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

Babak Moghimi, Sakunthala Muthugounder, Samy Jambon, Rachelle Tibbetts, Long Hung, Hamid Bassiri, Michael D. Hogarty, David M. Barrett, Hiroyuki Shimada and Shahab Asgharzadeh ()
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Babak Moghimi: Division of Hematology, Oncology and Blood & Marrow Transplantation, and The Saban Research Institute
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
Shahab Asgharzadeh: Division of Hematology, Oncology and Blood & Marrow Transplantation, and The Saban Research Institute

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-020-20785-x

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