title: Allelic exclusion and peripheral reconstitution by TCR transgenic T cells arising from transduced human hematopoietic stem/progenitor cells.
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.
authors: Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, California, USA. dkohn@mednet.ucla.edu
authors: Francesca
authors: F
authors: Giannoni
authors: Cinnamon L
authors: CL
authors: Hardee
authors: Jennifer
authors: J
authors: Wherley
authors: Eric
authors: E
authors: Gschweng
authors: Shantha
authors: S
authors: Senadheera
authors: Michael L
authors: ML
authors: Kaufman
authors: Rebecca
authors: R
authors: Chan
authors: Ingrid
authors: I
authors: Bahner
authors: Vivian
authors: V
authors: Gersuk
authors: Xiaoyan
authors: X
authors: Wang
authors: David
authors: D
authors: Gjertson
authors: David
authors: D
authors: Baltimore
authors: Owen N
authors: ON
authors: Witte
authors: James S
authors: JS
authors: Economou
authors: Antoni
authors: A
authors: Ribas
authors: Donald B
authors: DB
authors: Kohn
mesh_terms: D000483:Alleles; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D001773:Blood Cells / Q000166:cytology / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D022801:Complementarity Determining Regions / Q000737:chemistry / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D023061:Gene Order; D005822:Genetic Vectors / Q000235:genetics; D006085:Graft Survival; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D016086:Lentivirus / Q000235:genetics; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000276:immunology / Q000628:therapy; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D060168:Thymocytes / Q000166:cytology / Q000378:metabolism; D014161:Transduction, Genetic; D014183:Transplantation, Heterologous
chemical_list: D018952:Antigens, CD34; D022801:Complementarity Determining Regions; D018984:Epitopes, T-Lymphocyte; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D007371:Interferon-gamma
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