We have identified a combinational
immunotherapy termed TheraVac
vaccine (TheraVac) that can cure multiple large established mouse
tumors, but it failed to cure
melanoma in mice. TheraVac consists of an immunostimulating arm containing an agonist (
HMGN1 [N1]) for TLR4 and an agonist (R848) for TLR7/8 that synergize to activate
tumor-infiltrating dendritic cells (DCs) and promote Th1 immune responses. The second arm uses an
immune checkpoint blockade, anti-PDL-1, to diminish
tumor-associated immunosuppression. In this study, we investigated supplementation of TheraVac by a stimulator of IFN genes (
STING) agonist,
cyclic GMP-AMP (
cGAMP), because together they synergize in activating DCs and produced more immunostimulating IL-12p70 and TNF-α
cytokines. The synergistic activation and maturation of DCs is dependent on the activation of tank binding kinase-1 (TBK1). Treatment of three different
melanin-producing mouse
melanomas (B16F1, M3, and M4) with intratumoral delivery of
cGAMP and TheraVac eradicated 60-80% of these
melanomas. Immunoprofiling of M3
tumor treated with TheraVac plus
cGAMP showed an increase in CD8+ CTLs and macrophages in the
tumor. There was also a marked increase of CD4, CD8 effector and 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 these immunotherapeutics to cure
melanin-producing human
melanomas, without the need for exogenous
tumor Ags and no clear toxic effects in mice.