Phase I Study of Chimeric Antigen Receptor Engineered Central Memory T cells for the Treatment of Malignant Glioma

Under this CLIN2 award we have completed a phase I trial (NCT02208362) evaluating the therapeutic efficacy of stem-like memory T cells that have been gene modified to express a tumor-targeting chimeric antigen receptor (CAR) for the treatment of glioblastoma and other high-grade malignant gliomas.  More specifically, stem-like memory T cells were isolated from blood, modified to express a CAR that targets IL13Rα2, a protein expressed by glioma tumor cells, and the therapeutic cells were delivered into either the brain tumor site and/or the cerebrospinal fluid of each patient.  This trial treated 65 patients, the majority of whom had recurrent glioblastoma (rGBM), and demonstrated that weekly intratumoral (ICT) and/or intraventricular (ICV) administration of the CAR T cells was well-tolerated with clinically manageable adverse events. Stable disease or better was achieved in 50% of patients, with two partial responses, one complete response (CR) and a second CR after additional CAR T cycles off-protocol therapy.  Patients with rGBM treated with dual ICT/ICV delivery and an optimized manufacturing process exhibited superior overall median survival of 10.2 months compared to 6.1 months for other treatment arms. Central nervous system increases in inflammatory cytokines, including IFNγ, CXCL9 and CXCL10, were associated with CAR T cell administration and bioactivity. Further, pre-treatment levels of T cells in the tumor were positively associated with survival, indicating an interplay between host immunity and CAR T cells as a determinant of outcomes. These findings advance our understanding and support the future use of stem-like, memory T cell-derived CAR T cell immunotherapy for malignant brain tumors.