title: Immunotherapy for osteosarcoma: genetic modification of T cells overcomes low levels of tumor antigen expression.
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.zeta 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.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas 77030, USA.
authors.forename: Nabil
authors.initials: N
authors.lastname: Ahmed
authors.forename: Vita S
authors.initials: VS
authors.lastname: Salsman
authors.forename: Eric
authors.initials: E
authors.lastname: Yvon
authors.forename: Chrystal U
authors.initials: CU
authors.lastname: Louis
authors.forename: Laszlo
authors.initials: L
authors.lastname: Perlaky
authors.forename: Winfried S
authors.initials: WS
authors.lastname: Wels
authors.forename: Meghan K
authors.initials: MK
authors.lastname: Dishop
authors.forename: Eugenie E
authors.initials: EE
authors.lastname: Kleinerman
authors.forename: Martin
authors.initials: M
authors.lastname: Pule
authors.forename: Cliona M
authors.initials: CM
authors.lastname: Rooney
authors.forename: Helen E
authors.initials: HE
authors.lastname: Heslop
authors.forename: Stephen
authors.initials: S
authors.lastname: Gottschalk
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D016513:Mice, SCID; D012516:Osteosarcoma / Q000628:therapy*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell; D012190:Retroviridae / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000502:physiology*; D014161:Transduction, Genetic
chemical_list: D018106:CD28 Antigens; D018719:Erb-b2 Receptor Tyrosine Kinases; D011948:Receptors, Antigen, T-Cell