CCL3 as a Developmental Therapeutic to Enhance Brain Tumor Therapy

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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 <15 months. In contrast, immunotherapy promises an exquisitely precise approach, and substantial evidence suggests that T cells can eradicate large, well-established tumors in mice and humans even when tumors reside within the brain. 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%. The migration of vaccine-delivered DCs is low (~5%), and preclinical studies have demonstrated that preconditioning the vaccine site with the inflammatory cytokines can increase DC migration to the DLN and proportionately increase the magnitude of the antigen-specific T cell response. We hypothesized that preconditioning the vaccine site with the recall antigens in Tetanus/diphtheria toxoid (Td) would induce inflammation, increase DC migration, and elicit more consistently efficacious antitumor immunity. In a recent study in patients with newly diagnosed GBM published in Nature, we demonstrated that unilaterally preconditioning one vaccine site with Td resulted in increased bilateral DC migration to the DLNs and a significant increase in progression free survival and OS - with three of the six Td treated patients living past 4.5 years. A recapitulative murine model corroborated these findings, demonstrating that Td preconditioning both enhanced systemic DC migration to the DLNs and suppressed tumor growth in an antigen-dependent manner. Examination of both patient and murine sera revealed that the chemokine (C-C motif) ligand 3 (CCL3) was the only cytokine or chemokine significantly upregulated after Td preconditioning. Furthermore, in mice we demonstrated that the systemic increase in DC migration after Td preconditioning is dependent upon CD4+ memory effector T cells (CD4Td−mem) and CCL3. However, recent pilot data from our laboratory indicate that the CD4Td−mem are actually responsible for the production of CCL3, suggesting CCL3 serves as the primary driver of the improved antigen-dependent immunity from Td preconditioning. We hypothesize that in addition to enhancing the migration of DCs to the DLN, that CCL3 directly increases antigen-specific T cell magnitude and functionality as well as immune cell trafficking to tumor. This proposal will mechanistically determine the specific role of CCL3 in DC migration, antigen-specific T cell responses, as well as immune cell trafficking, and will further assess if the antitumor efficacy of DC vaccination can be further enhanced by the use of exogenous CCL3 as a vaccine-enhancing drug.