Project Objective: Melanoma is the main cause of death in patients with skin cancer. The incidence of melanoma has been increasing annually by 3.1% since 1992, and in 2012 nearly 76,000 were diagnosed with melanoma in the United States. Despite recent advances in cancer therapeutics, including surgery, chemotherapy, and radiation, approximately 9,000 melanoma patients died in 2012. In particular, metastatic Stage IV melanoma remains incurable. Notably, older U.S. military personnel aged 55 to 59 have been recently found to have a significantly increased chance of developing melanoma, compared with the counterparts in the U.S. general population. Therefore, finding a cure for melanoma is of high importance for both the U.S. general population and military personnel. To address this urgent, unmet medical challenge, we propose to develop a new nanotechnology-based strategy that can educate the immune system to recognize and kill melanomas. The proposed studies may lead to a new immunotherapy that can reduce and/or prevent metastasis and recurrence, thus significantly improving patient survival.

Rationale: Recent studies have shown the promise of immunotherapy based on immune checkpoint inhibitors that can sustain the cytotoxic functions of tumor-reactive T-cells. However, the full therapeutic potential of immunotherapy against melanomas has not been realized to date due to the lack of a proper vaccination strategy that can initiate strong anti-tumor immune responses. To that end, the Principal Investigator (PI) has previously developed a new nanoparticle system that can elicit unprecedented levels of T and B cell immune responses. Based on the compelling preliminary data presented in this application, the PI proposes to develop this novel nanotechnology to educate the immune system to recognize and eliminate melanoma cells.

The PI's Career Goals: The PI's career goal is to develop new drug delivery systems that can amplify immune functions as a new therapeutic strategy against melanoma. His interdisciplinary training in materials engineering and immunology has uniquely prepared him to tackle major challenges in the field of cancer immunotherapy. This Career Development Award will allow him to work in the laboratory of his mentor, Dr. Alfred Chang, MD (Professor of Surgery, Chief of Surgical Oncology in the University of Michigan Cancer Center) so that the PI can expand his knowledge in cancer immunology and learn state-of-the-art research techniques in cancer vaccination. This award will also allow the PI to complete core curriculum studies in clinical trial design and analyses, and pharmaceutical product development, which will help translate the findings from these studies to the bedside.

Benefits to Cancer Patients and Time Line for Clinical Outcome: Here, we will first optimize our nanotechnology and evaluate its therapeutic efficacy in murine models of melanoma using tumor lysate and tumor-specific mutated neo-antigens (Aims 1 and 2). We will then combine our vaccination approach with immune checkpoint blockade (Aim 3). Upon successful completion of our studies, we will be positioned to evaluate our strategy using human melanoma patients' samples, potentially leading to initiation of a Phase 1 clinical trial targeted for melanoma patients with resected Stage III and/or IV disease. Importantly, the core nanoparticle vaccine technology has been patented by the PI and is currently under product development for scale-up synthesis and Investigational New Drug application by a new start-up company. Thus, ongoing research activities in our commercial partner will synergize with our proposed studies and expedite clinical translation.

Contributions to Cancer Research and Patient Care: Development of a successful immunotherapy against melanoma will be a major breakthrough in cancer immunotherapy and will present a new paradigm for treatment and management of melanoma patients. More broadly, our innovative vaccination approach utilizing tumor lysate and neo-antigens may lead to a new platform nanotechnology that can be widely applied to other types of cancer, including leukemia, colorectal, brain, and pancreatic tumors. In addition, our studies will shed new light on the interaction between the adaptive immune system and tumor cells and provide a tremendous amount of new information on metastasis and recurrence.

Benefits to Military Beneficiaries: The U.S. military personnel are at high risk for melanoma and other skin cancers due to extended exposure to ultraviolet (UV) radiation and hazardous chemical and physical factors during military deployment. Thus, this research will have direct impact on military beneficiaries and the military health system.