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Blood, 16 July 2009, Vol. 114, No. 3, pp. 535-546. Prepublished online as a Blood First Edition Paper on May 18, 2009; DOI 10.1182/blood-2009-03-211714. This Article Full Text (PDF) All Versions of this Article: blood-2009-03-211714v1 114/3/535    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Johnson, L. A Articles by Rosenberg, S. A Search for Related Content PubMed PubMed Citation Articles by Johnson, L. A Articles by Rosenberg, S. A Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 18, 2009 Accepted May 5, 2009 Gene therapy with human and mouse T cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen Laura A Johnson, Richard A Morgan, Mark E Dudley, Lydie Cassard, James C Yang, Marybeth S Hughes, Udai S Kammula, Richard E Royal, Richard M Sherry, John R Wunderlich, Chyi-Chia R Lee, Nicholas P Restifo, Susan L Schwarz, Alexandria P Cogdill, Rachel J Bishop, Hung Kim, Carmen C Brewer, Susan F Rudy, Carter VanWaes, Jeremy L Davis, Aarti Mathur, Robert T Ripley, Debbie A Nathan, Carolyn M Laurencot, and Steven A Rosenberg* Surgery Branch, National Cancer Institute, Bethesda, MD, United States Laboratory of Pathology, National Cancer Institute, Bethesda, MD, United States Office of the Clinical Director, National Eye Institute, Bethesda, MD, United States Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders, Bethesda, MD, United States * Corresponding author; email: sar{at}nih.gov. Gene therapy of human cancer using genetically engineered autologous lymphocytes is dependent on the identification of highly reactive T cell receptors (TCR) with anti-tumor activity. We immunized HLA transgenic mice and also conducted high-throughput screening of human lymphocytes to generate TCR highly reactive to melanoma/melanocyte antigens. Genes encoding these TCR were engineered into retroviral vectors and used to transduce autologous peripheral lymphocytes administered to 36 patients with metastatic melanoma. Transduced patient lymphocytes were CD45RA- and CD45RO+ following ex-vivo expansion. After transfer in vivo the persisting transduced cells displayed a CD45RA+ and CD45RO- phenotype. Gene engineered cells persisted at high levels in the peripheral blood of all patients at one month after treatment, with responding patients demonstrating higher ex-vivo anti-tumor reactivity than non-responders. Objective cancer regressions were seen in 30% and 19% of patients who received the human or mouse TCR respectively. However, patients exhibited destruction of normal melanocytes in the skin, eye and ear, and sometimes required local steroid administration to successfully treat uveitis and hearing loss. Thus T cells expressing highly reactive TCR mediate cancer regression in humans and target rare cognate-antigen containing cells throughout the body, a finding that has important implications for the gene therapy of cancer. These studies were registered at www.clinicaltrials.gov under NCI-07-C-0174 and NCI-07-C-0175. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Okamoto, J. Mineno, H. Ikeda, H. Fujiwara, M. Yasukawa, H. Shiku, and I. Kato Improved Expression and Reactivity of Transduced Tumor-Specific TCRs in Human Lymphocytes by Specific Silencing of Endogenous TCR Cancer Res., December 1, 2009; 69(23): 9003 - 9011. [Abstract] [Full Text] [PDF] Y. Zhao, Q. J. Wang, S. Yang, J. N. Kochenderfer, Z. Zheng, X. Zhong, M. Sadelain, Z. Eshhar, S. A. Rosenberg, and R. A. Morgan A Herceptin-Based Chimeric Antigen Receptor with Modified Signaling Domains Leads to Enhanced Survival of Transduced T Lymphocytes and Antitumor Activity J. Immunol., November 1, 2009; 183(9): 5563 - 5574. [Abstract] [Full Text] [PDF] S. Wilde, D. Sommermeyer, B. Frankenberger, M. Schiemann, S. Milosevic, S. Spranger, H. Pohla, W. Uckert, D. H. Busch, and D. J. Schendel Dendritic cells pulsed with RNA encoding allogeneic MHC and antigen induce T cells with superior antitumor activity and higher TCR functional avidity Blood, September 3, 2009; 114(10): 2131 - 2139. [Abstract] [Full Text] [PDF] C. A. Klebanoff, Z. Yu, L. N. Hwang, D. C. Palmer, L. Gattinoni, and N. P. Restifo Programming tumor-reactive effector memory CD8+ T cells in vitro obviates the requirement for in vivo vaccination Blood, August 27, 2009; 114(9): 1776 - 1783. [Abstract] [Full Text] [PDF]

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