Nature communications, 2021-01, Vol.12 (1), p.511-15, Article 511
2021
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- Autor(en) / Beteiligte
- Titel
- Preclinical assessment of the efficacy and specificity of GD2-B7H3 SynNotch CAR-T in metastatic neuroblastoma
- Ist Teil von
- Nature communications, 2021-01, Vol.12 (1), p.511-15, Article 511
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2021
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-020-20785-xTitel-ID: cdi_doaj_primary_oai_doaj_org_article_92c07d10ceed4a499ccaa1bcf1c46793
- Format
- –
- Schlagworte
- 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, Humans, Immunotherapy, Adoptive - methods, Lymphocytes, Lymphocytes T, Metastases, Metastasis, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Neoplasm Metastasis, Neuroblastoma, Neuroblastoma - immunology, Neuroblastoma - pathology, Neuroblastoma - therapy, Neurotoxicity, Oxidative metabolism, Pain, Peripheral neuropathy, Receptors, Receptors, Antigen, T-Cell - immunology, Receptors, Antigen, T-Cell - metabolism, Receptors, Chimeric Antigen - immunology, Receptors, Chimeric Antigen - metabolism, Solid tumors, Systems analysis, Toxicity, Tumor Burden - immunology, Tumors, Xenograft Model Antitumor Assays - methods, Xenografts, Xenotransplantation