title: Suppression of human glioma xenografts with second-generation IL13R-specific chimeric antigen receptor-modified T cells.
abstract: OBJECTIVE
  Glioblastoma multiforme (GBM) remains highly incurable, with frequent recurrences after standard therapies of maximal surgical resection, radiation, and chemotherapy. To address the need for new treatments, we have undertaken a chimeric antigen receptor (CAR) "designer T cell" (dTc) immunotherapeutic strategy by exploiting interleukin (IL)13 receptor α-2 (IL13Rα2) as a GBM-selective target.
  
  
  METHODS
  We tested a second-generation IL13 "zetakine" CAR composed of a mutated IL13 extracellular domain linked to intracellular signaling elements of the CD28 costimulatory molecule and CD3ζ. The aim of the mutation (IL13.E13K.R109K) was to enhance selectivity of the CAR for recognition and killing of IL13Rα2(+) GBMs while sparing normal cells bearing the composite IL13Rα1/IL4Rα receptor.
  
  
  RESULTS
  Our aim was partially realized with improved recognition of tumor and reduced but persisting activity against normal tissue IL13Rα1(+) cells by the IL13.E13K.R109K CAR. We show that these IL13 dTcs were efficient in killing IL13Rα2(+) glioma cell targets with abundant secretion of cytokines IL2 and IFNγ, and they displayed enhanced tumor-induced expansion versus control unmodified T cells in vitro. In an in vivo test with a human glioma xenograft model, single intracranial injections of IL13 dTc into tumor sites resulted in marked increases in animal survivals.
  
  
  CONCLUSIONS
  These data raise the possibility of immune targeting of diffusely invasive GBM cells either via dTc infusion into resection cavities to prevent GBM recurrence or via direct stereotactic injection of dTcs to suppress inoperable or recurrent tumors. Systemic administration of these IL13 dTc could be complicated by reaction against normal tissues expressing IL13Ra1.
authors.affiliation: Brain Tumor Lab, Department of Neurosurgery, Biotherapeutics Development Lab, Boston University School of Medicine, Roger Williams Medical Center, Providence, Rhode Island02908, USA.
authors.forename: Seogkyoung
authors.initials: S
authors.lastname: Kong
authors.forename: Sadhak
authors.initials: S
authors.lastname: Sengupta
authors.forename: Betty
authors.initials: B
authors.lastname: Tyler
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Bais
authors.forename: Qiangzhong
authors.initials: Q
authors.lastname: Ma
authors.forename: Saryn
authors.initials: S
authors.lastname: Doucette
authors.forename: Jinyuan
authors.initials: J
authors.lastname: Zhou
authors.forename: Ayguen
authors.initials: A
authors.lastname: Sahin
authors.forename: Bob S
authors.initials: BS
authors.lastname: Carter
authors.forename: Henry
authors.initials: H
authors.lastname: Brem
authors.forename: Richard P
authors.initials: RP
authors.lastname: Junghans
authors.forename: Prakash
authors.initials: P
authors.lastname: Sampath
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D023061:Gene Order; D005909:Glioblastoma / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000276:immunology* / Q000378:metabolism; D009154:Mutation; D055503:Protein Multimerization; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D018106:CD28 Antigens; D018793:Interleukin-13; D053663:Interleukin-13 Receptor alpha2 Subunit; D011948:Receptors, Antigen, T-Cell