Clinical trials testing vaccine-mediated therapy against malignant melanoma have generated disappointing responses. The laboratory of Esteban Celis, MD, PhD, at the GRU Cancer Center proposes that this is due to an insufficient number of antigen-specific CD8 T cells generated by the vaccines. They hypothesize that increasing type-I interferon (IFN-I), which is known to stimulate CD8 T cell responses, would improve therapeutic anti-tumor results. The strategy reported recently by Dr. Celis and Zili Wang, PhD, in Cancer Immunology, Immunotherapy, takes advantage of the TriVax formulation that the laboratory has developed following more than a decade of optimizing peptide vaccines for maximized CD8 T cell responses. The approach combines TriVax (consisting of synthetic peptides targeting CD8 T cell epitopes, poly-IC, and costimulatory anti-CD40 antibodies) with cyclic diguanylate monophosphate (c-di-GMP), a factor that stimulates the production of IFN-I by activating stimulator of interferon genes (STING).
Results confirmed that the addition of c-di-GMP to TriVax significantly increased the number of antigen-specific CD8 T cells and that these cells recognized B16 melanoma cells with increased efficiency compared to when c-di-GMP was not used. B16 tumor growth in mice was likewise significantly lower with TriVax treatment, and even lower yet when c-di-GMP was combined with TriVax. Experiments using interferon receptor-deficient mice indicated that the effect was IFN-I-dependent, while experiments testing individual components of the TriVax/c-di-GMP strategy demonstrated the synergistic nature of the combination. The authors contend that significant production of antigen-specific T cells, as seen here with the TriVax plus c-di-GMP approach, is critical for impactful clinical responses.[Wang Z, Celis E. STING activator c-di-GMP enhances the anti-tumor effects of peptide vaccines in melanoma-bearing mice. Cancer Immunol Immunother. 2015 Aug;64(8):1057-66.]