Details

Autor(en) / Beteiligte

• Brown, Christine E
• Rodriguez, Analiz
• Palmer, Joycelynne
• Ostberg, Julie R
• Naranjo, Araceli
• Wagner, Jamie R
• Aguilar, Brenda
• Starr, Renate
• Weng, Lihong
• Synold, Timothy W
• Tran, Vivi
• Wang, Shelley
• Reik, Andreas
• D'Apuzzo, Massimo
• Ressler, Julie A
• Zhou, Yuanyue
• Mendel, Matthew
• Gregory, Philip D
• Holmes, Michael C
• Tang, Winson W
• Forman, Stephen J
• Jensen, Michael C
• Badie, Behnam

Titel

Off-the-shelf, steroid-resistant, IL13Rα2-specific CAR T cells for treatment of glioblastoma

Ist Teil von

• Neuro-oncology (Charlottesville, Va.), 2022-08, Vol.24 (8), p.1318-1330

Ort / Verlag

England: Oxford University Press

Erscheinungsjahr

2022

Link zum Volltext

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• 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. We generated for clinical use a healthy-donor derived IL13Rα2-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). 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. 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.