Enhancement of Th17-Inducing DC Vaccination for Ovarian Cancer Through PARPi-Mediated Activation of Innate Immunity in the Tumor Microenvironment
Abstract
Background: This proposal represents the fusion of two novel approaches to immunotherapy for ovarian cancer. The first observation focuses on a new class of drugs, known as PARP inhibitors, for treatment of ovarian cancer with BRCA1/2 mutations. BRCA1 and BRCA2 gene products are important for DNA repair in tumor cells, and BRCA-deficient tumors use PARP-mediated DNA repair as a backup mechanism to support tumor cell survival and growth. Consequently, BRCA-mutated tumor cells are sensitive to cell death upon PARP inhibition. A Phase III trial of maintenance olaparib in ovarian cancer patients with BRCA1/2 mutations who had a complete or partial response to platinum-based chemotherapy found a 70% lower risk of disease progression or death with the PARP inhibitor olaparib, compared with placebo. This pivotal trial supported FDA approval of maintenance olaparib for ovarian cancer with BRCA1 and/or BRCA2 mutations, which is about 20-25% of patients. Interestingly, PARP inhibitors have shown some clinical benefit independent of BRCA1/2 status, suggesting that PARP inhibitors may have antitumor activity through mechanisms other than inhibition of DNA repair. This is important because the majority of ovarian cancer patients do not have BRCA mutations. Recent studies have shown that PARP inhibitors such as olaparib can stimulate antitumor immune responses through mechanisms that are independent of DNA repair or BRCA mutation status. Notably, PARP inhibitors can enhance the benefit of immunotherapies such as immune checkpoint inhibition and tumor vaccination, which have generally been ineffective for ovarian cancer. Our research focuses on the use of powerful immune-stimulating cells called dendritic cells (DC) to activate immune responses against ovarian cancer. DC vaccines prepared from blood drawn from the patient have strong potential as a treatment to prevent ovarian tumor recurrence or progression after surgery and chemotherapy. We recently completed a phase I clinical trial of maintenance DC vaccination for stage IIIC–IV ovarian cancer patients following initial surgery and chemotherapy. DC vaccination induced durable immune responses, and of 18 evaluable patients, 39% remain recurrence-free beyond 36 months’ post-enrollment. Although our clinical results are encouraging, ovarian tumors create an environment that strongly suppresses the immune system, thus protecting the tumor from immunological attack. One of the leading mechanisms of suppression involves the infiltration and accumulation of specialized myeloid white blood cells within the tumor. We have found that myeloid cells are highly abundant in ovarian tumor ascites and profoundly suppress DC-stimulated immune responses. Consequently, the ability of a DC vaccine to stimulate immunity against ovarian cancer may not be sufficient to provide clinical benefit for ovarian cancer patients. Recent studies have suggested that PARP inhibitors can trigger anti-tumor inflammatory responses in tumor-associated myeloid cells, potentially reversing myeloid cell-associated immune suppression. Collectively, these observations make a compelling case for the treatment of ovarian cancers with the combination of olaparib and DC vaccination. Clinical Impact: This innovative pilot study will test combinatorial treatment of cisplatin, olaparib, and Th17-DC vaccination in BRCA-competent and BRCA-deficient mouse models of ovarian cancer. We will also determine whether olaparib treatment alleviates myeloid cell suppression of DC vaccine-induced ovarian tumor-specific immune responses. The recent Food and Drug Administration approval of olaparib for maintenance treatment of ovarian cancer is opportune because this treatment setting coincides with our approach to DC vaccination as maintenance treatment to prevent or delay tumor recurrence in stage IIIC/IV ovarian cancer patients. This alignment highlights the potential clinical opportunity of combining maintenance PARP
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010642
Entities
People
- Martin Cannon
Organizations
- United States Army
- University of Arkansas for Medical Sciences