Abstract TMIM-073: THE COMBINATION OF INTERFERONS ALPHA AND GAMMA AND MONOCYTES INDUCES OVARIAN CANCER CELL DEATH AND PROVIDE A RATIONALE FOR A NOVEL, ONGOING, IMMUNOTHERAPY PHASE 1 CLINICAL TRIAL
Authors: Green Daniel S. , Johnson Chase L. , Qi Chen-Feng , Tosh Kevin W. , Kamenyeva Olena , Zoon Kathryn C. , Annunziata Christina M. 
Published: June 2021

Standard of care for the treatment of ovarian cancer is surgical tumor debulking, followed by administration of a platinum based compound in combination with a taxane compound. While there is an initial good response to the therapy, especially in optimally debulked tumors, the disease is characterized by a high rate of relapse. There is no definitive second line treatment for patients. Ovarian cancer is largely retained in the peritoneal cavity, with metastases outside of the peritoneum occurring late in the course of the disease. The restriction of the bulk of the tumor burden to the peritoneal cavity makes intraperitoneal (IP) treatment a reasonable approach for ovarian cancer. This strategy was first employed for ovarian cancer using immunotherapy with IP administration of Interferon Alpha. However, one of the hallmarks of ovarian cancer a highly immunosuppressive environment. This environment includes the metastases themselves and the fluid of the peritoneum which contains a mix of pro and anti-inflammatory cells, cytokines and lipids. Tipping the balance towards a pro-inflammatory environment is necessary for the effective treatment of disease.

Herein, we define the mechanisms by which IFNs and monocytes are potent killers of ovarian cancer cells. While patients with ovarian cancer have normal whole blood counts, the tumoricidal activity of their monocytes has never been measured. We demonstrate that ovarian cancer patient monocytes are more tumoricidal when cultured with IFNs than monocytes from sex and age matched controls. In this work, we expand on our previous observations of synergistic killing of ovarian cancer cell lines by monocytes and IFNs by showing that an important mechanism of cell death is mediated by TRAIL expressed on monocytes, and the target cells die in a Caspase-8 dependent mechanism. We also found that the tumoricidal effect of IFNs and monocytes was independent of IRF9 and STAT2 signaling, and was instead dependent on IRF-1 and STAT1 signaling. Together, these data support a new, innate immune based, approach to immunotherapy of ovarian cancer.

We are currently determining the safety of using autologous monocytes treated ex vivo with IFNs and infused into the peritoneal cavity of patients with advanced ovarian cancer in a phase 1 clinical trial (NCT02948426). While the data presented here and previously published works show that innate mediators of the immune system can kill ovarian cancer cells and decrease disease burden, a durable clinical response is dependent on a strong adaptive immune response. In the clinical trial we will identify whether the highly pro-inflammatory properties of the combination of the innate immune effectors monocytes and IFNs can stimulate an existing, but tumor suppressed, adaptive anti-tumor immune response. Here we present a mechanistic understanding of how IFNs and monocytes can kill ovarian cancer cells and provide mechanistic insights into innate immune based immune therapy for the treatment of ovarian cancer.

Citation Format: Daniel S. Green, Chase L. Johnson, Chen-Feng Qi, Kevin W. Tosh, Olena Kamenyeva, Kathryn C. Zoon, Christina M. Annunziata. THE COMBINATION OF INTERFERONS ALPHA AND GAMMA AND MONOCYTES INDUCES OVARIAN CANCER CELL DEATH AND PROVIDE A RATIONALE FOR A NOVEL, ONGOING, IMMUNOTHERAPY PHASE 1 CLINICAL TRIAL [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr TMIM-073.