(SS#I) American Brain Tumor Association Young Investigator Award: Route of Administration and Antigen Specificity Drive Response to Toll-like Receptor-based Vaccination for Intracranial Melanoma Tumors

Introduction: Clinical trials investigating immunotherapies for brain tumors have largely failed to improve patient outcomes. Cancer vaccines are a novel avenue of enhancing immune responses against tumors. Prior studies in flank tumor models utilizing a vaccine consisting of a self-assembling micelle of TLR-7/8 agonists and tumor antigens demonstrated that route of administration impacts efficacy. Using this vaccine platform, we investigated 1) effects of vaccine route of administration on survival in a murine intracranial metastatic melanoma model and 2) immune response phenotypes based on route of administration and vaccine antigen specificity.

Methods: Mice orthotopically implanted with B16F10-OVA cells were given OVA-specific and non-specific TLR7/8 agonist vaccines through various routes of administration (intratumoral, intrathecal, intravenous, and intramuscular) to determine the effects of route of administration and antigen specificity on immune response, including overall survival. OVA expression was quantified by Western Blot analysis. Flow cytometry was used to immunophenotype the immune response.

Results: Intracranial administration of OVA-specific vaccine resulted in improved survival when compared to intrathecal, intravenous, and intramuscular routes, with a 40% long-term survivor rate (p < 0.001). On Western blot analysis, OVA expression was decreased in the brains of long-term survivors. When compared to mice treated with the OVA-specific TLR 7/8 agonist vaccine, mice treated with the non-specific TLR7/8 agonist vaccine had improved survival (p < 0.0001). Flow cytometry analysis of the lymphoid compartment demonstrated that groups that received the vaccine via the intracranial route of administration had increased T cells with a stem-like phenotype (Tcf1+PD-1+) (p < 0.01). Additionally, the composition of myeloid cell infiltrate varied among the groups, with increased activated dendritic cells in the intracranial groups and increased macrophages in the intracranial irrelevant antigen group (p < 0.001).

Conclusion : Intracranial administration of TLR7/8 agonist-based vaccines demonstrated promising initial survival and immunophenotyping results, and warrants further investigation as a potential strategy for the development of future therapies.