- CD8 Cytotoxic T cells (CTLs) are the main adaptive-immune cells that play a key role in anti-cancer immunity. CTLs functionality and fate rely on rewiring their metabolism to an oxidative glycolysis dependent.
- Adoptive T cell transfer therapy (ACT) is a rapidly emerging immunotherapy approach, collecting and using patients’ own immune cells to treat their cancer. There are several types of ACT but, thus far, the one that has advanced the furthest in clinical development is called CAR T-cell therapy, now known to be used for melanoma and a few other cancers, such as head & neck, bladder, or cervical cancer. ACT is currently one of the few immunotherapies that can induce objective clinical responses in significant numbers of patients with metastatic solid tumors.
- Based on the administration of ex vivo–activated and expanded autologous tumor-specific CTLs, ACT harnesses the natural ability of T cells, to specifically recognize and eliminate target cells, and directs it to the treatment of advanced-stage cancers. Cancer cells subvert the metabolic characteristics of the tumor microenvironment to shape immune responses within solid tumors. Specifically, it has been shown that glycolysis within tumor cells causes depletion of extracellular glucose which restricts glucose availability to T cells which causes suppression of glycolytic metabolism and effector functions within tumor infiltrating CTLs, and highly reduces ACT success probability.
- A modified novel cell line of “super T cells” to improve success rates of ACT: we engineer CTLs to be able to use trehalose, a carbon source not used by mammalian cells but rather by insect cells, as a carbon source instead of glucose.
- Trehalose is a highly stable, non-toxic disaccharide formed by a 1,1-glycosidic bond between two α-glucose units. We introduce both the trehalose transporter (Tret1) and the trehalose-hydrolyzing enzyme (Trehalase-Treh1) from insects into CTLs.
- The idea is to administer to the patient the super T cells together with external trehalose in the ACT treatment and thus increase ACT efficiency.
This approach has several highly applicable advantages:
- Privileged access for infected cells to abandoned glucose sources, with no competition from malignant cells or any other cells.
- Robust cells protection from stresses associated with malignant niches.
- Improvement of the cryopreservation of challenging immune subsets such as NK cells.
- Primary applications for our innovations:
1. Improving the efficacy of ACTs (TILs, TCRs, and CARs)
2. Enabling any immune cell used or to be used in immunotherapy to efficiently function within glucose-deprived tissues
3. Controlling the regions and the timing of immune cells’ activity during immunotherapy
- Secondary applications for our innovations:
1. Allowing highly efficient cryopreservation of immune cells such as NK cells
2. Increasing the resistance of immune cells to a variety of stress
3. Metabolic control of any cellular therapy