Abstract
INTRODUCTION
Dendritic cell (DC) vaccines have shown marginal success in treating glioblastoma (GBM), with inefficient vaccine migration a major limitation. Prior evidence from our clinical trials demonstrated that tetanus diphtheria (Td) preconditioning produced greater DC migration to vaccine draining lymph nodes (VDLNs) and long-term survival. Greater DC numbers reaching VDLNs was also associated with long-term survival. We found from preclinical studies and our patients that increased DC migration was dependent upon the chemokine (C-C motif) ligand 3 (CCL3).
METHODS
The effect of systemic CCL3 treatment on DC vaccine migration (n=5), antigen-specific T cell responses (n=5) and efficacy against orthotopic GL261-OVA and SMA560 tumors (n=10) was studied in C57Bl/6 and VMdK mice. DCs were electroporated with OVA-mRNA or pulsed with ODC1 neoantigen peptide. Median overall survival (mOS) was measure in days (d) post-intracranial implantation.
RESULTS
Intravenous CCL3 at the time of intradermal DC vaccination resulted in a dose-dependent increase in migration to VDLN (10ug p=0.036, 20ug p< 0.0001, 50ug p< 0.0001). Mean migration levels following CCL3 treatment were similar to Td-preconditioning (p=0.52) but showed significantly less variability between mice. Combined CCL3 and DC vaccination generated more tumor antigen-specific CD8+IFNγ+ T cells 7 days compared to DC vaccine alone (p=0.0045). CCL3+OVA-DC treatment resulted in significantly greater survival compared to OVA-DC alone (mOS 37 vs 19.5 d; p=0.0174) in established GL261-OVA. CCL3 treatment increased survival in mice with established SMA560 tumors treated with neoantigen ODC1 peptide-pulsed DCs (Tumor alone mOS: 21d, DCvac: 25d, CCL3+DCvac: 48d, p=0.002).
CONCLUSIONS
These data combined with previous success of our DC vaccine clinical trials reflect the potency of CCL3 to enhance DC vaccine-specific migration, immune responses and survival. CCL3 is a novel and safe adjuvant to overcome prior limitations in DC vaccine therapy and may be translatable to increase heterogeneous tumor antigen presentation following vaccine-targeted tumor killing.
CD40L coding oncolytic adenovirus allows long-term survival of humanized mice receiving dendritic cell therapy
