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
Brian Orr, Haider Mahdi, Yusi Fang, Mary Strange, Ibrahim Uygun, Mainpal Rana, Lixin Zhang, Adria Suarez Mora, Alexandra Pusateri, Esther Elishaev, Chaeryon Kang, George Tseng, William Gooding, Robert P Edwards, Pawel Kalinski, Anda M Vlad, Brian Orr, Haider Mahdi, Yusi Fang, Mary Strange, Ibrahim Uygun, Mainpal Rana, Lixin Zhang, Adria Suarez Mora, Alexandra Pusateri, Esther Elishaev, Chaeryon Kang, George Tseng, William Gooding, Robert P Edwards, Pawel Kalinski, Anda M Vlad
Abstract
Purpose: Increased prevalence of cytotoxic T lymphocytes (CTL) in the tumor microenvironment (TME) predicts positive outcomes in patients with epithelial ovarian cancer (EOC), whereas the regulatory T cells (Treg) predict poor outcomes. Guided by the synergistic activity of TLR3 ligands, IFNα, and COX-2 blockers in selectively enhancing CTL-attractants but suppressing Treg-attractants, we tested a novel intraperitoneal chemoimmunotherapy combination (CITC), to assess its tolerability and TME-modulatory impact in patients with recurrent EOC.
Patients and methods: 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 IFNα 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 IFNα 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 phase II trial. See related commentary by Aranda et al., p. 1993.
©2022 American Association for Cancer Research.
Figures
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Fig 4.
Treatment-induced changes in tumor tissue.…
Fig 4.
Treatment-induced changes in tumor tissue. (A) Heatmaps of DE genes at baseline and…
![Fig 4.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/9106847/bin/nihms-1773832-f0004.jpg)
Source: PubMed