Immunotherapy for osteosarcoma: Genetic modification of T cells overcomes low levels of tumor antigen expression

Nabil Ahmed, Vita S. Salsman, Eric Yvon, Chrystal U. Louis, Laszlo Perlaky, Winfried S. Wels, Meghan K. Dishop, Eugenie E. Kleinerman, Martin Pule, Cliona M. Rooney, Helen Heslop, Stephen Gottschalk

Research output: Contribution to journalArticle

115 Scopus citations

Abstract

Human epidermal growth factor receptor 2 (HER2) is expressed by the majority of human osteosarcomas and is a risk factor for poor outcome. Unlike breast cancer, osteosarcoma cells express HER2 at too low, a level for patients to benefit from HER2 monoclonal antibodies. We reasoned that this limitation might be overcome by genetically modifying T cells with HER2-specific chimeric antigen receptors (CARs), because even a low frequency of receptor engagement could be sufficient to induce effector cell killing of the tumor. HER2-specific T cells were generated by retroviral transduction with a HER2-specific CAR containing a CD28.ζ signaling domain. HER2-specific T cells recognized HER2-positive osteosarcoma cells as judged by their ability to proliferate, produce immunostimulatory T helper 1 cytokines, and kill HER2-positive osteosarcoma cell lines in vitro. The adoptive transfer of HER2-specific T cells caused regression of established osteosarcoma xenografts in locoregional as well as metastatic mouse models. In contrast, delivery of nontransduced (NT) T cells did not change the tumor growth pattern. Genetic modification of T cells with CARs specific for target antigens, expressed at too low a level to be effectively recognized by monoclonal antibodies, may allow immunotherapy to be more broadly applicable for human cancer therapy.

Original languageEnglish (US)
Pages (from-to)1779-1787
Number of pages9
JournalMolecular Therapy
Volume17
Issue number10
DOIs
StatePublished - 2009

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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