Clinical Neuroimmunology of CCL3 in Brain Tumors

ABSTRACT: Malignant primary brain tumors represent the most frequent cause of cancer death in children and young adults and account for more deaths than cancer of the kidney or melanoma. Glioblastoma (GBM) is uniformly lethal, and current therapy is non-specific and produces a median overall survival of <21 months. Moreover, patients with GBM are plagued by reduced systemic T cell counts, reduction in secondary lymph organ cellularity, increased mature T cells sequestered in the bone marrow (BM), and dysfunctional antigen presentation in tumor draining lymph nodes. This combination of BM sequestration of T cells and heterogeneous antigen expression leads to tumor escape and progression. Dendritic cells (DCs) bearing tumor antigen can be delivered as a vaccine and migrate to the draining lymph nodes (DLN) to trigger the formation of potent tumor- specific cytotoxic T lymphocytes (CTLs) capable of eradicating tumor while leaving normal tissue unharmed. However, despite individual cases of remarkable patient responses to antitumor DC vaccination, overall objective responses in early phase clinical trials have remained under 15%. We have found that post dendritic cell (DC) vaccination, both long-term survival and migration of DCs is dependent on the chemokine CCL3. Interestingly, CCL3 can enhance migration of both exogeneous DC vaccine to lymph nodes and endogenous DCs at the tumor site. Separately, but concurrently, T cell sequestration to the BM is also reversed with CCL3 administration. Here, we aim to build on this data preclinically and determine the optimal CCL3 dose for DC migration, determine the mechanism of CCL3 on T cell sequestration, and determine the efficacy of CCL3 in combination with DC vaccines on anti-heterogeneous glioma responses. We hypothesize that systemic administration of CCL3 will increase migration of both exogenous and endogenous DCs and maintain increased levels of activated T cells systemically and within the TME by eliminating sequestration. This proposal will promote the development of CCL3 as a novel anti-cancer drug that enhances the potency and diversity of immune responses generated by DCs will reduce antigen escape and improve the control of diffusely heterogeneous tumors