DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Combination Immunotherapies Offer New Hope for Chemotherapy-Resistant Ovarian Cancer Patients

Posted September 5, 2019
Dr. Dmitriy Zamarin, Memorial Sloan Kettering Cancer Center

Dr. Dmitriy Zamarin

Dr. Dmitriy Zamarin

Immunotherapy has emerged as a promising approach for ovarian cancer treatment. It enables patients’ immune systems to target cancer cells, and it may be effective where other chemotherapy and radiation have failed. Dr. Dmitriy Zamarin’s research focuses on understanding the mechanisms of immunotherapy in cancer with the hope of identifying new treatments for ovarian cancer patients. To facilitate a career as an independent investigator with a focus in immunotherapy and ovarian cancer, Dr. Zamarin sought support from the Ovarian Cancer Academy. In fiscal year 2015 (FY15), he received an Ovarian Cancer Academy – Early-Career Investigator Award, and with its support, he has investigated biomarkers indicating response or resistance to immunotherapies and developed novel immunotherapeutic ovarian cancer treatment strategies. Impressively, Dr. Zamarin’s research has resulted in a phase II clinical trial focusing on a treatment for ovarian cancer patients that are resistant to standard therapies.

With support from the FY15 award Dr. Zamarin found potential benefits for the use of immunotherapies in ovarian cancer patients, but also noticed limitations. When investigating the use of Programmed Cell Death Receptor 1 (PD-L1) inhibitor drugs, which block the receptors that enable cancer cells to evade the body’s immune response, Dr. Zamarin noted some success in ovarian cancer patients, but the responses were variable, as some patients did not respond to treatment. Dr. Zamarin also researched another type of immunotherapy that has recently emerged: oncolytic viruses (OVs). These molecules selectively target and infect tumor cells, marking them for destruction by the body’s immune system without harming normal tissue. What’s more, in addition to killing injected tumors, OVs induce destruction of distant tumors through the body’s generation of an anti-tumor immune response. Dr. Zamarin determined that OVs increased tumor cell death by the immune system; however, this success was limited by the tumor’s continued expression of PD-L1, which interfered with tumor cell death. 

Based on these results, Dr. Zamarin hypothesized that the application of PD-L1 inhibitors with OVs could prove to be a more effective treatment in ovarian cancer patients. By combining OVs and PD-L1 inhibitors, enhanced activation of the immune response to the tumor, along with tumor regression, was promoted in animal models, an effect that was not seen with either treatment alone. This exciting finding led Dr. Zamarin and colleagues to develop a phase II clinical trial to test the therapeutic combination of an OV, ONCOS-102, and PD-L1 inhibitor, durvalumab, in patients with ovarian cancer that has developed resistance to standard therapies. This trial is currently ongoing. 

Along the same lines, Dr. Zamarin and colleagues are studying whether activation of anti-tumor immune responses using anti-cancer vaccines could boost the efficacy of PD-L1 inhibitors. They have conducted a combination phase II trial of TPIV200, a vaccine targeting folate receptor, with the PD-L1 inhibitor, durvalumab, in patients that failed to show response to standard ovarian cancer treatment. Twenty-seven women with advanced ovarian cancer were enrolled in the trial. Post-immunotherapy follow-up showed an increase in patient survival, suggesting improved clinical benefit from the combination immunotherapy and warranting further exploration of the combined treatment. 

Resistance to chemotherapy is a major problem for women with advanced ovarian cancer, and alternative treatments are desperately needed. Dr. Zamarin’s research into a novel combined immunotherapy provides hope for women in the advanced stages of this disease.

Publications:

Ricca JM, Oseledchyk A, Walther T, Liu C, Mangarin L, Merghoub T, Wolchok JD, Zamarin D. 2018. Pre-existing Immunity to Oncolytic Virus Potentiates Its Immunotherapeutic Efficacy. Mol Ther Apr 4;26(4):1008-1019. doi:10.1016/j.ymthe.2018.01.019. Epub 2018 Jan 31. PubMed PMID: 29478729.

Zamarin D, Ricca JM, Sadekova S, Oseledchyk A, Yu Y, Blumenschein WM, Wong J, Gigoux M, Merghoub T, Wolchok JD. 2018. PD-L1 in Tumor Microenvironment Mediates Resistance to Oncolytic Immunotherapy. J Clin Invest Nov 1;128(11):5184. doi:10.1172/JCI125039. Epub 2018 Oct 2. PubMed PMID: 30277478; PubMed Central PMCID: PMC6205393.

Links:

Public and Technical Abstracts: Novel Approaches to Locoregional and Systemic Immunotherapy for Ovarian Cancer 

Clinical Trial: NCT02764333

Clinical Trial: NCT02963831

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Last updated Thursday, September 5, 2019