{
  "abstract": "Background Adoptive cell therapies, including T and natural killer T (NKT) cells expressing GD2-specific chimeric antigen receptors (CAR), have shown promise in treating relapsed/refractory neuroblastoma (NB) but remain non-curative. A significant barrier to improving these therapies is the reliance on xenogeneic models, which fail to capture the full spectrum of innate and adaptive immune responses. We recently reported that CAR-NKTs have superior in vivo antitumor activity in melanoma, colorectal, and bladder solid tumor models.1 In this study, we aim to develop syngeneic NB models for evaluating CAR-T and CAR-NKT cell therapies.Methods Murine NB cell lines expressing GD2 and B7H3 were created via lentiviral transduction and optimized through orthotopic implantation into C57BL/6 mice. These cell lines were engineered for cyclophosphamide (Cy) resistance to model relapsed/refractory NB and support lymphodepleting preconditioning. The tumor microenvironment (TME) was characterized using high-parameter flow cytometry. Murine T and NKT cells were transduced with GD2- or B7H3-specific CARs encoding CD28 or 4-1BB costimulatory domains. Cytotoxicity, cytokine production, and in vivo efficacy were evaluated.Results GD2 and B7H3 NB models exhibited high tumor inoculation rates and stable antigen expression. The TME featured diverse immune populations, predominantly myeloid cells. In vitro, CAR-Ts and CAR-NKTs eliminated antigen-specific NB cells. In vivo, both therapies reduced tumor burden post-Cy preconditioning, mirroring clinical trial outcomes but without achieving complete tumor control.Conclusions We developed Cy-resistant syngeneic orthotopic NB models with stable GD2 and B7H3 expression. These models enable detailed study of cell therapies in the context of an intact immune system and TME, advancing the development of effective immunotherapeutic strategies.Reference Zhou X, Wang Y, Dou Z, Delfanti G, Tsahouridis R, Zingarelli CP, Atassi G, Woodcock M, Casorati G, Dellabona P, Kim W, Savoldo B, Guo L, Tsagaratou A, Milner J, Metelitsa L, Dotti G. CAR-redirected natural killer T cells demonstrate superior antitumor activity to CAR-T cells through multimodal CD1d-dependent mechanisms. Nature Cancer. 2024;5:1607–1621.",
  "authors": [
    {
      "affiliations": [
        "Baylor College of Medicine, Houston, TX, USA"
      ],
      "name": "Ying Wang"
    },
    {
      "affiliations": [
        "Baylor College of Medicine, Houston, TX, USA"
      ],
      "name": "Linjie Guo"
    },
    {
      "affiliations": [
        "Baylor College of Medicine, Houston, TX, USA"
      ],
      "name": "Akshaya Adaikkalavan"
    },
    {
      "affiliations": [
        "Baylor College of Medicine, Houston, TX, USA"
      ],
      "name": "Amy N Courtney"
    },
    {
      "affiliations": [
        "Baylor College of Medicine, Houston, TX, USA"
      ],
      "name": "Xavier Rios"
    },
    {
      "affiliations": [
        "Center for Advanced Innate Cell Therapy, Texas Children’s Cancer and Hematology Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA"
      ],
      "name": "Xin Xu"
    },
    {
      "affiliations": [
        "Baylor College of Medicine, Houston, TX, USA"
      ],
      "name": "Erica Pierro"
    },
    {
      "affiliations": [
        "University of North Carolina, Chapel Hill, NC, USA"
      ],
      "name": "Xin Zhou"
    },
    {
      "affiliations": [
        "University of North Carolina, Chapel Hill, NC, USA"
      ],
      "name": "Gianpietro Dotti"
    },
    {
      "affiliations": [
        "Baylor College of Medicine, Houston, TX, USA"
      ],
      "name": "Leonid S Metelitsa"
    }
  ],
  "title": "1221 Optimized syngeneic neuroblastoma models to advance cell therapies",
  "uid": "7c9810c8-4b4f-54d5-906e-905bc66cfa28"
}