UCLA researchers in the Department of Medicine have generated novel pluripotent stem cell derived T cells that exhibit improved survival, expansion, and anti-tumor efficacy for use in cell therapy treatments.
BACKGROUND: The Food and Drug Administration has approved several chimeric antigen receptor-T (CAR-T) cell therapies since 2017 to combat lymphoma and lymphoblastic leukemia, among other malignancies. This treatment involves an ex vivo culture expansion typically ranging from 7 to 14 days and significant efforts have been made by the scientific community at large to optimize culture conditions to increase CAR T cell efficiency and speed of delivery to patients. Researchers have shown that CAR T cells progressively upregulate two molecules, Fas and Fas Ligand (FasL), among others. The interaction between Fas and FasL, T cells causes activation-induced cell death, a form of cell death induced by repeated T cell receptor stimulation. This finding was further validated when an additional research group showed that a mutation of the Fas protein was able to reduce T cell death and in turn increase the anti-tumor efficacy of the primary T cells. In order to enhance the manufacturing process of CAR T cells and increase their usage to other malignancies, T cell death must be decreased by inhibiting the Fas-FasL interaction.
INNOVATION: UCLA researchers led by Dr. Christopher Seet have developed protocols and methods for the use of gene editing to engineer pluripotent stem cells deficient in Fas and FasL. These PSCs were then used to generate T cells deficient in Fas and FasL expression. Dr. Seet’s group has shown that the resulting T cells do not undergo apoptosis in culture. This novel discovery can be readily applied to generate natural killer (NK) cells deficient in Fas and FasL that have a survival advantage compared to wild-type NK cells.
POTENTIAL APPLICATIONS:
- Generation of T cells without Fas-FasL dependent apoptosis.
- Generation of NK cells without Fas-FasL dependent apoptosis.
- Use to derive CAR-T cells with higher killing ability of tumor cells compared to current therapies.
ADVANTAGES:
- Increase the manufacturing speed of CAR-T cells as more cells will survive and not have to undergo Fas-FasL mediated cell death.
- Fas-FasL mutant T cells will have enhanced anti-tumor efficacy of T cells or NK cells.
DEVELOPMENT-TO-DATE: This technology has been shown to work in culture conditions using cell models.
KEYWORDS: CAR T cells, T Cells, Genome Engineering, Pluripotent Stem Cells, Immunotherapy