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Preclinical assessment of the efficacy and specificity of GD2-B7H3 SynNotch CAR-T in metastatic neuroblastoma

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  • Babak Moghimi

    (Division of Hematology, Oncology and Blood & Marrow Transplantation, and The Saban Research Institute
    Keck School of Medicine, University of Southern California)

  • Sakunthala Muthugounder

    (Division of Hematology, Oncology and Blood & Marrow Transplantation, and The Saban Research Institute)

  • Samy Jambon

    (Division of Hematology, Oncology and Blood & Marrow Transplantation, and The Saban Research Institute)

  • Rachelle Tibbetts

    (Division of Hematology, Oncology and Blood & Marrow Transplantation, and The Saban Research Institute)

  • Long Hung

    (Division of Hematology, Oncology and Blood & Marrow Transplantation, and The Saban Research Institute)

  • Hamid Bassiri

    (Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine)

  • Michael D. Hogarty

    (Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine)

  • David M. Barrett

    (Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine)

  • Hiroyuki Shimada

    (Division of Hematology, Oncology and Blood & Marrow Transplantation, and The Saban Research Institute
    Keck School of Medicine, University of Southern California)

  • Shahab Asgharzadeh

    (Division of Hematology, Oncology and Blood & Marrow Transplantation, and The Saban Research Institute
    Keck School of Medicine, University of Southern California)

Abstract

The ability to utilize preclinical models to predict the clinical toxicity of chimeric antigen receptor (CAR) T cells in solid tumors is tenuous, thereby necessitating the development and evaluation of gated systems. Here we found that murine GD2 CAR-T cells, specific for the tumor-associated antigen GD2, induce fatal neurotoxicity in a costimulatory domain-dependent manner. Meanwhile, human B7H3 CAR-T cells exhibit efficacy in preclinical models of neuroblastoma. Seeking a better CAR, we generated a SynNotch gated CAR-T, GD2-B7H3, recognizing GD2 as the gate and B7H3 as the target. GD2-B7H3 CAR-T cells control the growth of neuroblastoma in vitro and in metastatic xenograft mouse models, with high specificity and efficacy. These improvements come partly from the better metabolic fitness of GD2-B7H3 CAR-T cells, as evidenced by their naïve T-like post-cytotoxicity oxidative metabolism and lower exhaustion profile.

Suggested Citation

  • Babak Moghimi & Sakunthala Muthugounder & Samy Jambon & Rachelle Tibbetts & Long Hung & Hamid Bassiri & Michael D. Hogarty & David M. Barrett & Hiroyuki Shimada & Shahab Asgharzadeh, 2021. "Preclinical assessment of the efficacy and specificity of GD2-B7H3 SynNotch CAR-T in metastatic neuroblastoma," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20785-x
    DOI: 10.1038/s41467-020-20785-x
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