Development of Epitope-Focused Tumor Vaccine to Prevent Escape from Immune Surveillance by the NKG2D Pathway
Abstract
My long-term career goal is to develop novel therapies towards treating cancer and to make these therapies available and affordable to cancer patients worldwide. Acquiring funding through the Horizon Award will be a great support for me to successfully complete the proposed research project, which focuses on the development of a novel vaccine to treat melanoma, and further my intellectual development to become an independent investigator in the field of cancer research. The project will be of significant benefit to the public as we propose to develop a vaccine that could work both in the preventive (prevents the occurrence of melanoma) and therapeutic (effective treatment option to melanoma patients) setting. My proposed research goals will be achieved with the aid of a well-structured researcher development plan prepared with appropriate guidance from my mentor, Dr. Kai Wucherpfennig. My researcher development plan includes setting timelines towards achieving short-term project milestones, arranging weekly meetings with my mentor to discuss and track the progress of the project, attending immunology seminar series at Harvard Medical School to network with scientists who are experts in the field of cancer research, participating at journal clubs to discuss and critique about recent journal articles, and attending cancer immunotherapy conferences to acquire cutting-edge knowledge in the field. Melanoma accounts for majority of deaths (around 80 percent) due to skin cancer and is diagnosed in over 120,000 Americans each year. Our immune system usually destroys abnormal melanocytes before they become cancerous. Unfortunately, melanomas escape destruction by suppressing our immune system or by escaping the immune surveillance. Current advances in cancer therapies that harness the power of the immune system to fight tumor cells are providing new hopes for treating melanoma patients. For instance, monoclonal antibody therapy that targets the tumor antigens has demonstrated significant clinical benefits in melanoma patients. However, the downside of this therapy is that it requires repeated administration of lab-made antibodies to generate immune responses against tumor cells and is very expensive. We propose to develop a highly cost-effective melanoma vaccine that can help patients to make their own antibodies against tumor specific antigen, thus offering therapeutic benefit and long-term protection. The proposed project is based on the observation that a protein called MICA is expressed at high levels on the surface of melanoma cells and many other tumor cells but not expressed on healthy tissue. MICA expression flags the tumor cells for destruction by certain specialized cells of the immune system. However, tumor cells devise ways to shed MICA from their cell surface and the shed forms suppress the immune system. Melanoma patients responding to treatment with vaccines consisting of their own tumor cells and an antibody that improves immune function were found to develop antibodies specific towards MICA. The patient-derived antibodies bound to the alpha3 region of MICA that is involved in the shedding mechanism and exhibited strong therapeutic benefit. Based on this, we want to design a vaccine that induces the production of antibodies that bind to the alpha3 region of MICA and prevent its shedding. Retaining MICA expression on tumor cell surface will help in promoting immune responses towards melanoma and prevent its occurrence. One of the risk factors of this vaccine approach could be the effects of auto-antibodies developed against self-expressed MICA proteins. To account for this, we will carefully evaluate our vaccine in MICA sensitized melanoma mouse model system where the MICA expression levels are similar to what is observed in human patients. We estimate that it could take up to 2 years to achieve a clinically relevant outcome based on our outcomes. Active duty personnel are often exposed to s
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610257
Entities
People
- Soumya Badrinath
Organizations
- Dana–Farber Cancer Institute
- United States Army