Personnel: My qualifications for leading the proposed project to a successful end include my academic training in both clinical medicine and laboratory medical research, especially in immunotherapy for blood cancers. One of my significant contributions to the field of blood cancer treatment is my development of a second-generation lymphoma idiotype gene vaccine, which is now being moved to a Phase I clinical trial. I established my own research directions by developing novel technology to discover cell type-specific therapeutic targets for antibody and T cell therapies. Using this technology, I successfully developed two unique peptibodies that specifically depleted myeloid derived suppressor cells (MDSCs) in lymphoma-bearing mice. These discoveries set the foundation for our proposed research project, which aims to discover human MDSC-specific targets for antibody therapy. My mentor, Dr. Larry Kwak, is an internationally recognized physician scientist who is well known for pioneering bench-to-bedside translational development of cancer vaccine strategies. In 2010, Dr. Kwak was named a member of Time Magazine's 100 most influential people in the world in recognition of his contributions towards the lymphoma idiotype vaccine. A series of scientific reports of Dr. Kwak's research has been published in top peer-reviewed journals including Science and Nature Medicine. Dr. Kwak has secured multiple research grants including National Cancer Institute Lymphoma Specialized Programs of Research Excellence (SPOREs), to support his research in blood cancer immunotherapy.Career Development: My career goal is to lead my research group to develop novel immunotherapeutic reagents that could be translated from the bench to the bedside. My career development plan is thus designed to achieve this goal by improving my professional knowledge and faculty skills in advanced training in cancer immunology and immunotherapy, translational research, mentorship, grant application, manuscript preparation, and biomedical statistics.Research: Tumor-induced immune suppression is a major mechanism for tumor cells to escape immune attack. Recent studies showed that MDSCs are a major component of tumor-induced immune suppression. Variation between patients in the density of MDSC in their tumors is usually negatively correlated with survival. Current development of MDSC depletion therapy is hampered by the lack of a human MDSC-specific marker. The objective of this proposal is to identify novel human MDSC-specific markers and to develop novel strategies to inhibit MDSCs for therapeutic benefit in blood cancers. This objective will be achieved by three specific aims.Specific Aim 1: Fully characterize the target of murine MDSC-specific peptibodies. (1a: Identify the binding partner for the S100A9/A8 complex on the surface of mouse MDSC. 1b: In vitro validation of the findings from the quantitative structural proteomic analysis. 1c: In vivo confirmation of the identified molecular target of the MDSC-specific peptibodies.) Specific Aim 2: Determine the effect of murine MDSC-depleting peptibodies combined with immunotherapy in vivo. (2a: Determine whether combined peptibody treatment + specific immunotherapy is superior to either alone. 2b: Effects of MDSC depletion on systemic and intratumoral T-cell immunity.) Specific Aim 3: Identify human MDSC-specific markers that can be targeted. (3a: Confirm cell surface-bound S100 family proteins on human MDSC. 3b: Development and characterization of a human S100A9/A8-specific mAb. 3c: Identify additional, unknown human MDSC-specific markers for targeting.) Impact: We will overcome current limitations in the field by identifying novel human MDSC-specific markers, which will allow us to develop diagnostic and depleting therapeutic agents specific for MDSC that are positioned to enter first-in-human clinical trials in patients.Military Relevance: Recent studies show that during the Vietnam War, for military purposes, the U.S. Army used millions of gallons of herbicides that have been associated with blood cancers. The therapeutic benefits of immunotherapy in blood cancers are undermined by tumor-induced immune suppression. We will develop a novel therapeutic agent aiming to reverse the immune suppressive microenvironment in cancer patients. It can be combined with immunotherapies, improving their efficacy to treat blood cancer patients without increasing toxicity. Another model fit for cancer immunotherapy is melanoma due to well-identified melanoma-specific targets. A current epidemic study showed an increased risk of having melanoma in active duty military members who serve in sun-intense locales like Iraq and Afghanistan. This proposal will end up with a potential therapeutic agent to deplete MDSC in cancer patients, which will benefit both Veterans and active duty military members who face the potential for a risk of blood cancers and melanoma.
|Effective start/end date||9/1/15 → 8/31/18|
- Congressionally Directed Medical Research Programs: $576,001.00