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

Nat Commun. 2021 Jan 21;12(1):511. doi: 10.1038/s41467-020-20785-x.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Survival / immunology
  • Cytotoxicity, Immunologic / immunology
  • Gangliosides / immunology*
  • Gangliosides / metabolism
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Neoplasm Metastasis
  • Neuroblastoma / immunology
  • Neuroblastoma / pathology
  • Neuroblastoma / therapy*
  • Receptors, Antigen, T-Cell / immunology*
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Chimeric Antigen / immunology*
  • Receptors, Chimeric Antigen / metabolism
  • Tumor Burden / immunology
  • Xenograft Model Antitumor Assays / methods*


  • Gangliosides
  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen
  • ganglioside, GD2