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Benign tumors in TSC are amenable to treatment by GD3 CAR T cells in mice
Ancy Thomas, … , Richard P. Junghans, I. Caroline Le Poole
Ancy Thomas, … , Richard P. Junghans, I. Caroline Le Poole
Published November 22, 2021
Citation Information: JCI Insight. 2021;6(22):e152014. https://doi.org/10.1172/jci.insight.152014.
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Research Article Immunology Therapeutics

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

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Abstract

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.

Authors

Ancy Thomas, Saurav Sumughan, Emilia R. Dellacecca, Rohan S. Shivde, Nicola Lancki, Zhussipbek Mukhatayev, Cristina C. Vaca, Fei Han, Levi Barse, Steven W. Henning, Jesus Zamora-Pineda, Suhail Akhtar, Nikhilesh Gupta, Jasmine O. Zahid, Stephanie R. Zack, Prathyaya Ramesh, Dinesh Jaishankar, Agnes S.Y. Lo, Joel Moss, Maria M. Picken, Thomas N. Darling, Denise M. Scholtens, Daniel F. Dilling, Richard P. Junghans, I. Caroline Le Poole

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Figure 1

GD3 is overexpressed in human TSC lesions, and GD3 overexpression fails to raise cellular immune responses to the antigen in human TSC tissues.

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GD3 is overexpressed in human TSC lesions, and GD3 overexpression fails ...
(A) Percentage of GD3-expressing cells quantified (%). (B) GD3 expression quantified as GD3 synthase–positive cells per area. (C) Quantification of TSC lesional cells as phospho-S6+ cells per area. (D) Quantification of T cells and NK cells shown as CD3+ and CD56+; NKT cells are evaluated as CD3/CD56 double-positive cells in kidney tissue (enlarged representation) with iNKT cells quantified as CD3+ and CD56+, TCR Vα24-Jα18+ cells. (E) Quantification of CD1d- and CD1d-CD11c–expressing cells per area. Statistical analysis was performed using 2-tailed Student’s t tests assuming equal variance among groups. Where 3 tissue sources were displayed, we performed a 1-way ANOVA (***P < 0.001) followed by Holm-Šídák multiple comparisons test to compare TSC-affected tissues with controls. In all quantifications, n = 3; *P < 0.05, **P < 0.01, ***P < 0.001. Graphs show individual values and mean values ± SD.

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