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

• Published in: Nature communications 2021-01, Vol.12 (1), p.511-15, Article 511
• Main Authors: Moghimi, Babak, Muthugounder, Sakunthala, Jambon, Samy, Tibbetts, Rachelle, Hung, Long, Bassiri, Hamid, Hogarty, Michael D., Barrett, David M., Shimada, Hiroyuki, Asgharzadeh, Shahab
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/21; 13/31; 13/44; 13/51; 14; 14/5; 38; 38/39; 631/250/1619/554/1834/1269; 631/250/580; 631/67/1059/2325; 692/308/2778; Animal models; Animals; Antibodies; Antigen (tumor-associated); Antigens; Cell Line, Tumor; Cell Survival - immunology; Chimeric antigen receptors; Cytotoxicity; Cytotoxicity, Immunologic - immunology; Gangliosides - immunology; Gangliosides - metabolism; Humanities and Social Sciences; Humans; Immunotherapy, Adoptive - methods; Lymphocytes; Lymphocytes T; Metastases; Metastasis; Mice; Mice, 129 Strain; Mice, Inbred C57BL; multidisciplinary; Neoplasm Metastasis; Neuroblastoma; Neuroblastoma - immunology; Neuroblastoma - pathology; Neuroblastoma - therapy; Neurotoxicity; Oxidative metabolism; Peripheral neuropathy; Receptors; Receptors, Antigen, T-Cell - immunology; Receptors, Antigen, T-Cell - metabolism; Receptors, Chimeric Antigen - immunology; Receptors, Chimeric Antigen - metabolism; Science; Science (multidisciplinary); Solid tumors; Systems analysis; Toxicity; Tumor Burden - immunology; Tumors; Xenograft Model Antitumor Assays - methods; Xenografts; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• 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. 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.