T lymphocytes redirected against the chondroitin sulfate proteoglycan-4 control the growth of multiple solid tumors both in vitro and in vivo

Claudia Geldres, Barbara Savoldo, Valentina Hoyos, Ignazio Caruana, Ming Zhang, Eric Yvon, Michele Del Vecchio, Chad J. Creighton, Michael Ittmann, Soldano Ferrone, Gianpietro Dotti

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: 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 antibodybased 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. Experimental Design:Wefirst 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 ofhuman tumors.Weconstructed a second-generation CSPG4-specific CARalso 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.

Original languageEnglish
Pages (from-to)962-971
Number of pages10
JournalClinical Cancer Research
Volume20
Issue number4
DOIs
Publication statusPublished - 2014

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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