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

Autor:	Moghimi B; Children's Hospital Los Angeles, Children's Center for Cancer and Blood Diseases, Division of Hematology, Oncology and Blood & Marrow Transplantation, and The Saban Research Institute, Los Angeles, CA, USA.; Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Muthugounder S; Children's Hospital Los Angeles, Children's Center for Cancer and Blood Diseases, Division of Hematology, Oncology and Blood & Marrow Transplantation, and The Saban Research Institute, Los Angeles, CA, USA., Jambon S; Children's Hospital Los Angeles, Children's Center for Cancer and Blood Diseases, Division of Hematology, Oncology and Blood & Marrow Transplantation, and The Saban Research Institute, Los Angeles, CA, USA., Tibbetts R; Children's Hospital Los Angeles, Children's Center for Cancer and Blood Diseases, Division of Hematology, Oncology and Blood & Marrow Transplantation, and The Saban Research Institute, Los Angeles, CA, USA., Hung L; Children's Hospital Los Angeles, Children's Center for Cancer and Blood Diseases, Division of Hematology, Oncology and Blood & Marrow Transplantation, and The Saban Research Institute, Los Angeles, CA, USA., Bassiri H; Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA, USA., Hogarty MD; Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA, USA., Barrett DM; Children's Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, PA, USA., Shimada H; Children's Hospital Los Angeles, Children's Center for Cancer and Blood Diseases, Division of Hematology, Oncology and Blood & Marrow Transplantation, and The Saban Research Institute, Los Angeles, CA, USA.; Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Asgharzadeh S; Children's Hospital Los Angeles, Children's Center for Cancer and Blood Diseases, Division of Hematology, Oncology and Blood & Marrow Transplantation, and The Saban Research Institute, Los Angeles, CA, USA. sasgharzadeh@chla.usc.edu.; Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. sasgharzadeh@chla.usc.edu.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2021 Jan 21; Vol. 12 (1), pp. 511. Date of Electronic Publication: 2021 Jan 21.
DOI:	10.1038/s41467-020-20785-x
Abstrakt:	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.
Databáze:	MEDLINE
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