Vatakis, Dimitrios N. and Koya, Richard C. and Nixon, Christopher C. and Wei, Liu and Kim, Sohn G. and Avancena, Patricia and Bristol, Gregory and Baltimore, David and Kohn, Donald B. and Ribas, Antoni and Radu, Caius G. and Galic, Zoran and Zack, Jerome A. (2011) Antitumor activity from antigen-specific CD8 T cells generated in vivo from genetically engineered human hematopoietic stem cells. Proceedings of the National Academy of Sciences of the United States of America, 108 (51). E1408-E1416. ISSN 0027-8424 http://resolver.caltech.edu/CaltechAUTHORS:20120113-153637328
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The goal of cancer immunotherapy is the generation of an effective, stable, and self-renewing antitumor T-cell population. One such approach involves the use of high-affinity cancer-specific T-cell receptors in gene-therapy protocols. Here, we present the generation of functional tumor-specific human T cells in vivo from genetically modified human hematopoietic stem cells (hHSC) using a human/mouse chimera model. Transduced hHSC expressing an HLA-A*0201–restricted melanoma-specific T-cell receptor were introduced into humanized mice, resulting in the generation of a sizeable melanoma-specific naïve CD8^+ T-cell population. Following tumor challenge, these transgenic CD8^+ T cells, in the absence of additional manipulation, limited and cleared human melanoma tumors in vivo. Furthermore, the genetically enhanced T cells underwent proper thymic selection, because we did not observe any responses against non–HLA-matched tumors, and no killing of any kind occurred in the absence of a human thymus. Finally, the transduced hHSC established long-term bone marrow engraftment. These studies present a potential therapeutic approach and an important tool to understand better and to optimize the human immune response to melanoma and, potentially, to other types of cancer.
|Additional Information:||© 2011 National Academy of Sciences. Edited by Michael B. A. Oldstone, The Scripps Research Institute, La Jolla, CA, and approved November 2, 2011 (received for review September 15, 2011). Published online before print November 28, 2011. We thank Salehi Khosrowdad, Alvin Welch, Bernard Levin, and Larry Pang for their technical assistance and the University of California, Los Angeles (UCLA) AIDS Institute/UCLA Center for AIDS Research Mouse/Human Chimera Core and its director Dr. Scott Kitchen for the development and housing of BLT mice. This work was funded in part by National Institutes of Health (NIH) Grant P50 CA086306; California Institute for Regenerative Medicine (CIRM) Grants RC1-00149-1 (to J.A.Z.) and RS1-00203-1 (to Z.G.); CIRM New Faculty Award RN2-00902-1 and support from the California Institute of Technology-UCLA Joint Center for Translational Medicine (to A.R.); UCLA Center for AIDS Research NIH/National Institute of Allergy and Infectious Diseases Grant AI028697, and by UCLA AIDS Institute, and the CIRM Tools and Technology Award RT1-01126 (to C.G.R.). Author contributions: D.N.V. and J.A.Z. designed research; D.N.V., R.C.K., C.C.N., L.W., S.G.K., P.A., G.B., and C.G.R. performed research; R.C.K., D.B., D.B.K., A.R., C.G.R., and Z.G. contributed new reagents/analytic tools; D.N.V. and J.A.Z. analyzed data; and D.N.V., D.B., D.B.K., A.R., Z.G., and J.A.Z. wrote the paper.|
|Subject Keywords:||stem cell therapy; hematopoietic progenitors; T-cell engineering; tumor immunotherapy; BLT mice|
|Usage Policy:||No commercial reproduction, distribution, display or performance rights in this work are provided.|
|Deposited By:||Jason Perez|
|Deposited On:||17 Jan 2012 22:24|
|Last Modified:||17 Jan 2012 22:24|
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