Even when treated with aggressive current therapies, most patients with primary malignant brain tumors survive less than two years. Our goal is to develop novel immunotherapies against malignant glioma that are based on activating and targeting tumor-associated macrophages (TAMs) to the glioma. Although immunotherapy is being studied as a potential treatment, the blood-brain barrier and local tumor immunosuppressive milieu often prevent penetration of cytotoxic antibodies or immune cells into the brain. The local delivery of immunostimulatory molecules such as CpG can overcome this suppressive environment, However, high CpG doses could cause toxic brain inflammation. Therefore, there is a pressing need for a safer, more effective, targeted strategy that will enhance the CNS immune response to malignant brain tumors. We recently took advantage of the inherent phagocytic properties of TAMs to enhance CpG uptake by the cells using carbon nanoparticles and demonstrated a 60% cure rate in treated mice bearing gliomas. In these experiments however, the activated TAMs cleared from the tumor environment within seven days of the first nanoparticle injection, which might have contributed to the treatment failure in some mice that were not cured of their tumors. We hypothesize that methods which prolong the presence of activated TAMs within brain tumors should enhance the anti-tumor efficacy of this nanoparticle-based therapy. The objective of this proposal is to test a dynamically programmable, low-intensity magnetic field (DPMF) for its ability to selectively route and traffic brain microglia and macrophages that have been treated with CpG conjugated to iron oxide nanoparticles (IONP-CpG). Unlike current methods of generating magnetic fields, our grid-generated DPMF allow us a broad range of control over the spatial and temporal profile of the magnetic field, which should potentially enhance TAM routing to gliomas. We will first define conditions for DPMF-mediated motility of IONP-treated microglia cells in vitro. After optimizing the DPMF programming and functionalization of IONP, we will then develop our technique to modulate the trafficking and retention of microglia and macrophage in normal mouse brains. Finally, we will determine the in vivo efficacy of DPMF-IONP therapy in mice with intracranial gliomas. We expect DPMF to retain and traffic the activated macrophage and microglia to the tumors, thereby enhancing the therapeutic efficacy of this novel therapy. The results from these studies will not only significantly impact the treatment of gliomas, but should also impact treatment of other CNS pathologies such as stroke or trauma, in which microglia and macrophages are known to participate in the disease process and/or CNS repair. Finally, combined use of IONP and DPMF has the potential to modulate and direct neural stem cell trafficking following CNS transplantation.
Our goal is to develop a novel, combined magnetic and nanoparticle-based method to enhance the response of immunotherapeutic agents to brain tumors. Our new approach is expected to significantly impact the treatment not only of malignant brain tumors, but also other brain pathologies such as stroke, trauma, and degenerative disease.
|Chen, Xuebo; Zhang, Leying; Zhang, Ian Y et al. (2014) RAGE expression in tumor-associated macrophages promotes angiogenesis in glioma. Cancer Res 74:7285-97|