Generating Metabolically Superior T Cells as a Novel Immunotherapy to Treat Solid Tumors

Harnessing the ability of T cells to specifically recognize and eliminate cancer, adoptive T cell transfer therapy (ACT), is currently one of the few immunotherapies that can induce objective clinical responses in significant numbers of patients.

However, this approach is limited when treating solid tumors due to a hostile tumor microenvironment (TME) characterized by reduction in glucose availability to T cells, thus limiting ACT of solid tumors.

Therefore, success against solid tumors requires a “metabolically superior T cell” that has been engineered to overcome the glucose-deficient TME. For this purpose, we are developing a technology that allows the engineering of CTLs to be able to use trehalose as a carbon source instead of glucose. Trehalose is a diglucose that is used by insect cells as a carbon source. Human cells do not have the genes that allow them to uptake and catabolize intra-cellular trehalose. Therefore, introducing both the trehalose transporter (Tret1) and the trehalose-hydrolyzing enzyme (Trehalase- Treh1) from insects into T cells has the potential to promote metabolically superior CTLs and to improve ACT therapy of solid tumors. To test our hypothesis, we have cloned Treh1 and Tret1 from drosophila into a lentiviral vector and demonstrated that their co-expression allows human cells to utilize trehalose for glycolysis. Moreover, co-expression of these two genes allows glucose-obligatory T cell line to survive and proliferate in a glucose-free media supplemented with trehalose. Currently, we are planning to go forward with testing our technology in primary T cells in vivo models for solid tumors.