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Benign tumors in TSC are amenable to treatment by GD3 CAR T cells in mice
Ancy Thomas1,2, Saurav Sumughan2, Emilia R Dellacecca2
1Department of Dermatology, Feinberg School of Medicine.
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.
Insights
Targeting ganglioside D3 (GD3) with chimeric antigen receptor (CAR) T cells shows promise for treating tuberous sclerosis complex (TSC). This immunotherapy approach effectively reduced tumors in preclinical models by targeting GD3-expressing cells.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Tuberous sclerosis complex (TSC) is characterized by tumors resulting from biallelic mutations in TSC1 or TSC2, leading to hyperactive mammalian target of rapamycin complex 1 (mTORC1).
- Tumor growth and activation of mTORC1 may depend on ganglioside D3 (GD3) expression, presenting a potential therapeutic target.
- Despite GD3 overexpression in TSC tissues, natural immune responses are often insufficient.
Purpose of the Study:
- To investigate GD3 expression in TSC-affected tissues and aging mice with TSC mutations.
- To evaluate the efficacy of GD3-targeted chimeric antigen receptor (CAR) T cells in preclinical TSC models.
Main Methods:
- Compared GD3 expression in tissues from TSC patients and controls, and in aging Tsc2+/- mice.
- Developed and tested GD3 CAR T cells in mouse models with Tsc2-/- tumor cells.
- Assessed tumor burden, T cell infiltration, and tumor-free survival in treated aged Tsc2+/- mice.
Main Results:
- GD3 was significantly overexpressed in affected TSC tissues and in aging Tsc2+/- mice.
- GD3 CAR T cells demonstrated cytotoxicity against GD3-overexpressing targets.
- CAR T cell treatment led to substantial, durable tumor burden reduction in mice with Tsc2-/- tumors.
- A majority of aged Tsc2+/- mice treated with GD3 CAR T cells became tumor-free, unlike control groups.
Conclusions:
- GD3 is overexpressed in TSC, suggesting its role in disease pathogenesis.
- GD3-targeted CAR T cell therapy is a potent and effective treatment strategy for TSC.
- This approach holds significant promise for managing TSC-related tumors.
