{
  "abstract": "Background RedTail (RT) is a next-generation gene therapy platform designed for systemic delivery with enhanced tumor-selective targeting. RT utilizes an extracellular enveloped form of vaccinia virus which exhibits significantly greater resistance to immune clearance compared to non-enveloped variants. The virus is modified to express CD55 receptor in its envelope to further enhance immune evasion and allow for efficient systemic administration. In syngeneic preclinical models, robust targeting and elimination of metastatic lesions is observed after systemic administration.The RT platform enables direct delivery of therapeutic genetic payloads into metastatic sites. CLD-401 transforms tumors into producers of an IL-15 superagonist (IL-15(N72D)-IL-15Rα), a next-generation cytokine known to activate and expand natural killer (NK) cells and CD8+ T cells—both critical for antitumor immunity and with demonstrated clinical efficacy.Methods The resistance of RT to humoral immunity was assessed using modified plaque assays. RT was systemically administered in various tumor-bearing models to evaluate its tumor selectivity and its ability to induce in situ production of the IL-15 superagonist. Flow cytometry was used to analyze changes in the tumor immune microenvironment.Results CLD-401 exhibited strong resistance to both human complement-mediated lysis and neutralizing antibodies, thereby supporting the robust application of this platform for the systemic delivery of genetic medicines.Following systemic administration, CLD-401 specifically homed to tumors and primed the tumor microenvironment (TME), inducing substantial immune cell infiltration. Importantly, CLD-401 amplified within tumors, delivering the IL-15 superagonist transgene, which led to high levels of local therapeutic gene expression.This localized cytokine expression led to profound remodeling of the TME and ultimately, complete tumor regression in murine breast and lung cancer models. Treated mice developed immunological memory and were resistant to tumor rechallenge.Conclusions Our findings demonstrate that RedTail gene therapy, via CLD-401, effectively targets tumors, primes the immune microenvironment, and reprograms tumors to produce IL-15 superagonist in situ. This strategy achieved complete responses in metastatic models and induced durable immunological memory. The RedTail platform offers a promising approach for localized delivery of diverse therapeutic payloads while minimizing systemic toxicity, addressing a critical challenge in the treatment of metastatic disease.",
  "authors": [
    {
      "affiliations": [
        "Calidi Biotherapeutics, San Diego, CA, USA"
      ],
      "name": "Yunyi Kang"
    },
    {
      "affiliations": [
        "Calidi Biotherapeutics, San Diego, CA, USA"
      ],
      "name": "Duong Nguyen"
    },
    {
      "affiliations": [
        "Calidi Biotherapeutics, San Diego, CA, USA"
      ],
      "name": "Stephanie Songco"
    },
    {
      "affiliations": [
        "Calidi Biotherapeutics, San Diego, CA, USA"
      ],
      "name": "Mary Casis"
    },
    {
      "affiliations": [
        "Calidi Biotherapeutics, San Diego, CA, USA"
      ],
      "name": "Trevor Smith"
    },
    {
      "affiliations": [
        "Calidi Biotherapeutics, San Diego, CA, USA"
      ],
      "name": "David Nguyen"
    },
    {
      "affiliations": [
        "StemVAC GmbH, Bernried, Bavaria, Germany"
      ],
      "name": "Lina Schulte"
    },
    {
      "affiliations": [
        "StemVAC GmbH, Bernried, Bavaria, Germany"
      ],
      "name": "Hongli Zhang"
    },
    {
      "affiliations": [
        "StemVAC GmbH, Bernried, Bavaria, Germany"
      ],
      "name": "Sinje Tigges"
    },
    {
      "affiliations": [
        "StemVAC GmbH, Bernried, Bavaria, Germany"
      ],
      "name": "Fabian Kortum"
    },
    {
      "affiliations": [
        "StemVAC GmbH, Bernried, Bavaria, Germany"
      ],
      "name": "Daniela Kleinholz"
    },
    {
      "affiliations": [
        "Calidi Biotherapeutics, San Diego, CA, USA"
      ],
      "name": "Susan Tamraz"
    },
    {
      "affiliations": [
        "Calidi Biotherapeutics, San Diego, CA, USA"
      ],
      "name": "Ivelina Minev"
    },
    {
      "affiliations": [
        "Calidi Biotherapeutics, San Diego, CA, USA"
      ],
      "name": "Evan Cassavaugh"
    },
    {
      "affiliations": [
        "Calidi Biotherapeutics, San Diego, CA, USA"
      ],
      "name": "Travis Clifton"
    },
    {
      "affiliations": [
        "StemVAC GmbH, Bernried, Bavaria, Germany"
      ],
      "name": "Barbara Hartl"
    },
    {
      "affiliations": [
        "StemVAC GmbH, Bernried, Bavaria, Germany"
      ],
      "name": "Thomas Herrmann"
    },
    {
      "affiliations": [
        "Calidi Biotherapeutics, San Diego, CA, USA"
      ],
      "name": "Antonio F Santidrian"
    }
  ],
  "title": "1175 In situ tumor delivery of IL-15 superagonist via RedTail gene therapy achieves durable tumor clearance",
  "uid": "47009d73-2dd3-53a6-b54d-dbcc11ff893d"
}