Allelic Exclusion and Peripheral Reconstitution by TCR Transgenic T Cells Arising From Transduced Human Hematopoietic Stem/Progenitor Cells |
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| Authors: | Francesca Giannoni Cinnamon L Hardee Jennifer Wherley Eric Gschweng Shantha Senadheera Michael L Kaufman Rebecca Chan Ingrid Bahner Vivian Gersuk Xiaoyan Wang David Gjertson David Baltimore Owen N Witte James S Economou Antoni Ribas Donald B Kohn |
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| Affiliation: | 1. Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, California, USA;2. Department of Molecular Medicine, University of South Florida College of Medicine, Tampa, Florida, USA;3. Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA;4. Department of Medicine Statistics Core, University of California, Los Angeles, California, USA;5. Department of Biostatistics, School of Public Health, University of California, Los Angeles, California, USA;6. Division of Biology, California Institute of Technology, Pasadena, California, USA;7. Molecular Biology Institute, University of California, Los Angeles, California, USA;8. Division of Surgical Oncology, University of California, Los Angeles, California, USA;9. Department of Molecular and Medical Pharmacology, University of California, Los Angeles, California, USA;10. Department of Medicine, Hematology/Oncology, UCLA School of Medicine, University of California, Los Angeles, California, USA;11. Department of Pediatrics, Hematology/Oncology, UCLA School of Medicine, University of California, Los Angeles, California, USA |
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| Abstract: | Transduction and transplantation of human hematopoietic stem/progenitor cells (HSPC) with the genes for a T-cell receptor (TCR) that recognizes a tumor-associated antigen may lead to sustained long-term production of T cells expressing the TCR and confer specific antitumor activity. We evaluated this using a lentiviral vector (CCLc-MND-F5) carrying cDNA for a human TCR specific for an HLA-A*0201-restricted peptide of Melanoma Antigen Recognized by T cells (MART-1). CD34+ HSPC were transduced with the F5 TCR lentiviral vector or mock transduced and transplanted into neonatal NSG mice or NSG mice transgenic for human HLA-A*0201 (NSG-A2). Human CD8+ and CD4+ T cells expressing the human F5 TCR were present in the thymus, spleen, and peripheral blood after 4–5 months. Expression of human HLA-A*0201 in NSG-A2 recipient mice led to significantly increased numbers of human CD8+ and CD4+ T cells expressing the F5 TCR, compared with control NSG recipients. Transduction of the human CD34+ HSPC by the F5 TCR transgene caused a high degree of allelic exclusion, potently suppressing rearrangement of endogenous human TCR-β genes during thymopoiesis. In summary, we demonstrated the feasibility of engineering human HSPC to express a tumor-specific TCR to serve as a long-term source of tumor-targeted mature T cells for immunotherapy of melanoma. |
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