{
  "abstract": "Background Intratumoral immunotherapy ITIT can reverse local tumor-mediated immune suppression, enable effective antitumor immune responses against treated tumors, and generate immune pressure against untreated tumors (abscopal effects). However, the best reagent combinations for ITIT are not yet clear. We and others have shown that IL-12 by itself can mediate effective ITIT that includes abscopal effects. Our focus is identifying combinations of IL-12 with other ITIT reagents, including immune stimulating proteins, to generate superior local and systemic cancer treatment using ITITMethods IL-12 is expressed in mouse B16F10 tumors by in vivo electroporation (IVEP) of the tumor following injection of plasmids that express IL-12. The treatments are done twice a week apart in mice that have a tumor on each side with one tumor treated and the other untreated, to document both local and systemic immune impact. This was combined with other expression plasmids to identify proteins that synergize with IL-12 locally and systemically. IL-12 IVEP was also combined with intratumoral delivery of cowpea mosaic virus (CPMV), a reagent previously identified by us as a robust ITIT agent.Results IL-12 IVEP combined with CD154 (CD40 ligand) greatly improved local control but did not improve systemic/abscopal control of untreated tumors. Combining IL-12 with IVEP of CCL3 or with intratumoral CPMV injection improves both local and abscopal tumor responses, with elimination of all (CPMV) or almost all (CCL3) treated tumors and reduction in growth rate of untreated tumors. Expressed GMCSF and FLT3 ligand had minimal impact locally or abscopally by themselves or combined with IL-12 were. None of the treatments caused observable adverse events in mice.Conclusions There is great potential for ITIT to improve responses to immunotherapy by itself or in combination with other immunotherapies, however the optimal approaches and reagents are not clear. IL-12 is a central cytokine for antitumor responses with value for ITIT that can be improved by addition of other expressed proteins or immune stimulating reagents. We show that CCL3 and CD154 improve IL-12 intratumoral immunotherapy and combining IL-12 expression with intratumoral CPMV for ITIT generates stronger local and systemic antitumor immune responses than either agent alone.Acknowledgements We acknowledge support from NCI funding R01 CA224605, R01CA253615 and R01CA274640.",
  "authors": [
    {
      "affiliations": [
        "Dartmouth Geisel School of Medicine, Lebanon, NH, USA"
      ],
      "name": "Kevine Silihe Kamga"
    },
    {
      "affiliations": [
        "Dartmouth Geisel School of Medicine, Lebanon, NH, USA"
      ],
      "name": "Alicia Santos"
    },
    {
      "affiliations": [
        "Dartmouth, Hanover, NH, USA"
      ],
      "name": "Alex Misiaszek"
    },
    {
      "affiliations": [
        "Dartmouth College, Lebanon, NH, USA"
      ],
      "name": "Gregory W Ho"
    },
    {
      "affiliations": [
        "University of California San Diego, San Diego, CA, USA"
      ],
      "name": "Jessica F Affonso de Oliveira"
    },
    {
      "affiliations": [
        "Dartmouth Geisel School of Medicine, Lebanon, NH, USA"
      ],
      "name": "Pamela Rosato"
    },
    {
      "affiliations": [
        "Dartmouth Cancer Center, Lebanon, NH, USA"
      ],
      "name": "Mary Jo Turk"
    },
    {
      "affiliations": [
        "Case Western Reserve University, Cleveland, NH, USA"
      ],
      "name": "Nicole F Steinmetz"
    },
    {
      "affiliations": [
        "Dartmouth Geisel School of Medicine, Lebanon, NH, USA"
      ],
      "name": "Steven Fiering"
    }
  ],
  "title": "886 Intratumoral immunotherapy agents combined with IL-12 generate superior local and abscopal effects",
  "uid": "6f480e84-9308-596d-9aef-cd5c194562ad"
}