Description:
Background
A key barrier to CAR-T cell therapies for solid tumors is the immunosuppressive tumor microenvironment, where cytokines like TGF-β inhibit T cell proliferation, cytotoxicity, and persistence. TGF-β suppresses immune responses by activating Smad-dependent signaling pathways, leading to T cell anergy and exhaustion. Traditional approaches to overcome this suppression, such as dominant-negative receptors or gene knockouts, often compromise safety, exhibit limited durability, or fail to provide sufficient activation signals. These shortcomings reveal a critical need for strategies that not only neutralize TGF-β’s suppressive influence but also convert it into a functional advantage for engineered T cells.
USC Solution
This technology features engineered TGF-β redirectors that transform immunosuppressive TGF-β signals into pro-inflammatory stimuli in CAR-T cells. By fusing the TGF-β receptor’s extracellular domain with intracellular domains from IL-2, IL-7, or IL-12 receptors, these synthetic constructs activate NF-κB, STAT3, and STAT5 pathways to enhance T cell survival and function. The system also integrates with focused ultrasound (FUS) using a heat-responsive promoter, enabling localized, sustained CAR expression. This dual approach boosts tumor targeting, persistence, and in vivo efficacy, as demonstrated by extended CAR expression and improved tumor regression in mouse models.
Benefits
- Converts suppressive TGF-β signals into activating pathways to boost CAR-T cell function
- Sustains CAR expression via self-reinforcing feedback, enhancing persistence and cytotoxicity
- Minimizes off-tumor effects through FUS-guided spatial control
- Modular, fully human design allows targeting of diverse tumors with low immunogenicity risk
Commercial Applications
- Solid tumor immunotherapy
- CAR-T cell engineering platforms
- Ultrasound-guided cancer treatments