Benign tumors in TSC are amenable to treatment by GD3 CAR T cells in mice.

Autor: Thomas A; Department of Dermatology, Feinberg School of Medicine.; Robert H. Lurie Comprehensive Cancer Center., Sumughan S; Robert H. Lurie Comprehensive Cancer Center., Dellacecca ER; Robert H. Lurie Comprehensive Cancer Center., Shivde RS; Robert H. Lurie Comprehensive Cancer Center., Lancki N; Quantitative Data Sciences Core, Robert H. Lurie Comprehensive Cancer Center; and., Mukhatayev Z; Robert H. Lurie Comprehensive Cancer Center., Vaca CC; Robert H. Lurie Comprehensive Cancer Center., Han F; Department of Dermatology, Feinberg School of Medicine.; Robert H. Lurie Comprehensive Cancer Center., Barse L; Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA., Henning SW; Robert H. Lurie Comprehensive Cancer Center., Zamora-Pineda J; Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University, Maywood, Illinois, USA., Akhtar S; Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University, Maywood, Illinois, USA., Gupta N; Robert H. Lurie Comprehensive Cancer Center.; Illinois Mathematics and Science Academy, Aurora, Illinois, USA., Zahid JO; Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University, Maywood, Illinois, USA., Zack SR; Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University, Maywood, Illinois, USA., Ramesh P; Robert H. Lurie Comprehensive Cancer Center., Jaishankar D; Robert H. Lurie Comprehensive Cancer Center., Lo AS; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA., Moss J; Pulmonary Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland, USA., Picken MM; Department of Pathology, Loyola University, Maywood, Illinois, USA., Darling TN; Department of Dermatology, School of Medicine, Uniformed Services University, Bethesda, Maryland, USA., Scholtens DM; Quantitative Data Sciences Core, Robert H. Lurie Comprehensive Cancer Center; and.; Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA., Dilling DF; Department of Medicine, Stritch School of Medicine, Loyola University, Maywood, Illinois, USA., Junghans RP; Department of Hematology/Oncology, School of Medicine, Boston University, Boston, Massachusetts, USA., Le Poole IC; Department of Dermatology, Feinberg School of Medicine.; Robert H. Lurie Comprehensive Cancer Center.; Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2021 Nov 22; Vol. 6 (22). Date of Electronic Publication: 2021 Nov 22.
DOI: 10.1172/jci.insight.152014
Abstrakt: Mutations underlying disease in tuberous sclerosis complex (TSC) give rise to tumors with biallelic mutations in TSC1 or TSC2 and hyperactive mammalian target of rapamycin complex 1 (mTORC1). Benign tumors might exhibit de novo expression of immunogens, targetable by immunotherapy. As tumors may rely on ganglioside D3 (GD3) expression for mTORC1 activation and growth, we compared GD3 expression in tissues from patients with TSC and controls. GD3 was overexpressed in affected tissues from patients with TSC and also in aging Tsc2+/- mice. As GD3 overexpression was not accompanied by marked natural immune responses to the target molecule, we performed preclinical studies with GD3 chimeric antigen receptor (CAR) T cells. Polyfunctional CAR T cells were cytotoxic toward GD3-overexpressing targets. In mice challenged with Tsc2-/- tumor cells, CAR T cells substantially and durably reduced the tumor burden, correlating with increased T cell infiltration. We also treated aged Tsc2+/- heterozygous (>60 weeks) mice that carry spontaneous Tsc2-/- tumors with GD3 CAR or untransduced T cells and evaluated them at endpoint. Following CAR T cell treatment, the majority of mice were tumor free while all control animals carried tumors. The outcomes demonstrate a strong treatment effect and suggest that targeting GD3 can be successful in TSC.
Databáze: MEDLINE
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