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Allelic Exclusion and Peripheral Reconstitution by TCR Transgenic T Cells Arising From Transduced Human Hematopoietic Stem/Progenitor Cells

Giannoni, Francesca and Hardee, Cinnamon L. and Wherley, Jennifer and Gschweng, Eric and Senadheera, Shantha and Kaufman, Michael L. and Chan, Rebecca and Bahner, Ingrid and Gersuk, Vivian and Wang, Xiaoyan and Gjertson, David and Baltimore, David and Witte, Owen N. and Economou, James S. and Ribas, Antoni and Kohn, Donald B. (2013) Allelic Exclusion and Peripheral Reconstitution by TCR Transgenic T Cells Arising From Transduced Human Hematopoietic Stem/Progenitor Cells. Molecular Therapy, 21 (5). pp. 1044-1054. ISSN 1525-0016. PMCID PMC3666644. https://resolver.caltech.edu/CaltechAUTHORS:20130702-113609364

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1038/mt.2013.8DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3666644/PubMed CentralArticle
ORCID:
AuthorORCID
Baltimore, David0000-0001-8723-8190
Witte, Owen N.0000-0003-4461-4533
Additional Information:© 2013 The American Society of Gene & Cell Therapy. Received 2 November 2012; accepted 27 December 2012; advance online publication 5 February 2013. This work was funded by the National Institutes of Health (PO1 CA132681, D Baltimore, PI), the Samuel Waxman Foundation (J. Economou, PI), the California Institute for Regenerative Medicine New Faculty Award 2 (RN2-00902-A. Ribas, PI), and the W.M. Keck Foundation (J Economou, PI) with support from the University of California, Los Angeles (UCLA), Eli & Edythe Broad Center of Regenerative Medicine & Stem Cell Research and the UCLA Jonsson Comprehensive Cancer Center. O.N.W. is an Investigator of the Howard Hughes Medical Institute. The services of the UCLA Immunogenetics Center, the Broad Stem Cell Research Center Flow Cytometry Core and the UCLA CFAR (AI028697)/JCCC Virology Core were used for these studies. We thank the nurses and Obstetric Residents at the UCLA Ronald Reagan Medical Center Labor and Delivery Center for obtaining umbilical cord blood units for this research. The other authors declared no conflict of interest.
Funders:
Funding AgencyGrant Number
NIHPO1 CA132681
Samuel Waxman FoundationUNSPECIFIED
California Institute for Regenerative Medicine (CIRM)RN2-00902-A
W. M. Keck FoundationUNSPECIFIED
UCLAUNSPECIFIED
Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell ResearchUNSPECIFIED
UCLA Jonsson Comprehensive Cancer CenterUNSPECIFIED
Issue or Number:5
PubMed Central ID:PMC3666644
Record Number:CaltechAUTHORS:20130702-113609364
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20130702-113609364
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:39185
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:02 Jul 2013 23:12
Last Modified:16 Apr 2020 18:43

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