{
  "abstract": "Background Mesothelin (MSLN)-targeted chimeric antigen receptor (CAR)-T cell therapy shows an effective and long-lasting response in high MSLN-expressing tumors, but fails to treat tumors with heterogeneous levels of antigen expression. Here we describe an innovative approach where a stable tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) chimera, referred to as membrane-bound (MB)-TRAIL, is expressed on the cell surface of MSLN-specific (M28z) CAR-T cells. This potentiates their overall anticancer activity by overcoming heterogeneous antigen expression in tumor lesions.Methods We engineered MB-TRAIL-armored MSLN-directed M28z CAR-T cells and assessed their in vitro toxicity using flow cytometry against tumor target cells with heterogeneous MSLN expression. Triple-multiplex bioluminescence imaging using three different reporter genes enabled simultaneous in vivo non-invasive and longitudinal assessment of CAR-T cell dynamics, as well as MSLN+ and MSLN− tumor responses in xenograft models of MSTO-211H pleural mesothelioma (PM) and A549 non-small cell-lung cancer (NSCLC) with heterogeneous antigen expression. We further tested the therapeutic benefit of combining MB-TRAIL-armored CAR-T cells with the clinically used TRAIL sensitizer, doxorubicin, in an A549 xenograft model.Results MB-TRAIL M28z CAR-T cell therapy provides pro-apoptotic stimuli to both MSLN+ and MSLN− tumors, significantly improving survival in models of MSTO-211H PM and A549 NSCLC with heterogeneous antigen expression. We also demonstrated that our treatment confers sustained protection against metastatic spread in the MSTO-211H model, whereas doxorubicin overcomes TRAIL resistance rendering the A549 model more susceptible to MB-TRAIL M28z CAR-T cell therapy and reducing metastatic growth.Conclusions Our strategy confers superior antitumor efficacy relative to clinically trialed M28z CAR-T cells by directly targeting heterogeneous tumor antigen expression. These results constitute the foundation for developing a new class of clinically translatable TRAIL-armored CAR-T cell immunotherapies for the treatment of a wider range of malignancies.",
  "authors": [
    {
      "affiliations": [
        "Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA"
      ],
      "name": "Alessia Volpe"
    },
    {
      "affiliations": [
        "Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA"
      ],
      "name": "Juan Zurita"
    },
    {
      "affiliations": [
        "Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA"
      ],
      "name": "Larissa Shenker"
    },
    {
      "affiliations": [
        "Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA",
        "Hunter College, Department of Chemistry, The City University of New York, New York, New York, USA"
      ],
      "name": "Mayuresh M Mane"
    },
    {
      "affiliations": [
        "Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA",
        "Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, New York, USA"
      ],
      "name": "Prasad S Adusumilli"
    },
    {
      "affiliations": [
        "Cancer Molecular Therapeutics Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA"
      ],
      "name": "Alexander Aleshin"
    },
    {
      "affiliations": [
        "Zafrens Inc, San Diego, California, USA",
        "PrecisionAxis Bio LLC, Portland, Oregon, USA"
      ],
      "name": "Dmitri Rozanov"
    },
    {
      "affiliations": [
        "Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York, USA",
        "Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, New York, USA"
      ],
      "name": "Vladimir Ponomarev"
    }
  ],
  "title": "Membrane-bound TRAIL-armoring augments CAR-T cells in mesothelin-positive solid malignancies",
  "uid": "6baea926-f0e5-5b48-8e85-7af63c62fccc"
}