Therapeutic Vaccine (TheraVac) in combination with cGAMP cures more differentiated melanomas in mice

Abstract We have identified a combination of immunotherapeutics, termed TheraVac, capable of curing multiple large established mouse tumors, but it failed to cure melanoma in mice. TheraVac consists of an immunostimulating arm containing an agonist (HMGN1) for TLR4 and an agonist (R848) for TLR7/8 that synergize to activate tumor-infiltrating dendritic cells (DCs) and upregulate the polarization of Th1 immune responses. The second arm uses an immune checkpoint blockade inhibitor, αPDL-1, to diminish tumor associated immunosuppression. Here, we investigated supplementation of TheraVac by a STING agonist, cGAMP, because they synergize in activating DC’s and produced more immunostimulating IL-12p70 and TNFα cytokines. We therefore treated five different tumor types including melanin producing B16F1, M3, and M4 mouse melanomas that are homologous to human melanomas with intratumoral delivery of cGAMP and TheraVac. This eradicated 80% of the B16F1, 80% of the M3 and 60% of the M4 tumors, but still failed to cure the non-melanin producing undifferentiated M1 and M2 tumors. Biopsies of M3 tumor treated with TheraVac plus cGAMP showed a significant increase of CD8+ CTL’s infiltrating into the tumor. Importantly, there was a marked increase of both CD4 and CD8 memory T cells and generation of functional tumor specific CTLs in tumor-draining lymph nodes. The resultant tumor-free mice were selectively resistant to subsequent challenge with the same tumors, indicating long-term tumor specific protective immunity. Overall, our findings have important implications for clinical trials with a combination of immunotherapeutics to cure melanin producing human melanomas, without the need for exogenous tumor antigens and no obvious toxic effects in mice.