Off-the-shelf, steroid-resistant, IL13Ralpha2-specific CAR T cells for treatment of glioblastoma.
This is a first-in-human study of locally administered, glucocorticoid resistant, allogeneic CAR T cells for the treatment of recurrent GBM as an off-the-shelf therapy. The efficiency and specificity of zinc finger nucleasedirected disruption of the glucocorticoid receptor (GR) locus enabled the engineering of dexamethasoneresistant IL13Rα2-targeted CAR T cells. These steroidresistant CAR T cells retained effector function in the presence of dexamethasone, which was used clinically to attenuate tumor-related neuro-edema, as well as the rejection of the therapeutic allogeneic cells. The CAR T cell product displayed a defined TCR profile without evidence of graft-versus-host alloreactivity. This study demonstrates the safety and feasibility of such genemodified cells for use as an off-the-shelf allogeneic CAR T cell product. Evidence of transient anti-tumor effects in four of the six treated GBM patients further sets the stage for future adoptive therapy studies using off-theshelf, glucocorticoid resistant CAR T cells for the treatment of brain tumors.
BACKGROUND: Wide-spread application of chimeric antigen receptor (CAR) T cell therapy for cancer is limited by the current use of autologous CAR T cells necessitating the manufacture of individualized therapeutic products for each patient. To address this challenge, we have generated an off-the-shelf, allogeneic CAR T cell product for the treatment of glioblastoma (GBM), and present here the feasibility, safety, and therapeutic potential of this approach. METHODS: We generated for clinical use a healthy-donor derived IL13Ralpha2-targeted CAR+ (IL13-zetakine+) cytolytic T-lymphocyte (CTL) product genetically engineered using zinc finger nucleases (ZFNs) to permanently disrupt the glucocorticoid receptor (GR) (GRm13Z40-2) and endow resistance to glucocorticoid treatment. In a phase I safety and feasibility trial we evaluated these allogeneic GRm13Z40-2 T cells in combination with intracranial administration of recombinant human IL-2 (rhIL-2; aldesleukin) in six patients with unresectable recurrent GBM that were maintained on systemic dexamethasone (4-12 mg/day). RESULTS: The GRm13Z40-2 product displayed dexamethasone-resistant effector activity without evidence for in vitro alloreactivity. Intracranial administration of GRm13Z40-2 in four doses of 108 cells over a two-week period with aldesleukin (9 infusions ranging from 2500-5000 IU) was well tolerated, with indications of transient tumor reduction and/or tumor necrosis at the site of T cell infusion in four of the six treated research subjects. Antibody reactivity against GRm13Z40-2 cells was detected in the serum of only one of the four tested subjects. CONCLUSIONS: This first-in-human experience establishes a foundation for future adoptive therapy studies using off-the-shelf, zinc-finger modified, and/or glucocorticoid resistant CAR T cells.