Engineering Next-Generation CAR T Cells to Treat Pediatric AML: Enhancing Safety Through Dynamic Control and Specificity
Abstract
Over the course of the last year we have developed synthetic cellular circuitry to: 1) titrate cytotoxic activity of a CAR T cell using a gamma secretase inhibitor drugs. Specifically, we have successfully engineered CAR T cells with a reversible OFF switch by using a synthetic Notch (synNotch) receptor that drives expression of a CAR. The synNotch receptor is a new type of antigen triggered receptor that can induce a transcriptional response. SynNotch induction of CAR expression can be tightly regulated by inhibition of the intracellular gamma secretase cleavage site by gamma secretase inhibitors. We have shown that CAR expression and cytotoxic activity can be titrated by this class of small molecules. We have demonstrated the cytotoxic activity, specificity and dynamics of this titratable CAR T cell in vitro and have developed a protocol to test the OFF-switch in immunocompromised mice. From last years data, we have not been able to test Nirogacestat in vivo as the price has been prohibitive ($1,000/mouse/experiment). We therefore turned towards another GSI, crenigacestat, which was evaluated safe in a phase 1 clinical trial and is currently being tested in association with BCMA CAR T cell therapy in a clinical trial. Our preliminary in vitro data suggest that this new drug could be a great alternative to Nirogacestat. The cost of the drug for the in vivo application is affordable~ $50/mouse/experiment. 2) demonstrate in vivo that we can target abnormal combinations of cell surface antigens using combinatorial recognition approach using mouse model of glioblastoma. Using a conceptually similar circuit based of a synNotch driving a CAR for glioblastoma cancer treatment, we were able to show that synNotch-CAR T cells showed less differentiation, less exhaustion in vitro and additionally showed that this circuit efficiently and durably cleared the glioblastoma cancer in vivo.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2021
- Accession Number
- AD1148033
Entities
People
- Mignon Loh
- Wendell Lim
Organizations
- University of California Regents