title: Anti-KIT designer T cells for the treatment of gastrointestinal stromal tumor.
abstract: BACKGROUND
  Imatinib mesylate is an effective treatment for metastatic gastrointestinal stromal tumor (GIST). However, most patients eventually develop resistance and there are few other treatment options. Immunotherapy using genetically modified or designer T cells (dTc) has gained increased attention for several malignancies in recent years. The aims of this study were to develop and test novel anti-KIT dTc engineered to target GIST cells.
  
  
  METHODS
  Human anti-KIT dTc were created by retroviral transduction with novel chimeric immune receptors (CIR). The gene for stem cell factor (SCF), the natural ligand for KIT, was cloned into 1st generation (SCF-CD3ζ, 1st gen) and 2nd generation (SCF-CD28-CD3ζ, 2nd gen) CIR constructs. In vitro dTc proliferation and tumoricidal capacity in the presence of KIT+ tumor cells were measured. In vivo assessment of dTc anti-tumor efficacy was performed by treating immunodeficient mice harboring subcutaneous GIST xenografts with dTc tail vein infusions.
  
  
  RESULTS
  We successfully produced the 1st and 2nd gen anti-KIT CIR and transduced murine and human T cells. Average transduction efficiencies for human 1st and 2nd gen dTc were 50% and 42%. When co-cultured with KIT+ tumor cells, both 1st and 2nd gen dTc proliferated and produced IFNγ. Human anti-KIT dTc were efficient at lysing GIST in vitro compared to untransduced T cells. In mice with established GIST xenografts, treatment with either 1st or 2nd gen human anti-KIT dTc led to significant reductions in tumor growth rates.
  
  
  CONCLUSIONS
  We have constructed a novel anti-KIT CIR for production of dTc that possess specific activity against KIT+ GIST in vitro and in vivo. Further studies are warranted to evaluate the therapeutic potential and safety of anti-KIT dTc.
authors: Roger Williams Medical Center, Department of Surgery, Providence, RI/Boston University School of Medicine, Boston, MA, USA. skatz@chartercare.org
authors: Steven C
authors: SC
authors: Katz
authors: Rachel A
authors: RA
authors: Burga
authors: Seema
authors: S
authors: Naheed
authors: Lauren A
authors: LA
authors: Licata
authors: Mitchell
authors: M
authors: Thorn
authors: Doreen
authors: D
authors: Osgood
authors: Cang T
authors: CT
authors: Nguyen
authors: N Joseph
authors: NJ
authors: Espat
authors: Jonathan A
authors: JA
authors: Fletcher
authors: Richard P
authors: RP
authors: Junghans
mesh_terms: D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation; D017931:DNA Primers; D046152:Gastrointestinal Stromal Tumors / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016133:Polymerase Chain Reaction; D019009:Proto-Oncogene Proteins c-kit / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology
chemical_list: D017931:DNA Primers; D019009:Proto-Oncogene Proteins c-kit