Intraperitoneal Monocytes plus IFNs as a Novel Cellular Immunotherapy for Ovarian Cancer: Mechanistic Characterization and Results from a Phase I Clinical Trial

Author:

Green Daniel S.12ORCID,Ning Franklin1ORCID,Duemler Anna1ORCID,Myers Timothy G.3ORCID,Trewhitt Kathryn1ORCID,Ekwede Irene1ORCID,McCoy Ann1ORCID,Houston Nicole1ORCID,Lee Jung-min1ORCID,Lipkowitz Stanley1ORCID,Zimmer Alexandra1ORCID,Pavelova Miroslava1ORCID,Villanueva Erin N.1ORCID,Smith Leslie1ORCID,Blakely Andrew4ORCID,Casablanca Yovanni5ORCID,Highfill Steven L.6ORCID,Stroncek David F.6ORCID,Collins-Johnson Naoza6ORCID,Panch Sandhya6ORCID,Procter JoLynn6ORCID,Pham Chauha6ORCID,Korrapati Soumya1,Holland Steven M.7ORCID,Rosen Lindsey B.7ORCID,Nunes Ana T.1ORCID,Zoon Kathryn C.2ORCID,Cole Christopher B.1ORCID,Annunziata Christina M.1ORCID

Affiliation:

1. 1Women's Malignancies Branch, Center for Cancer Research (CCR), NCI, Bethesda, Maryland.

2. 2Laboratory of Infectious Diseases, National Institutes of Allergy and Infectious Diseases, NIH, Bethesda, Maryland.

3. 3Genomic Technologies Section, National Institutes of Allergy and Infectious Diseases, NIH, Bethesda, Maryland.

4. 4Surgical Oncology Program, Center for Cancer Research (CCR), NCI, Bethesda, Maryland.

5. 5Gynecologic Oncology, Walter Reed National Military Medical Center, Bethesda, Maryland.

6. 6Center for Cellular Engineering, Department of Transfusion Medicine, Clinical Center, NIH, Bethesda, Maryland.

7. 7Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland.

Abstract

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

Funder

National Cancer Institute

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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