A combination of TLR9 and STING agonists induces potent neopeptide-specific T cell immunity and improves ICB efficacy in tumor models

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Abstract Immunotherapies such as immune checkpoint blockade (ICB) therapies have been developed in the last years as a promising strategy for the treatment of cancer, however there remains a need to improve their efficacy. The most critical factor that affects the efficacy of ICB therapies, is the frequency of tumor mutations, the associated neoantigens generated and the T-cell response against them. Therefore, it is expected that neoantigen vaccinations would improve ICB therapy efficacy by boosting the neoantigen-specific T cell response. The aim of this study is to develop an effective vaccine using a combination of TLR9 and STING agonists together with synthetic long peptides to induce a potent neoantigen-specific cytotoxic CD8+ T cell response. We first analyzed the efficacy of the vaccine formulation containing 20-mer OVA peptide and found that mice immunized with OVA peptide together with the adjuvant combination induced potent antigen-specific T cell responses and are capable of controlling tumor growth and improving survival in B16-F10-OVA tumor bearing mice. Moreover, we found that the vaccine together with OVA peptide is able to synergize with anti-PD-1 treatment in controlling tumor growth. Finally, we examined the immunogenicity of the vaccine formulation with neopeptides identified from two different tumor models. The vaccine formulation induced potent neoantigen-specific T cell responses in vivo. Our findings demonstrate that the vaccine formulation using the combination of TLR9 and STING agonists induces potent T cell immunity against synthetic long peptides and can serve as a promising immunogenic neoantigen vaccine platform. Supported by the Department of Immunology of the Erasmus MC the Dutch Cancer Society (KWF grant 12837) and in part by a grant from International Joint Usage/Research Center, the Institute of Medical Science, the University of Tokyo, and Japan Agency for Medical Research and Development (AMED).

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