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

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 naive T-like post-cytotoxicity oxidative metabolism and lower exhaustion profile. Antibodies targeting a tumor antigen, GD2, show some efficacy for neuroblastoma but induce severe neuropathic pain and peripheral neuropathy. Here the authors design a gated chimeric antigen receptor (CAR), using GD2 as the gate and another tumor antigen, B7H3, as the target, to find this GD2-B7H3 CAR capable of suppressing neuroblastoma in mouse models with little adverse effects.

Automated summary

The study highlights the importance of developing gated systems for predicting clinical toxicity of CAR T cells in solid tumors. By utilizing murine and human CAR-T cells specific for tumor antigens, the researchers were able to generate a GD2-B7H3 CAR-T with improved metabolic fitness and efficacy in controlling neuroblastoma growth in preclinical models. This innovative approach shows promising results in suppressing neuroblastoma with minimal adverse effects.