{
  "abstract": "Background Treatments that yield deep and durable responses against many solid tumors remain lacking. CAR T cell therapy is promising but is hindered by a lack of tumor-specific targets, leading to a narrow therapeutic window and negative effects on healthy cells. In addition, the solid tumor microenvironment is hostile for the immune system, leading to dysfunction of engineered and endogenous cells. To overcome these limitations, we use a tumor-specific virus to deliver a specific CAR T antigen, termed a Flare, to universally target epithelial tumor types, while also creating an inflammatory microenvironment that amplifies CAR T killing. This virus is a replicating, tumor-selective adenovirus, clinically validated for systemic administration. When CAR T cells, engineered to target Flare, lyse virally infected cells they release mature viral particles. These viral particles reinfect the surrounding tumor cells, targeting them for clearance and creating a positive feedback loop of cell killing.Methods We explored Flare molecules derived from both natural and synthetic origins. We designed two Flare forms for expression: a membrane-bound version for direct labeling of infected tumor cells, and a secreted form for local targeting of neighboring uninfected tumor cells. Multiple cancer cell lines were tested for viral infection, followed by addition of CAR T cells. Viral replication, payload expression, and tumor viability were assessed by flow cytometry, ELISA, RNAseq, and live microscopy in multiple models.Results Infection with engineered viruses led to expression of Flare in cancer cells but not primary normal cells. Viral infection alone resulted in limited tumor killing, but strong payload expression and an associated inflammatory gene signature. Co-culture of virus-infected tumor cells with CAR T resulted in specific CAR T activation and tumor cell killing. We observed an increase in overall Flare production following CAR T cell addition, demonstrating a positive feedback loop of viral release, tumor re-infection and further killing of tumor cells.Conclusions We demonstrate that tumor cells were effectively and specifically infected by our engineered viruses and induced to express a Flare molecule for CAR T mediated killing. In addition to target delivery, viral infection produces an inflammatory signature supportive of CAR T cell activity. Infected cells are recognized and cleared by Flare-specific CAR T cells, followed by ongoing cycles of viral replication and T cell killing. Together the data establishes our Flare platform as an effective means to specifically label cancer cells of epithelial origin for CAR T killing, while creating a supportive microenvironment for immune function.",
  "authors": [
    {
      "affiliations": [
        "Dispatch Biotherapeutics, San Francisco, CA, USA"
      ],
      "name": "Raymond Liu"
    },
    {
      "affiliations": [
        "Dispatch Biotherapeutics, Philadelphia, PA, USA"
      ],
      "name": "Tatiana M Garcia-Bates"
    },
    {
      "affiliations": [
        "Dispatch Biotherapeutics, Philadelphia, PA, USA"
      ],
      "name": "Jonathan F Hale"
    },
    {
      "affiliations": [
        "Dispatch Biotherapeutics, Philadelphia, PA, USA"
      ],
      "name": "David Heo"
    },
    {
      "affiliations": [
        "Dispatch Biotherapeutics, Philadelphia, PA, USA"
      ],
      "name": "Chun-Wei Lee"
    },
    {
      "affiliations": [
        "Dispatch Biotherapeutics, Philadelphia, PA, USA"
      ],
      "name": "Lisa Cucolo"
    },
    {
      "affiliations": [
        "Dispatch Biotherapeutics, Philadelphia, PA, USA"
      ],
      "name": "Christina Del Casale"
    },
    {
      "affiliations": [
        "Dispatch Biotherapeutics, Philadelphia, PA, USA"
      ],
      "name": "Justin Taft"
    },
    {
      "affiliations": [
        "Dispatch Biotherapeutics, Philadelphia, PA, USA"
      ],
      "name": "Korneel Grauwet"
    },
    {
      "affiliations": [
        "Dispatch Biotherapeutics, San Francisco, CA, USA"
      ],
      "name": "Cathy Sierra"
    },
    {
      "affiliations": [
        "Dispatch Biotherapeutics, Philadelphia, PA, USA"
      ],
      "name": "Benjamin H Schott"
    },
    {
      "affiliations": [
        "Dispatch Biotherapeutics, Philadelphia, PA, USA"
      ],
      "name": "John Lee Johnson"
    },
    {
      "affiliations": [
        "Dispatch Biotherapeutics, San Francisco, CA, USA"
      ],
      "name": "Barbra J Sasu"
    },
    {
      "affiliations": [
        "Dispatch Biotherapeutics, Philadelphia, PA, USA"
      ],
      "name": "Lexus R Johnson"
    }
  ],
  "title": "394 Combination of a tumor-specific virus and CAR T to specifically and universally target tumors of epithelial origin and overcome challenges of the tumor microenvironment",
  "uid": "31a55c7a-1b3c-556e-87ad-bade55a49676"
}