CD206-Targeted Alleviation of Immune Suppression by Ovarian Tumor-Associated Macrophages
Abstract
Background: Our research focuses on the use of powerful immune-stimulating cells called dendritic cells (DC) to activate immune responses against ovarian tumor cells. 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 have found that DC can be educated to activate a Th17 T cell response against ovarian cancer. This is an exciting prospect because recent clinical studies have shown that patients with a Th17 lymphocyte (T cell) infiltrate in tumors enjoy a markedly longer overall survival. This observation has prompted the development of a Th17-inducing DC vaccine that is currently being tested in patients with stage IIIC/IV ovarian cancer following first-line surgery and chemotherapy. To date, 8 of 9 patients completing the induction phase of five DC vaccinations show a strong Th17 response to tumor antigen, and 11 of 15 patients show no evidence of disease recurrence or progression after completion. Although interim clinical results are encouraging, ovarian tumors create an environment that strongly suppresses the immune system, thus protecting the tumor from immunological attack. The leading mechanisms of suppression involve the accumulation of specialized white blood cells called tumor-associated CD14+ macrophages and regulatory T cells (Treg) within the tumor. Macrophages likely contribute to accumulation of Treg, the presence of which is associated with increased morbidity and mortality in ovarian cancer. We have found that CD14+ macrophages are highly abundant in ovarian tumor ascites and profoundly suppress Th17-inducing DC-stimulated immune responses. Consequently, the ability of a DC vaccine to stimulate Th17 immunity against ovarian cancer may not be sufficient to provide clinical benefit for ovarian cancer patients. Identification of novel agents that alleviate immune suppression by ovarian tumor-associated CD14+ macrophages is of fundamental importance for the field and will advance development of adjuvant treatments that boost the clinical efficacy of Th17-inducing DC vaccination as we move forward to Phase II clinical trials. Research Plan: A novel peptide agent known as RP182 can selectively bind a receptor expressed by human ovarian tumor-associated macrophages. Preclinical testing has shown that RP182 can target macrophages and modify immune function and that RP182 has anti-tumor activity in several mouse models of cancer, including breast, prostate, and pancreatic cancer. This proposal will determine whether RP182 can block immune suppression by ascites CD14+ macrophages from ovarian cancer patients and will test whether RP182 adjuvant treatment can enhance anti-tumor immune responses and extend survival when combined with Th17-inducing DC vaccination in an innovative mouse model of ovarian cancer that is characteristic of high-grade serous ovarian carcinoma. Clinical Impact: In partnership with the Mayo Clinic (Rochester, MN), we are conducting a Phase I clinical trial for Th17-inducing DC vaccination of stage IIIC/IV ovarian cancer patients with no radiologic evidence of disease following primary surgery and chemotherapy. The primary end point of the Phase I trial will be safety, with secondary end points of time to disease recurrence and overall survival. Our goal is to develop an autologous Th17-inducing DC vaccine that prevents or delays recurrence of ovarian cancer for patients following initial treatment. Agents that block immune suppression and enhance DC-activated immune responses will be critically needed as adjuvants for DC vaccination in Phase II clinical trials, for which the primary end point will be clinical efficacy. The Phase I trial will run concurrently with this proposal, such that we will be positioned to advance to Phase II trials of DC vaccination combined with adjuvant blockade of immune suppression within 2-3 years. RP182 is a p
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710142
Entities
People
- Martin Cannon
Organizations
- United States Army
- University of Arkansas for Medical Sciences