Application

  • CD8 Cytotoxic T cells (CTLs) are the main adaptive-immune cells that play a key role in anti-cancer immunity. CTLs functionality and persistency depend on glucose-dependent metabolism.
  • Adoptive T cell transfer therapy (ACT) is an innovative immunotherapy approach that harnesses the patient’s own immune cells, specifically T cells, to combat cancer. This method involves isolating T cells from the patient’s body, activating and expanding them ex vivo, and then reintroducing them to target cancer cells. One prominent form of ACT is CAR T-cell therapy, which has achieved remarkable success in treating blood cancers, with a 90% complete remission rate in clinical trials for B-cell acute lymphoblastic leukemia. However, the effectiveness of CAR T-cell therapy, like other forms of ACT, remains limited in solid tumors.
  • The challenge lies in the hostile tumor microenvironment, characterized by reduced oxygen, glucose, and other nutrients. Cancer cells manipulate these conditions, depleting extracellular glucose, which creates a dependency that restricts glucose availability to infiltrating CTLs. This decreased glucose availability suppresses glycolytic metabolism within T cells, leading to their dysfunction and ultimately limiting the efficacy of ACT in solid tumors. Therefore, addressing these metabolic challenges is critical to enhancing T cell activity against malignant cells.

Our Innovation

  • Our invention is based on the strategy of changing T-cells to become “metabolically-superior T-cell” (MSTC) by engineering them to overcome the glucose-deficient tumor microenvironment that characterizes many advanced solid tumors; 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.
  • Metabolic studies demonstrate that trehalose fully integrates into T cell metabolism, supporting glycolysis, TCA cycle, and the pentose phosphate pathway.
  • 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.

Clinical Data

  • In-vitro studies show maintained human T cell viability and effector functions in glucose-free conditions when supplemented with trehalose
  • Modified T cells demonstrate effective killing of melanoma cells in glucose-depleted environments
  • Glioblastoma mouse model shows 35% increase in survival with trehalose-modified CAR-T cells
  • NK92 cells expressing Tret1/Treh1 show successful selection and growth in trehalose media

Figure: Treh1/Tret1 technology improves the efficiency of CAR T-cell therapy in vivo

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

Opportunity

Primary applications for our innovations:

  • Improving the efficacy of ACTs (TILs, TCRs, and CARs)
  • Enabling any immune cell used or to be used in immunotherapy to efficiently function within glucose-deprived tissues
  • Controlling the regions and the timing of immune cells’ activity during immunotherapy

Secondary applications for our innovations:

  • Allowing highly efficient cryopreservation of immune cells such as NK cells
  • Increasing the resistance of immune cells to a variety of stress
  • Metabolic control of any cellular therapy