-9,-10,-11), MHC I/II, perforin, and granzymes. These changes were present 2 days after chemokine modulation and subsided within 1 week. Conclusions: The chemokine-modulating intraperitoneal-CITC is safe, tolerable, and associated with ISG changes that favor CTL chemoattraction and function. This combination (plus DC vaccine) will be tested in a II trial.

Automated summary

The purpose of this study was to investigate the safety and modulatory effects on the tumor microenvironment of a novel intraperitoneal chemoimmunotherapy combination in patients with epithelial ovarian cancer. The results showed that this combination therapy was well tolerated and associated with enhanced chemotaxis and function of cytotoxic T lymphocytes.