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Blood, 1 November 2005, Vol. 106, No. 9, pp. 2995-3003. Prepublished online as a Blood First Edition Paper on July 19, 2005; DOI 10.1182/blood-2004-12-4906. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-12-4906v1 106/9/2995    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 Citing Articles via Google Scholar Google Scholar Articles by Moeller, M. Articles by Darcy, P. K. Search for Related Content PubMed PubMed Citation Articles by Moeller, M. Articles by Darcy, P. K. Related Collections Neoplasia Immunotherapy Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Adoptive transfer of gene-engineered CD4+ helper T cells induces potent primary and secondary tumor rejection Maria Moeller, Nicole M. Haynes, Michael H. Kershaw, Jacob T. Jackson, Michele W. L. Teng, Shayna E. Street, Loretta Cerutti, Stephen M. Jane, Joseph A. Trapani, Mark J. Smyth, and Phillip K. Darcy From the Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, CA; and Rotary Bone Marrow Research Laboratory, Royal Melbourne Hospital, Parkville, Victoria, Australia. Because CD4+ T cells play a key role in aiding cellular immune responses, we wanted to assess whether increasing numbers of gene-engineered antigen-restricted CD4+ T cells could enhance an antitumor response mediated by similarly gene-engineered CD8+ T cells. In this study, we have used retroviral transduction to generate erbB2-reactive mouse T-cell populations composed of various proportions of CD4+ and CD8+ cells and then determined the antitumor reactivity of these mixtures. Gene-modified CD4+ and CD8+ T cells were shown to specifically secrete Tc1 (T cytotoxic-1) or Tc2 cytokines, proliferate, and lyse erbB2+ tumor targets following antigen ligation in vitro. In adoptive transfer experiments using severe combined immunodeficient (scid) mice, we demonstrated that injection of equivalent numbers of antigenspecific engineered CD8+ and CD4+ T cells led to significant improvement in survival of mice bearing established lung metastases compared with transfer of unfractionated (largely CD8+) engineered T cells. Transferred CD4+ T cells had to be antigen-specific (not just activated) and secrete interferon (IFN-) to potentiate the antitumor effect. Importantly, antitumor responses in these mice correlated with localization and persistence of geneengineered T cells at the tumor site. Strikingly, mice that survived primary tumor challenge could reject a subsequent rechallenge. Overall, this study has highlighted the therapeutic potential of using combined transfer of antigen-specific gene-modified CD8+ and CD4+ T cells to significantly enhance T-cell adoptive transfer strategies for cancer therapy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Moeller, M. H. Kershaw, R. Cameron, J. A. Westwood, J. A. Trapani, M. J. Smyth, and P. K. Darcy Sustained Antigen-Specific Antitumor Recall Response Mediated by Gene-Modified CD4+ T Helper-1 and CD8+ T Cells Cancer Res., December 1, 2007; 67(23): 11428 - 11437. [Abstract] [Full Text] [PDF] C. M. Kowolik, M. S. Topp, S. Gonzalez, T. Pfeiffer, S. Olivares, N. Gonzalez, D. D. Smith, S. J. Forman, M. C. Jensen, and L. J.N. Cooper CD28 Costimulation Provided through a CD19-Specific Chimeric Antigen Receptor Enhances In vivo Persistence and Antitumor Efficacy of Adoptively Transferred T Cells. Cancer Res., November 15, 2006; 66(22): 10995 - 11004. [Abstract] [Full Text] [PDF] H.-R. Jiang, D. E. Gilham, K. Mulryan, N. Kirillova, R. E. Hawkins, and P. L. Stern Combination of Vaccination and Chimeric Receptor Expressing T Cells Provides Improved Active Therapy of Tumors J. Immunol., October 1, 2006; 177(7): 4288 - 4298. [Abstract] [Full Text] [PDF] R. A. Willemsen, Z. Sebestyen, C. Ronteltap, C. Berrevoets, J. Drexhage, and R. Debets CD8{alpha} Coreceptor to Improve TCR Gene Transfer to Treat Melanoma: Down-Regulation of Tumor-Specific Production of IL-4, IL-5, and IL-10 J. Immunol., July 15, 2006; 177(2): 991 - 998. [Abstract] [Full Text] [PDF]

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