{
  "abstract": "Background The development of vaccines to elicit a robust immune response against cancer holds great promise for improving patient survival. Significant efforts are already underway to determine the efficacy of cancer vaccines in combination with immune modulators for various cancers. In the tumor microenvironment, adenosine is known to act as a strong immune modulator that promotes cancer progression by inhibiting anti-tumor immunity. Elevated extracellular adenosine levels prevent T cell activation, hinder NK cell maturation, trigger recruitment of MDSCs to the tumor microenvironment, and drive a Treg phenotype through the expression of FoxP3. Adenosine inhibitors have been of interest in cancer, but here we newly address their synergy with cancer vaccines.Methods Two small molecule inhibitors, TT-10 and TT-4 (Portage Biotech) targeting type A2A and A2B receptors, respectively, expressed in both immune and tumor cells, were tested in combination with tumor-specific vaccines across three murine models: TC1, B16F10, and CT26. Peptide-based vaccines using E7 (TC1) and gp100 (B16F10) as antigens were employed in syngeneic C57BL/6 mice, while irradiated CT26 cells served as a whole-cell vaccine in BALB/c mice to assess efficacy in the CT26 colon cancer in this genetically distinct immune background.Results The synergy seen in this triple combination, A2A and A2B receptor inhibitors plus tumor-specific therapeutic vaccine, significantly suppressed tumor growth, improved survival, and elicited specific intratumoral CD8 + T cell responses supported by flow cytometry data (figure 1). Notably, several mice receiving this combination displayed complete tumor regression and resisted tumor rechallenge in the TC1 model, without a need for addition of checkpoint inhibitors.Conclusions The complementary nature of this triple combination is due to an elevated immune response from the activation and infiltration of cytotoxic CD8 + T cells in the tumor microenvironment driven by the therapeutic cancer vaccine and the adenosine inhibitors that block the inhibitory signals from extracellular adenosine to immune cells. These results support the conclusion that immune modulators and therapeutic tumor-specific vaccines can synergize to provide a robust resistance to tumors that should be translatable to humans.Abstract 662 Figure 1Treating TC1 tumors with adenosine inhibitor",
  "authors": [
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Paloma A Moreno"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Shweta Tiwary"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Noriko Seishima"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "William Becker"
    },
    {
      "affiliations": [
        "Portage Bio, Westport, CT, USA"
      ],
      "name": "Ian B Walters"
    },
    {
      "affiliations": [
        "RAKramer Consulting, Newtown, PA"
      ],
      "name": "Robert Kramer"
    },
    {
      "affiliations": [
        "National Cancer Institute, National Institutes of Health, Bethesda, MD, USA"
      ],
      "name": "Jay A Berzofsky"
    }
  ],
  "title": "662 Cancer vaccines synergize with adenosine inhibitors to improve survival and delay tumor progression in lung, colon, and melanoma cancer models in vivo",
  "uid": "75c3fcdf-d8a6-5a6f-b23f-42698a508560"
}