title: Bioactivity and Safety of IL13Rα2-Redirected Chimeric Antigen Receptor CD8+ T Cells in Patients with Recurrent Glioblastoma.
abstract: OBJECTIVE
  A first-in-human pilot safety and feasibility trial evaluating chimeric antigen receptor (CAR)-engineered, autologous primary human CD8(+) cytotoxic T lymphocytes (CTL) targeting IL13Rα2 for the treatment of recurrent glioblastoma (GBM).
  
  
  METHODS
  Three patients with recurrent GBM were treated with IL13(E13Y)-zetakine CD8(+) CTL targeting IL13Rα2. Patients received up to 12 local infusions at a maximum dose of 10(8) CAR-engineered T cells via a catheter/reservoir system.
  
  
  RESULTS
  We demonstrate the feasibility of manufacturing sufficient numbers of autologous CTL clones expressing an IL13(E13Y)-zetakine CAR for redirected HLA-independent IL13Rα2-specific effector function for a cohort of patients diagnosed with GBM. Intracranial delivery of the IL13-zetakine(+) CTL clones into the resection cavity of 3 patients with recurrent disease was well-tolerated, with manageable temporary brain inflammation. Following infusion of IL13-zetakine(+) CTLs, evidence for transient anti-glioma responses was observed in 2 of the patients. Analysis of tumor tissue from 1 patient before and after T-cell therapy suggested reduced overall IL13Rα2 expression within the tumor following treatment. MRI analysis of another patient indicated an increase in tumor necrotic volume at the site of IL13-zetakine(+) T-cell administration.
  
  
  CONCLUSIONS
  These findings provide promising first-in-human clinical experience for intracranial administration of IL13Rα2-specific CAR T cells for the treatment of GBM, establishing a foundation on which future refinements of adoptive CAR T-cell therapies can be applied.
authors.affiliation: Department of Cancer Immunotherapy and Tumor Immunology, City of Hope Beckman Research Institute and Medical Center, Duarte, California. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Beckman Research Institute and Medical Center, Duarte, California. cbrown@coh.org.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Brown
authors.affiliation: Department of Neurosurgery, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
authors.forename: Behnam
authors.initials: B
authors.lastname: Badie
authors.affiliation: Department of Neurosciences, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Barish
authors.affiliation: Department of Cancer Immunotherapy and Tumor Immunology, City of Hope Beckman Research Institute and Medical Center, Duarte, California. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
authors.forename: Lihong
authors.initials: L
authors.lastname: Weng
authors.affiliation: Department of Cancer Immunotherapy and Tumor Immunology, City of Hope Beckman Research Institute and Medical Center, Duarte, California. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
authors.forename: Julie R
authors.initials: JR
authors.lastname: Ostberg
authors.affiliation: Department of Cancer Immunotherapy and Tumor Immunology, City of Hope Beckman Research Institute and Medical Center, Duarte, California. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
authors.forename: Wen-Chung
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Department of Cancer Immunotherapy and Tumor Immunology, City of Hope Beckman Research Institute and Medical Center, Duarte, California. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
authors.forename: Araceli
authors.initials: A
authors.lastname: Naranjo
authors.affiliation: Department of Cancer Immunotherapy and Tumor Immunology, City of Hope Beckman Research Institute and Medical Center, Duarte, California. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
authors.forename: Renate
authors.initials: R
authors.lastname: Starr
authors.affiliation: Department of Cancer Immunotherapy and Tumor Immunology, City of Hope Beckman Research Institute and Medical Center, Duarte, California. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
authors.forename: Jamie
authors.initials: J
authors.lastname: Wagner
authors.affiliation: Department of Cancer Immunotherapy and Tumor Immunology, City of Hope Beckman Research Institute and Medical Center, Duarte, California. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
authors.forename: Christine
authors.initials: C
authors.lastname: Wright
authors.affiliation: Department of Cancer Immunotherapy and Tumor Immunology, City of Hope Beckman Research Institute and Medical Center, Duarte, California. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
authors.forename: Yubo
authors.initials: Y
authors.lastname: Zhai
authors.affiliation: Department of Cancer Immunotherapy and Tumor Immunology, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
authors.forename: James R
authors.initials: JR
authors.lastname: Bading
authors.affiliation: Department of Diagnostic Radiology, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Ressler
authors.affiliation: Department of Medical Oncology and Therapeutics Research, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
authors.forename: Jana
authors.initials: J
authors.lastname: Portnow
authors.affiliation: Department of Pathology, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
authors.forename: Massimo
authors.initials: M
authors.lastname: D'Apuzzo
authors.affiliation: Department of Cancer Immunotherapy and Tumor Immunology, City of Hope Beckman Research Institute and Medical Center, Duarte, California. Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Beckman Research Institute and Medical Center, Duarte, California.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Forman
authors.affiliation: Center for Childhood Cancer, Seattle Children's Research Institute, Seattle, Washington.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Jensen
mesh_terms: D000328:Adult; D000368:Aged; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000276:immunology / Q000628:therapy*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D005240:Feasibility Studies; D005260:Female; D005909:Glioblastoma / Q000276:immunology / Q000628:therapy*; D005910:Glioma / Q000276:immunology / Q000628:therapy; D006680:HLA Antigens / Q000737:chemistry; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007249:Inflammation; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D061214:Patient Safety; D010865:Pilot Projects; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D012008:Recurrence; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D006680:HLA Antigens; C000609461:IL13-zetakine; D053663:Interleukin-13 Receptor alpha2 Subunit; D011948:Receptors, Antigen, T-Cell