Immune-Stimulating Combinatorial Therapy for Prostate Cancer
Abstract
Despite advances in treatment, prostate cancer continues to claim the lives of thousands of men around the world. Most deaths from prostate cancer occur from metastasis, when the cancer spreads to distant organs due to failure of treatments to arrest the disease. Aggressive treatment of high-grade disease with current therapies carries significant risks (toxicities) that limit treatment to sub-optimal doses, thus contributing to failure. The potential offered by the most powerful agent, a patient s own immune system, has recently raised considerable optimism among scientists, clinicians, and patients. Successfully stimulating the immune system to recognize cancer cells offers the potential to harness dynamic and adaptable disease defenses to recognize and destroy tumor cells. Prostate cancer cells, however, can manipulate the immune system to enhance their escape from detection and elimination. Indeed, prostate cancers are typically resistant to immunotherapy. It is now becoming clear that some therapies can re-engage immune surveillance (detection and elimination) by altering cancer cells and tumors. Ionizing radiation and heat are energies that, through different and complementary mechanisms, cause changes in cells leading to immune-modulating alterations of the tumor. When combined with heat therapy (HT), radiation therapy (RT) is more effective to reduce tumor volume without increasing toxicity. Immune-modulation with RT +/- immunotherapy (IT) is a focus of intensified preclinical and clinical investigation. Simultaneously, recently published results are reshaping concepts of HT, which has potential to affect both innate and adaptive immune systems. Combined RT+HT is already used clinically to manage some locally advanced and recurrent cancers, but none of the current clinical practices are optimized to trigger an immune response. Interestingly, the immunologic consequences of combining RT+HT have not been studied. Another exciting development is the recognition that engineered nanoparticles provide a potent platform as vaccines or vaccine adjuvants. Our long-term goal is to overcome treatment failure by developing strategies and technology that reduce tumor burden and re-engage the immune system to recognize cancer cells. We intend to enhance anticancer immune-recognition with combinatorial immune (vaccine or immune-checkpoint antibody), radiation, and magnetic iron oxide nanoparticle (MION) heat therapies. In this effort, we will provide proof of principle by using a mouse model of prostate cancer (transgenic adenocarcinoma of mouse prostate, or TRAMP) with MIONs to devise strategies that will elucidate the role of various tumor-infiltrating immune cells following treatments in which dose and timing (heat and radiation) are varied. This information will be used to develop specific "targeted" MIONs having an engineered molecular signature to enhance immune-system anti-tumor effect to eventually lead to effective long-term management of lethal prostate cancer. MIONs, heat, and radiation each damage cancer cells in different and complementary ways. We hypothesize that combining these (low dose, minimally toxic) with immune therapies will reduce tumors, including untreated distal tumors, by producing a complex interaction between tumors and the immune system arising from damaged cancer cells. The proposed effort addresses the Prostate Cancer Research Program (PCRP) Overarching Challenges to develop effective treatments and the PCRP focus areas of therapy and tumor microenvironment biology with particular emphasis on tumor immune modulation. If successful, the results will enable development of a nanoparticle-prostate cancer vaccine platform. We hypothesize that tumor cell death resulting from nanoparticle-mediated hyperthermia+RT leads to enhanced immune recognition relative to cell death from either agent alone. Our objectives are to (1) induce anti-tumor effects with focal tumor heating from
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510667
Entities
People
- Robert Ivkov
Organizations
- Johns Hopkins University
- United States Army