The Therapeutic Effects of Ultrasound-Mediated Immune Responses in Melanoma
Abstract
Melanoma is a skin cancer originating in pigment-producing cells called melanocytes. The disease is particularly swift and deadly in cases where it metastasizes to other sites in the body. Current clinical evidence suggests that strategies aimed to elicit an anti-tumor immune response may be effective in advanced melanoma where tumor infiltration with T lymphocytes is associated with improved clinical outcome. However, until recently, such strategies have not demonstrated success despite tremendous efforts to harness the anti-tumor properties of the immune system. Patients treated with interleukin-2, ipilimumab, adoptive T cell therapy, vaccines, and PD-1 antibody have shown improved clinical response, and all of these act through anti-tumor activity of T cells. The redundancy within the multiple signaling pathways activated in melanoma, along with the likelihood of drug resistance and immune tolerance, suggests that combination therapy strategies will be required for effective disease management. However, not all patients treated with immunotherapies demonstrate durable responses. Focused Ultrasound (FUS) is an emerging non-invasive modality for localized treatment of cancers. One of the outcomes of FUS treatment is the induction of dying tumor cells tumor, resulting in the release of tumor antigens and danger signals. Such a microenvironment could attract dendritic cells to the treatment site, where they can capture the tumor antigens, mature, and migrate to adjacent draining lymph nodes to initiate an antitumor immune response. We hypothesize that FUS induces danger signals and this enhances the generation of an in situ vaccine. However, the response generated is not sufficient to be therapeutically significant, and additional immunotherapeutic interventions might enable it to result in meaningful anti-tumor immunity. To test this hypothesis, we need to understand the extent to which efficacy can be improved without the potential toxicities caused by immune check point inhibitors such as CTLA-4 inhibitors. The above hypotheses will be tested in two specific aims: (1) determine the capacity of FUS to stimulate systemic and tumor infiltrating T cell response and (2) investigate synergistic effects of FUS and CTLA-4 inhibition to improve the control of melanoma. In this study, we plan to test whether the combination of local FUS to the primary tumor with CTLA-4 blockade can induce therapeutically significant antitumor immunity to the poorly immunogenic B16-F10 metastatic melanoma mouse model. First FUS will be applied to a single tumor nodule to create stable and precisely controlled heating. The animals will be also given CTLA-4 inhibitors and activation of immune modulators, tumor growth and survival will be monitored. In some experiments, we will combine FUS with ionizing radiation to obtain a synergize the effect. We believe that this approach will increase the percentage of patients who will respond to immunotherapies by stimulating a melanoma-specific systemic immune response. We envision a treatment that can immunize melanoma patients against their own future metastases. The impact of the basic science advances of this project will be amplified through subsequent application in the development of clinically useful approaches for metastatic melanoma therapy for active duty Service members, their families, and other military beneficiaries.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510394
Entities
People
- Kumari Andarawewa
Organizations
- United States Army
- University of Virginia