{
  "abstract": "Background Bispecific T cell-engagers (BTEs) are engineered antibodies that redirect T cells to target antigen-expressing tumors. BTEs targeting tumor-specific antigens such as interleukin 13 receptor alpha 2 (IL13RA2) and epidermal growth factor receptor variant III (EGFRvIII) have been developed for glioblastoma (GBM). However, there is limited mechanistic understanding of the action of BTE since prior studies were mostly conducted in immunocompromised animal models. To close this gap, the function of BTEs was assessed in the immunosuppressive tumor microenvironment (TME) of orthotopic and genetically engineered mouse models (GEMM) with intact immune systems.Methods A BTE that bridges CD3 epsilon on murine T cells to IL13RA2-positive GBM cells was developed, and the therapeutic mechanism was investigated in immunocompetent mouse models of GBM. Multicolor flow cytometry, single-cell RNA sequencing (scRNA-seq), multiplex immunofluorescence, and multiparametric MRI across multiple preclinical models of GBM were used to evaluate the mechanism of action and response.Results BTE-mediated interactions between murine T cells and GBM cells triggered T cell activation and antigen-dependent killing of GBM cells. BTE treatment significantly extended the survival of mice bearing IL13RA2-expressing orthotopic glioma and de novo forming GBM in the GEMM. Quantified parametric MRI validated the survival data, showing a reduction in glioma volume and decreased glioma viability. Flow cytometric and scRNA-seq analyses of the TME revealed robust increases in activated and memory T cells and decreases in immunosuppressive myeloid cells within the brains of mice following BTE treatment.Conclusions Our data demonstrate that the survival benefits of BTEs in preclinical models of glioma are due to the ability to engage the host immune system in direct killing, induction of immunological memory, and modulation of the TME. These findings provide a deeper insight into the mechanism of BTE actions in GBM.",
  "authors": [
    {
      "affiliations": [
        "Department of Neurological Surgery, Northwestern University, Chicago, IL, USA",
        "Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA"
      ],
      "name": "Markella Zannikou"
    },
    {
      "affiliations": [
        "Department of Neurological Surgery, Northwestern University, Chicago, IL, USA",
        "Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA"
      ],
      "name": "Joseph T Duffy"
    },
    {
      "affiliations": [
        "Deparment of Radiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"
      ],
      "name": "Daniele Procissi"
    },
    {
      "affiliations": [
        "Department of Neurological Surgery, Northwestern University, Chicago, IL, USA",
        "Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA"
      ],
      "name": "Hinda Najem"
    },
    {
      "affiliations": [
        "Department of Neurological Surgery, Northwestern University, Chicago, IL, USA",
        "Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA"
      ],
      "name": "Rebecca N Levine"
    },
    {
      "affiliations": [
        "Department of Neurological Surgery, Northwestern University, Chicago, IL, USA",
        "Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA"
      ],
      "name": "Aditi Thakur"
    },
    {
      "affiliations": [
        "Department of Pediatrics, The Tisch Cancer Institute, Mount Sinai Icahn School of Medicine, New York, NY, USA"
      ],
      "name": "Dolores Hambardzumyan"
    },
    {
      "affiliations": [
        "Department of Neurological Surgery, Northwestern University, Chicago, IL, USA",
        "Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA"
      ],
      "name": "Catalina Lee-Chang"
    },
    {
      "affiliations": [
        "Deparment of Radiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"
      ],
      "name": "Lara Leoni"
    },
    {
      "affiliations": [
        "Department of Neurological Surgery, Northwestern University, Chicago, IL, USA",
        "Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA",
        "Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"
      ],
      "name": "Craig M Horbinski"
    },
    {
      "affiliations": [
        "Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA",
        "Colorado Center for Nanomedicine and Nanosafety, University of Colorado Anschutz Medical Campus, Aurora, CO, USA"
      ],
      "name": "Dmitri Simberg"
    },
    {
      "affiliations": [
        "Department of Medicine, Hematology/Oncology Division, Northwestern University Feinberg School of Medicine, Chicago, IL, USA"
      ],
      "name": "Bin Zhang"
    },
    {
      "affiliations": [
        "Department of Neurological Surgery, Northwestern University, Chicago, IL, USA",
        "Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA"
      ],
      "name": "Amy B Heimberger"
    },
    {
      "affiliations": [
        "Department of Neurological Surgery, Northwestern University, Chicago, IL, USA",
        "Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA"
      ],
      "name": "Jason Miska"
    },
    {
      "affiliations": [
        "Department of Neurological Surgery, Northwestern University, Chicago, IL, USA",
        "Northwestern Medicine Malnati Brain Tumor Institute of the Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA"
      ],
      "name": "Irina V Balyasnikova"
    }
  ],
  "title": "Bi-specific T cell-engaging antibody triggers protective immune memory and glioma microenvironment remodeling in immune-competent preclinical models",
  "uid": "bb9d09a0-60b2-53f7-9f8d-ba594df020c8"
}