BATF3+ Dendritic Cells for the Treatment of Malignant Gliomas
Abstract
Scientific Rationale and Objective: Malignant gliomas (MGs) are a class of highly aggressive and currently incurable forms of cancer that afflict individuals of all ages. The most common and aggressive MG is glioblastoma (GBM), making up ~60% of all primary malignant brain tumor cases, and patients with GBM survive only ~15 months after diagnosis. Conventional treatment options for GBM and other MGs fail largely because they are unable to selectively eradicate every malignant tumor cell that invades into healthy brain tissue, and, as a result, residual MG cells that remain following treatment can go on to repopulate a new tumor. Immunotherapy represents a promising treatment option for MGs due to the ability of tumor-specific immune cells (namely T lymphocytes) to migrate to and destroy invasive tumor cells. While there have been a few encouraging outcomes in clinical trials using immunotherapy for MGs, successes are not as widespread as they are for other types of cancer, such as blood-borne cancers and solid tumors not situated in the brain. One of the major impediments to immunotherapy for MGs is the recruitment of sufficient numbers of tumor-specific T lymphocytes from the blood into the brain due to a highly restrictive blood-brain barrier. Furthermore, the few tumor-specific T lymphocytes that do localize to MGs are rendered dysfunctional by the highly immunosuppressive glioma environment. Together, these two factors have represented the Achilles’ heel of brain tumor immunotherapy. Our lab has recently shown that some patients with recurrent GBM who received intratumorally injected poliovirus experienced prolonged survival, which is remarkably atypical for this highly aggressive form of cancer. Through mechanistic studies, we have found that poliovirus exerts its antitumor effects by activating host dendritic cells (DCs), which in turn prompts T lymphocyte activation and their recruitment into tumors. Taken together, these data suggest that enhancing the number of activated DCs within MGs may improve T lymphocyte-mediated antitumor responses. Therefore, in this study, we will determine whether the injection of activated DCs directly into MGs can enhance the therapeutic effects of glioma-specific T lymphocytes. This approach is supported by preliminary experiments, wherein we have found that the injection of activated DCs directly into mouse melanoma tumors increased the infiltration of T lymphocytes into tumors and dramatically delayed tumor growth. Principle Investigator Career Goals: My goal is to establish myself as a leading independent researcher in the field of immunotherapeutics development, with a concentration on immunotherapies for MGs. The Peer Reviewed Cancer Research Program Horizon Award will enable me to improve my skills in this area that I have been developing over the last 5 years throughout my doctoral research. This work will be mentored by Drs. Smita Nair and John Sampson, who are highly accomplished researchers in the field of brain tumor immunotherapy and have been involved in the development and clinical evaluation of numerous immunotherapies for the treatment of MGs. Additionally, the highly collaborative teams that make up the Brain Tumor Immunotherapy Program at Duke will continue to provide expert guidance throughout my studies, as they have graciously done in the past. Military relevance: Epidemiological studies suggest that military personnel have a higher risk of developing brain tumors, such as GBM and other MGs. These diseases can have a negative impact on mission readiness and quality of life of our Service members given their highly debilitating nature and lack of treatability. In this proposed study, we are investigating a novel immunotherapeutic approach that addresses known limitations of brain tumor immunotherapy. Consequently, this work may potentially lead to improved treatment options for patients with MGs and may benefit military personnel, Veterans, their fa
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010627
Entities
People
- Adam Swartz
Organizations
- Duke University
- United States Army