Malignant brain tumors in adults account for more deaths than Hodgkin's disease, melanoma, and cancers of the bladder or kidney. Glioblastoma multiforme (GBM) is the most common malignant brain tumor with a median survival of 15 months. Despite aggressive surgery, high-dose radiation, and toxic chemotherapy, GBM is almost universally fatal. Moreover, current therapy is limited by collateral damage to surrounding healthy brain. Immunotherapy directed against tumor cells holds the potential to precisely target GBM while sparing healthy brain tissue. The use of dendritic cells (DCs) as cancer vaccine adjuvants is a promising strategy to induce anti- tumor immune responses, and we are currently evaluating the use of DCs to stimulate immunity and prolong survival in GBM patients. Clinical trials routinely focus on T cell function and persistence as predictive biomarkers of vaccine efficacy, but these measurements rarely correlate with clinical responses. In a recently completed randomized clinical trial, we found that migration of injected DCs to local lymph nodes strongly correlated with clinical outcomes in GBM patients and that DC migration to lymph nodes was significantly enhanced by conditioning the injection site with a recall antigen. Our preclinical data corroborate these effects of enhanced DC migration and additionally elucidate that conditioning with the recall antigen 1) provides a sustained elevation in tumor antigen-specific T cells over time and 2) significantly suppresses malignant tumor growth. Preliminary data reveals that the memory T cell compartment plays a critical role in mediating DC migration, which suggests a novel role for the recall response in governing DC homing to lymph nodes. In this proposal, we will identify the cellular subsets and cell-derived soluble mediators that drive DC migration. Furthermore, we intend to improve our DC vaccine therapies through identification of serologic biomarkers that can predict efficient DC migration and ultimately superior anti-tumor responses. Lastly, we will evaluate the quality of immune responses that follow enhanced DC migration and lead to increased survival in a preclinical GBM model. This proposal addresses several research aims presented in the 2012 NCI research action plan, specifically those related to developing more effective and efficient treatments for cancer while maintaining safety to the patient. Eliciting the mechanisms by which immunologic memory responses drive DC lymph node homing addresses a critical immunobiologic question and provides translatable modalities aimed at overcoming the inherent boundaries in peripherally administering DC vaccines. Methods derived from this research to enhance DC migration have a significant potential to enhance the efficacy of our ongoing efforts at Duke in treating patients with GBM and other aggressively fatal cancers.
Primary malignant brain tumors are most fatal, with patients typically living less than 15 months after initial diagnosis. Cellular immunotherapy to specificall target infiltrative tumor cells while sparing normal brain has been a proposed solution, but there remain constraints on immunologic responses in these patients that must be overcome in order to achieve long-lasting clinical responses. This proposal will greatly facilitate our efforts to improve the function of anti-tumor immune cells used in our cellular therapy protocols, and has significant potential to improve the clinical response to immunotherapy directed against malignant brain tumors.