Transcriptional Modulation of Tumor-Associated Macrophages to Facilitate Prostate Cancer Immunotherapy
Abstract
Prostate cancers include normal white blood cells called macrophages that contribute to tumor growth. These tumor-associated macrophages (TAMs) suppress the immune system s ability to fight prostate cancer, and they are present in greater numbers in more aggressive prostate cancers, including those that have become resistant to initial therapies that block the androgen male hormone. This proposal seeks to alter prostate cancer TAMs so that instead of helping the cancer grow, they now help the immune system fight the cancer. TAMs come in two varieties, M1 and M2. M2 TAMs aid whereas M1 TAMs fight the cancer. Like all cells, TAMs contain genes within their DNA that govern their function. Mutation of several different genes, termed p50, KLF4, and PU.1, changes M2 into M1 TAMs. We first propose to determine whether prostate cancer grows more slowly in mice with defective p50, KLF4, or PU.1 genes. We then propose to determine whether infusion of genetically altered white blood cells from these mice prevents prostate cancer growth and resistance to anti-androgen therapy. These infused cells need to land in the prostate cancer tumor, which already contains M2 TAMs. We will therefore also test whether infusing a small molecule or an antibody that kills these already present M2 TAMs cooperates with subsequent infusion of genetically altered M1 TAMs to slow tumor growth. Finally, we will determine whether our cell therapy cooperates with existing antibodies that help activate the immune system to even further slow prostate cancer growth in mouse models. At the same time, we will monitor recipient mice for side effects, including signs of inflammation. Overall, the aim of this proposal is to use mouse prostate cancer models to optimize a novel cell therapy for prostate cancer using genetically modified white blood cells. By increasing the ability of the immune system to attack and cure the cancer, this new therapy will help patients with initially aggressive cancer limited to the prostate and those with metastatic disease that has developed after initial antiandrogen therapy. To transfer this new therapy to the clinic, we plan to develop means to genetically modify white blood cells from patients, targeting the p50, KLF4, or PU.1 genes, and then to re-infuse these, alone or with cooperating agents, as optimized by proposed studies. We anticipate initiating relevant clinical trials within 1-2 years after completion of the experiments outlined in this proposal.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610334
Entities
People
- Alan Friedman
Organizations
- Johns Hopkins University
- United States Army