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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 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 Citation Map 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 Google Scholar Articles by Johnson, L. A. Articles by Rosenberg, S. A. PubMed PubMed Citation Articles by Johnson, L. A. Articles by Rosenberg, S. A. Related Collections Immunobiology Clinical Trials and Observations Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen Laura A. Johnson1, Richard A. Morgan1, Mark E. Dudley1, Lydie Cassard1, James C. Yang1, Marybeth S. Hughes1, Udai S. Kammula1, Richard E. Royal1, Richard M. Sherry1, John R. Wunderlich1, Chyi-Chia R. Lee2, Nicholas P. Restifo1, Susan L. Schwarz1, Alexandria P. Cogdill1, Rachel J. Bishop3, Hung Kim4, Carmen C. Brewer4, Susan F. Rudy4, Carter VanWaes4, Jeremy L. Davis1, Aarti Mathur1, Robert T. Ripley1, Debbie A. Nathan1, Carolyn M. Laurencot1, and Steven A. Rosenberg1 1 Surgery Branch, National Cancer Institute (NCI), Hatfield Clinical Research Center, Bethesda, MD; 2 Laboratory of Pathology, NCI, Bethesda, MD; 3 Office of the Clinical Director, National Eye Institute, Bethesda, MD; and 4 Otolaryngology Branch, National Institute on Deafness and Other Communication Disorders, Bethesda, MD Gene therapy of human cancer using genetically engineered lymphocytes is dependent on the identification of highly reactive T-cell receptors (TCRs) with antitumor activity. We immunized transgenic mice and also conducted high-throughput screening of human lymphocytes to generate TCRs highly reactive to melanoma/melanocyte antigens. Genes encoding these TCRs 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+ after ex vivo expansion. After infusion, the persisting cells displayed a CD45RA+ and CD45RO– phenotype. Gene-engineered cells persisted at high levels in the blood of all patients 1 month after treatment, responding patients with higher ex vivo antitumor reactivity than nonresponders. 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 treat uveitis and hearing loss. Thus, T cells expressing highly reactive TCRs mediate cancer regression in humans and target rare cognate–antigen-containing cells throughout the body, a finding with important implications for the gene therapy of cancer. This trial was registered at www.ClinicalTrials.gov as 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: 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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