title: T lymphocytes redirected against the chondroitin sulfate proteoglycan-4 control the growth of multiple solid tumors both in vitro and in vivo.
abstract: OBJECTIVE
  Because of its high expression on various types of tumors and its restricted distribution in normal tissues, chondroitin sulfate proteoglycan-4 (CSPG4) represents an attractive target for the antibody-based therapy of several solid tumors. We tested whether T cells transduced with a CSPG4-specific chimeric antigen receptor (CAR) inhibited the growth of CSPG4-expressing tumor cells both in vitro and in vivo.
  
  
  METHODS
  We first independently validated by immunohistochemistry (IHC) the expression of CSPG4 in an extensive panel of tumor arrays and normal tissues as well as queried public gene expression profiling datasets of human tumors. We constructed a second-generation CSPG4-specific CAR also encoding the CD28 costimulatory endodomain (CAR.CSPG4). We then evaluated human T lymphocytes expressing this CAR for their ex vivo and in vivo antitumor activity against a broad panel of solid tumors.
  
  
  RESULTS
  IHC showed that CSPG4 is highly expressed in melanoma, breast cancer, head and neck squamous cell carcinoma (HNSCC), and mesothelioma. In addition, in silico analysis of microarray expression data identified other important potential tumors expressing this target, including glioblastoma, clear cell renal carcinoma, and sarcomas. T lymphocytes genetically modified with a CSPG4-CAR controlled tumor growth in vitro and in vivo in NSG mice engrafted with human melanoma, HNSCC, and breast carcinoma cell lines.
  
  
  CONCLUSIONS
  CAR.CSPG4-redirected T cells should provide an effective treatment modality for a variety of solid tumors.
authors: Authors' Affiliations: Center for Cell and Gene Therapy; Departments of Pediatrics, Pathology and Immunology, and Medicine, Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine; Houston Methodist Hospital and Texas Children's Hospital; Department of Surgery, Michael E. DeBakey Department of Veterans Affairs Medical Center; Dan L. Duncan Cancer Center Division of Biostatistics, Baylor College of Medicine, Houston, Texas; and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
authors: Claudia
authors: C
authors: Geldres
authors: Barbara
authors: B
authors: Savoldo
authors: Valentina
authors: V
authors: Hoyos
authors: Ignazio
authors: I
authors: Caruana
authors: Ming
authors: M
authors: Zhang
authors: Eric
authors: E
authors: Yvon
authors: Michele
authors: M
authors: Del Vecchio
authors: Chad J
authors: CJ
authors: Creighton
authors: Michael
authors: M
authors: Ittmann
authors: Soldano
authors: S
authors: Ferrone
authors: Gianpietro
authors: G
authors: Dotti
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D018270:Carcinoma, Ductal, Breast / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D011508:Chondroitin Sulfate Proteoglycans / Q000276:immunology / Q000378:metabolism*; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D006258:Head and Neck Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D006801:Humans; D008545:Melanoma / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D008654:Mesothelioma / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000378:metabolism; D011946:Receptors, Antigen / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D008565:Membrane Proteins; D011946:Receptors, Antigen; C101390:CSPG4 protein, human; D000099216:Chondroitin Sulfate Proteoglycan 4