Christine E Brown1, Analiz Rodriguez2, Joycelynne Palmer3, Julie R Ostberg1, Araceli Naranjo1, Jamie R Wagner1, Brenda Aguilar1, Renate Starr1, Lihong Weng1, Timothy W Synold4, Vivi Tran4, Shelley Wang5, Andreas Reik5, Massimo D'Apuzzo6, Julie A Ressler7, Yuanyue Zhou5, Matthew Mendel5, Philip D Gregory5, Michael C Holmes5, Winson W Tang5, Stephen J Forman1, Michael C Jensen8, Behnam Badie2. 1. Department of Hematology & Hematopoietic Cell Transplantation (T Cell Therapeutics Research Laboratories), City of Hope Beckman Research Institute and Medical Center; Duarte, California, USA. 2. Department of Neurosurgery, City of Hope Beckman Research Institute and Medical Center; Duarte, California, USA. 3. Department of Computational and Quantitative Medicine, City of Hope Beckman Research Institute and Medical Center; Duarte, California, USA. 4. Department of Cancer Biology, City of Hope Beckman Research Institute and Medical Center; Duarte, California, USA. 5. Sangamo Therapeutics, Inc., Richmond, California, USA. 6. Department of Pathology, City of Hope Beckman Research Institute and Medical Center; Duarte, California, USA. 7. Department of Diagnostic Radiology, City of Hope Beckman Research Institute and Medical Center; Duarte, California, USA. 8. Ben Town Center for Childhood Cancer, Seattle Children's Research Institute, Seattle, Washington, USA.
Abstract
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 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). 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. Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2022.
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 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). 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. Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2022.
Entities:
Keywords:
IL13Rα2-CAR T cells; allogeneic; glioblastoma; glucocorticoid receptor; off-the-shelf
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