Journal
MOLECULAR THERAPY
Volume 17, Issue 10, Pages 1779-1787Publisher
CELL PRESS
DOI: 10.1038/mt.2009.133
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Funding
- Alex's Lemonade Stand Foundation
- Cure Foundation
- Justin Porter American Brain Tumor Association Fellowship
- American Brain Tumor Translational Grant
- NIH [CA 42992]
- Doris Duke Distinguished Clinical Scientist Award
- Doris Duke Clinical Scientist Development Award
- NATIONAL CANCER INSTITUTE [R01CA042992] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [T32DK064717] Funding Source: NIH RePORTER
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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 osteo-sarcoma 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 mono-clonal antibodies, may allow immunotherapy to be more broadly applicable for human cancer therapy.
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