Intraperitoneal Monocytes plus IFNs as a Novel Cellular Immunotherapy for Ovarian Cancer: Mechanistic Characterization and Results from a Phase I Clinical Trial
Daniel S. Green, Franklin Ning, Anna Duemler, Timothy G. Myers, Kathryn Trewhitt, Irene Ekwede, Ann McCoy, Nicole Houston, Jung‐Min Lee, Stanley Lipkowitz, Alexandra S. Zimmer, Miroslava Pavelova, Erin N. Villanueva, Leslie Smith, Andrew M. Blakely, Yovanni Casablanca, Steven L. Highfill, David F. Stroncek, Naoza Collins-Johnson, Sandhya R. Panch, JoLynn Procter, Chauha Pham, Soumya Korrapati, Steven M. Holland, Lindsey B. Rosen, Ana T. Nunes, Kathryn C. Zoon, Christopher B. Cole, Christina M. Annunziata
Abstract
PURPOSE: Ovarian cancer is the most lethal gynecologic cancer and intrinsically resistant to checkpoint immunotherapies. We sought to augment innate immunity, building on previous work with IFNs and monocytes. PATIENTS AND METHODS: Preclinical experiments were designed to define the mechanisms of cancer cell death mediated by the combination of IFNs α and γ with monocytes. We translated these preclinical findings into a phase I trial of autologous IFN-activated monocytes administered intraperitoneally to platinum-resistant or -refractory ovarian cancer patients. RESULTS: IFN-treated monocytes induced caspase 8-dependent apoptosis by the proapoptotic TRAIL and mediated by the death receptors 4 and 5 (DR4 and DR5, respectively) on cancer cells. Therapy was well tolerated with evidence of clinical activity, as 2 of 9 evaluable patients had a partial response by RECIST criteria, and 1 additional patient had a CA-125 response. Upregulation of monocyte-produced TRAIL and cytokines was confirmed in peripheral blood. Long-term responders had alterations in innate and adaptive immune compartments. CONCLUSIONS: Given the mechanism of cancer cell death, and the acceptable tolerability of the clinical regimen, this platform presents a possibility for future combination therapies to augment anticancer immunity. See related commentary by Chow and Dorigo, p. 299.