Jennifer L. Clarke, MD, Clinical Accelerator Investigator University of California, San Francisco Area of Research: Brain Cancer To safely and effectively target glioblastoma (GBM)-associated antigens (GAAs), Dr. Clarke has adopted a novel synthetic Notch ‘synNotch’ receptor system. In this system, the first antigen, which is expressed exclusively on GBM cells (e.g., EGFRvIII), primes the T cells to induce expression of a CAR that recognizes IL-13Rα2 and EphA2, thereby eradicating GBM cells expressing either EphA2 or IL-13Rα2. Dr. Clarke has demonstrated that EGFRvIII-synNotch primed EphA2/IL-13Rα2 CAR (E-SYNC) are effectively but restrictedly activated by EGFRvIII as the GBM-specific signal, thereby leading to complete eradication of orthotopic patient-derived xenografts (PDX) with heterogeneous EGFRvIII expression, without attacking EphA2/IL-13Rα2-positive cells outside of the CNS. Furthermore, these synNotch-CART cells were significantly more efficacious than conventional EphA2/IL-13Rα2 CART cells, associated with excellent persistence, and more juvenile in phenotype than conventional CART cells5. In this study, Dr. Clarke will conduct a first-in-human phase I study to evaluate the hypothesis that a single IV infusion of E-SYNC T cells in patients with EGFRvIII+ GBM will be safe and that the IV-infused E-SYNC T cells will demonstrate local priming in prospectively resected GBM tissue. The study has been developed with the following sequential two cohorts to evaluate: 1. The safety of IV-infused E-SYNC T cells in patients with newly diagnosed GBM (Cohort 1) as a dose-escalation cohort. 2. The infiltration and priming of the pre-surgically IV-infused E-SYNC T cells in the resected tumor tissue (Cohort 2). Projects and Grants Phase 1 study of autologous anti-EGFRvIII synNotch receptor-induced anti-EphA2/IL-13Rα2 CAR (E-SYNC) T Cells in adult participants with EGFRvIII+ glioblastoma University of California, San Francisco | Brain Cancer | 2024
