CXCR4 Antagonist as an Adjuvant in Immunotherapy of Epithelial Ovarian Cancer
Abstract
The rationale and objective of the proposed work: The chemokine receptor CXCR4 and its cognate ligand CXCL12 chemokine form a pivotal signaling pathway for enabling metastasis by epithelial ovarian carcinomas. We have developed a CXCR4 inhibitor that can be selectively delivered to a tumor site by an oncolytic vaccinia virus. This reagent inhibits cancer cell migration, angiogenesis, and immunosuppressive networks in the tumor microenvironment, indicating that inhibition of this pathway may result in control of tumor growth. Several soluble CXCR4 antagonists have demonstrated antitumor efficacy in preclinical models and have been evaluated in clinical trials. However, while the disruption of the CXCL12/CXCR4 pathway inhibits tumor growth and metastatic spread, it can also affect the development and efficacy of antitumor immune responses because of expression of CXCR4 on several subsets of immune cells. Therefore, the form of CXCR4 antagonist delivery (soluble or tumor-targeted through expression by an oncolytic virus) can be an important factor in modulating the induction, migration, and function of tumor-specific T cells due to differences in concentration of the CXCR4 antagonist in the tumor versus systemic tissues. In this application, we propose to compare the effects of soluble versus tumor-delivered CXCR4 antagonists on tumor development in the setting of therapeutic dendritic cell vaccines and adoptively transferred T cells in murine ovarian cancer models. The biology-driven rational design of novel immunotherapies will be critical for the development of a low side-effect cancer treatment that is based on the antitumor effect of CXCR4 inhibition on multiple aspects of ovarian tumor growth. The central problem in ovarian cancer addressed in the proposed research: The central problem addressed in the proposed studies is to examine whether soluble and tumor-targeted CXCR4 antagonists can be used as efficient adjuvants in boosting efficacies of anticancer vaccines and adoptively transferred T cells against ovarian tumors. The ability of CXCR4 antagonists to inhibit metastatic dissemination of the tumor and simultaneously augment antitumor immunity would create a unique approach to successfully eradicate highly aggressive ovarian carcinomas. How the proposed research is relevant to the vision and mission of the Ovarian Cancer Research Program (OCRP): Consistent with the mission of OCRP to support patient-centered research to treat and cure ovarian cancer, this project is focusing on promoting synergistic antitumor responses by acting directly on the tumor as well as inhibiting tumor-induced immune tolerance. The impact that the proposed study could, whether short-term or long-term, have on ovarian cancer: - Which individuals will it help, and how will it help them? - What are the potential clinical applications, benefits, and risks (potential long-term outcomes)? - What is the potential impact of the proposed research on the health and welfare of military Service members, their Families, and other military beneficiaries? CXCR4 expression has been found to be a prognostic marker in several cancers including epithelial ovarian carcinomas, indicating that the CXCR4 axis presents a therapeutic target in ovarian tumor-bearing patients. However, because the CXCR4 is expressed by several subsets of immune cells, prolonged systemic CXCR4 inhibition has numerous side effects including immunosuppression. We are unique in demonstrating that targeting CXCR4 signaling through an oncolytic vaccinia virus yields a significant therapeutic impact against metastatic ovarian cancer, efficacy of which can be enhanced by a combination with antitumor dendritic cell vaccines and adoptive T cell transfer. In those complex regimens, rational adjustment of single treatments and their scheduling provides a challenge to fully exploit the potential of cancer immunotherapy. Successful outcome of these studies will allow us
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610146
Entities
People
- Danuta Kozbor
Organizations
- United States Army