New Method of mTOR Regulation by TSC2 Modification

Unmet Need
Immunotherapies that boost T cell responses have demonstrated therapeutic efficacy in numerous cancers. To improve the efficacy and expand the clinical utility of immunotherapy, improved methods of stimulating T cell responses are needed. mTORC1 is a critical regulator of T cell activation, differentiation and function. While modulating mTORC1 signaling is a promising approach to improve immunotherapies, mTORC1 is critical for global cellular homeostasis. Current methods of targeting mTORC1 can be toxic or immunosuppresive. Consequently, improved methods of selectively altering mTORC1 signaling is a promising approach to treat cancer and mTORC1-mediated diseases.

Technology Overview
This invention is a therapeutic approach to modulate mTORC1 signaling for the treatment of cancer and mTOR1-medicated diseases. JHU researchers found that TSC2 modulates mTORC1 signaling when phosphorylated. They also demonstrated that certain gain- or loss-of-function mutations in TSC2 could be used for the bidirectional control of mTORC1 activity.

To control mTORC1 activity, the inventors engineered TSC2 polypeptides that either cannot be phosphorylated or behave as though they are constitutively phosphorylated. The TSC2 polypeptides that cannot be phosphorylated can be used to promote T cell activation, while the TSC2 polypeptides that are constitutively phosphorylated suppress mTORC1-mediated growth. Importantly, these polypeptides did not alter the basal expression of mTORC1, suggesting that this approach can be used for the activation or suppression of T cell responses with limited negative global effects.

While these engineered TSC2 polypeptides may be an important off the shelf immunotherapy, they have numerous other potential applications. In particular, using these TSC2 polypeptides to generate engineered immune cells may improve cellular therapies such as chimeric antigen receptor (CAR) T Cells. Additionally, these polypeptides may have useful applications in other therapeutic indications, such as autoimmune, cardiac, and neurodegenerative diseases.
 
Stage of Development
JHU researchers have demonstrated the ability of TSC2 to modulate mTORC1 signaling in vivo and in vitro.

Publications
Ranek MJ, et al. Circulation. 2018 March. Abstract.
Ranek MJ, et al. Nature. 2019 Feb. 566:264-269.
 

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