1. ¹Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, The Methodist Hospital, Houston, Texas, USA
2. ²Texas Children's Cancer Center, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas, USA
3. ³Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas, USA
4. ⁴Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus, Frankfurt am Main; Germany
5. ⁵Department of Pathology, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas, USA
6. ⁶Division of Pediatrics, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA
7. ⁷Department of Immunology, Baylor College of Medicine, Houston, Texas, USA
8. ⁸Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA
9. ⁹Department of Medicine, Baylor College of Medicine, Houston, Texas, USA

Correspondence: Stephen Gottschalk, Center for Cell and Gene Therapy, Baylor College of Medicine, 6621 Fannin Street MC 3-3320, Houston, Texas 77030, USA. Email: smg@bcm.edu

Received 4 November 2008; Accepted 21 May 2009; Published online 16 June 2009.

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. 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.