{
  "abstract": "Background In situ vaccination (ISV) with Newcastle Disease Virus (NDV) can promote antitumor immunity, yielding remarkable albeit limited success in clinical studies. Seeking a more efficacious virotherapy, we previously conducted several in vivo screens of avian avulaviruses related to NDV. We identified APMV-4 as a superior candidate inducing a 100% complete remission rate in CT26 colorectal carcinoma (CRC).1 Methods In our current studies, we leveraged the CT26 murine model to evaluate the clinical applicability of APMV-4 in CRC. We utilized a systems immunology approach, utilizing both single and bilateral CT26 tumor models, and integrated bulk RNAseq of treated tumors, serum cytokine analysis and conventional and spectral flow cytometry of bilateral tumors and tumor draining lymph nodes to unveil the effects of APMV-4 ISV on host immune responses. Ex vivo splenocyte stimulation was utilized to confirm the specificity of the adaptive immune response triggered by the virotherapy.Results We determined that ISV with APMV-4 as a monotherapy induced abscopal effect in a bilateral tumor model. At the treated tumor site, APMV-4 elicited rapid yet transient interferon signatures, and cellular and transcriptomic T cell programs predictive of response to immunotherapy. Informed by these signatures as well as clinical precedent for use of Ipilimumab in CRC, we strategically developed a regimen supplementing APMV-4 ISV with a single, low-dose of aCTLA-4. While aCTLA-4 on its own had no effect, the combination induced complete remissions in both tumor sites and extension in survival. Spectral flow cytometry and correlation analysis of tumors and draining lymph nodes revealed that this response was mediated by T cell activation andTh1 polarization of the treated lesion and draining lymph node. Furthermore, responders induced expansion of circulating memory T cells upon rechallenge, and ex vivo splenocyte stimulation from these animals revealed the presence of tumor-specific T cells upon intracellular cytokine staining, consistent with a durable antitumor response.Conclusions These findings indicate a strong synergy between APMV-4 ISV and CTLA-4 blockade in activating antitumor immunity. Outcomes achieved using the CT26 model are of particular interest considering that it is mismatch repair proficient, a characteristic generally associated with resistance to immunotherapy in CRC. Our combinatorial regimen serves as a proof-of-principle for future clinical translation, limiting adverse effects commonly observed with aCTLA-4 in the clinic while maximizing likelihood of response to therapy.Reference Javaheri A, Bykov Y, Mena I, García-Sastre A, Cuadrado-Castano S. Avian paramyxovirus 4 antitumor activity leads to complete remissions and long-term protective memory in preclinical melanoma and colon carcinoma models. Cancer Res Commun. 2022;2(7):602-615.Ethics Approval Murine studies were performed in accordance with Institutional Animal Care and Use committee (IACUC) guidelines and have been approved by the IACUC of Icahn School of Medicine at Mount Sinai (IACUC-2014-0234).",
  "authors": [
    {
      "affiliations": [
        "Icahn School of Medicine at Mount Sinai, New York, NY, USA"
      ],
      "name": "Yonina Bykov"
    },
    {
      "affiliations": [
        "Emory School of Medicine, Atlanta, GA, USA"
      ],
      "name": "Naseem Sadek"
    },
    {
      "affiliations": [
        "Icahn School of Medicine at Mount Sinai, New York, NY, USA"
      ],
      "name": "Gloria O Dawodu"
    },
    {
      "affiliations": [
        "Emory School of Medicine, Atlanta, GA, USA"
      ],
      "name": "Jeffrey Tomalka"
    },
    {
      "affiliations": [
        "Icahn School of Medicine at Mount Sinai, New York, NY, USA"
      ],
      "name": "Daniel Lozano-ojalvo"
    },
    {
      "affiliations": [
        "Icahn School of Medicine at Mount Sinai, New York, NY, USA"
      ],
      "name": "Adolfo Garcia-Sastre"
    },
    {
      "affiliations": [
        "Icahn School of Medicine at Mount Sinai, New York, NY, USA"
      ],
      "name": "Sara Cuadrado-Castaño"
    }
  ],
  "title": "632 In situ APMV-4 vaccination achieves systemic tumor clearance and long-term antitumor immunity, priming response to sub-therapeutic dosing of aCTLA-4 in colorectal carcinoma",
  "uid": "f62a69d2-f025-5092-90b6-bc253be3330e"
}