Enhancing Prostate Cancer Immune Responses by Pharmacological Reprogramming of Intratumoral Myeloid Cells
Abstract
In the past 10 years, immunotherapy has revolutionized the treatment of advanced malignancies. Immunotherapy has enabled long-term survival and even cures of metastatic cancer in patients who otherwise have few options left to treat their disease or prolong survival. Unfortunately, the promise of immunotherapy has yet to be fulfilled for the large majority of men suffering from advanced prostate cancer. That immunotherapy can work in prostate cancer is underscored by the Food and Drug Administration approval of SipuleucelT for the treatment of advanced forms of the disease. However, much progress has yet to be made to have large numbers of men benefit from immunotherapy. Most immunotherapeutic approaches target and activate immune cells (T lymphocytes), which can directly kill tumor cells. Here, we will test the idea that certain drugs (cysteine modifying compounds (CMAs)) with validated anti-tumor effects in mice act on a separate but complementary arm of the immune system. Specifically, preliminary work by us and others suggests that CMAs can inhibit and reduce the activity of myeloid-derived suppressor cells (MDSCs) in tumors. As suggested by their name, MDSCs themselves hinder immune responses in tumor tissues and blunt the efficacy of T lymphocyte-directed immunotherapeutic approaches. It follows that neutralizing MDSCs is expected to increase efficacy of T lymphocyte-directed therapeutic agents which, on their own, are poorly efficient in combating prostate cancer. This synergistic combination approach to immunotherapy of prostate cancer may help to break through the limitations of single therapies. The experimental design of this application focuses on two agents, which both have proven activity against prostate cancer. We will monitor the effects of these two agents on MDSCs in mice bearing human and mouse prostate cancer cells and assess whether effects on MDSCs are required for anti-tumor effects by these agents. Perhaps most importantly, we will combine these agents with T cell stimulators similar to those currently in use in human patients to see whether we can boost the efficacy of these agents. If successful, this work may be directly translated into clinical trials. Specifically, one of the two agents under investigation (RTA 408) is in clinical development for the treatment of the skin tumor malignant melanoma. Thus, encouraging results from the work proposed here will open the door to expedited clinical testing in locally advanced and metastatic prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610679
Entities
People
- Ulrich Rodeck
Organizations
- Thomas Jefferson University
- United States Army