Glioblastoma (GBM) remains uniformly lethal and current therapy is ineffective and incapacitating. Standard therapies are limited by nonspecific toxicity, and the median overall survival for patients with GBM remains <15 months. Immunotherapy for GBM holds significant promise, as substantial evidence suggests that T cells can eradicate large, well-established tumors in mice and humans. Dendritic cell (DC) vaccines can, in some cases, effectively stimulate such T-cell responses as shown by several remarkable cases of individual patient responders. However, overall objective responses in early-phase clinical trials with tumor-targeted DC vaccination have remained under 15%. In a recent study in patients with newly diagnosed GBM published in Nature, we demonstrated that unilaterally preconditioning one vaccine site with the inflammatory recall antigens Tetanus/diphtheria toxoid (Td) resulted in increased bilateral DC migration to the draining lymph nodes and a significant increase in progression-free survival and overall survival—with half of the Td-treated patients living past 4.5 years. The benefit of vaccine site preconditioning could be recapitulated in a mouse model, as we found that Td increased DC migration to the draining lymph nodes and suppressed tumor growth in an antigen-dependent manner. In a search for potential mediators of these effects, we found that the only cytokine or chemokine significantly upregulated after Td preconditioning in both patients and mice was the chemokine (C-C motif) ligand 3 (CCL3). Furthermore, our data show that a source for CCL3 appears to be Td-specific CD4+ memory effector T cells (CD4Td-mem). In experiments where wild-type mice received either CCL3(-/-) or wild-type CD4Td-mem, DC migration was increased only in the wild-type CD4Td-mem setting, signifying that CCL3 from these cells is necessary for DC migration. Finally, we have found that exogenous CCL3 alone can enhance bilateral DC migration to the draining lymph nodes and reduce tumor growth similar to Td preconditioning, suggesting that exogenous CCL3 may be used to treat patients and increase objective responses associated with DC vaccines.
Citation Format: Teilo H. Schaller, Kristen A. Batich, Kelly Hotchkiss, Xiuyu Cui, Luis Sanchez-Perez, John H. Sampson. The effects of CCL3 on dendritic cell migration and immune cell activation [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A80.