SEARCH:   Advanced

This Article Full Text Full Text (PDF) 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 Gottschalk, S. Articles by Rooney, C. M. Search for Related Content PubMed PubMed Citation Articles by Gottschalk, S. Articles by Rooney, C. M. Related Collections Immunotherapy Plenary Papers Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 February 2001, Vol. 97, No. 4, pp. 835-843 PLENARY PAPER An Epstein-Barr virus deletion mutant associated with fatal lymphoproliferative disease unresponsive to therapy with virus-specific CTLs Stephen Gottschalk, Catherine Y. C. Ng, Margot Perez, Colton A. Smith, Clare Sample, Malcolm K. Brenner, Helen E. Heslop, and Cliona M. Rooney From the Center for Cell and Gene Therapy, Department of Pediatrics, Baylor College of Medicine, Houston, TX; and St Jude Children's Research Hospital, Memphis, TN. There is a growing interest in using antigen-specific T cells for the treatment of human malignancy. For example, adoptive transfer of Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) has been effective prophylaxis and treatment of EBV-associated lymphoproliferative disease in immunocompromised patients. For all immunotherapies, however, there has been a hypothetical concern that mutations in tumor-specific antigens may lead to tumor escape. We now demonstrate that such events may indeed occur, with lethal outcome. A patient who developed lymphoma after marrow transplantation received donor-derived, EBV-specific CTLs but died with progressive disease. The tumor cells proved substantially less sensitive to cytolysis than the EBV-transformed B-cell line used for CTL generation. The major cytolytic activity of the donor CTL was directed against 2 HLA-A11-restricted epitopes in the viral EBNA-3B antigen. Sequence analysis of this gene in the tumor virus revealed a 245-base pair deletion, which removed these 2 CTL epitopes. Hence, the viral antigen in the tumor had mutated in a way that allowed escape from CTLs. Analysis of EBV polymorphisms demonstrated that before CTL infusion, more than one virus was present, including a virus with wild-type EBNA-3B. After CTL infusion, only the virus with the EBNA-3B deletion could be detected, suggesting that the infused CTLs had selected a resistant strain in vivo. Such an occurrence, even when polyclonal CTL lines are used against genetically stable virus antigens, suggests that escape mutants may be a serious problem when CTL therapy is directed against more unstable tumor cell-derived targets. © 2001 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. M. Bollard, S. Gottschalk, A. M. Leen, H. Weiss, K. C. Straathof, G. Carrum, M. Khalil, M.-f. Wu, M. H. Huls, C.-C. Chang, et al. Complete responses of relapsed lymphoma following genetic modification of tumor-antigen presenting cells and T-lymphocyte transfer Blood, October 15, 2007; 110(8): 2838 - 2845. [Abstract] [Full Text] [PDF] B. Savoldo, J. A. Goss, M. M. Hammer, L. Zhang, T. Lopez, A. P. Gee, Y.-F. Lin, R. E. Quiros-Tejeira, P. Reinke, S. Schubert, et al. Treatment of solid organ transplant recipients with autologous Epstein Barr virus-specific cytotoxic T lymphocytes (CTLs) Blood, November 1, 2006; 108(9): 2942 - 2949. [Abstract] [Full Text] [PDF] R. D. Feigin Prospects for the Future of Child Health Through Research JAMA, September 21, 2005; 294(11): 1373 - 1379. [Abstract] [Full Text] [PDF] K. C. Straathof, A. M. Leen, E. L. Buza, G. Taylor, M. H. Huls, H. E. Heslop, C. M. Rooney, and C. M. Bollard Characterization of Latent Membrane Protein 2 Specificity in CTL Lines from Patients with EBV-Positive Nasopharyngeal Carcinoma and Lymphoma J. Immunol., September 15, 2005; 175(6): 4137 - 4147. [Abstract] [Full Text] [PDF] A. Chen, M. DiVisconte, X. Jiang, C. Quink, and F. Wang Epstein-Barr Virus with the Latent Infection Nuclear Antigen 3B Completely Deleted Is Still Competent for B-Cell Growth Transformation In Vitro J. Virol., April 1, 2005; 79(7): 4506 - 4509. [Abstract] [Full Text] [PDF] W. J. Simmons, M. Koneru, M. Mohindru, R. Thomas, S. Cutro, P. Singh, R. H. DeKruyff, G. Inghirami, A. J. Coyle, B. S. Kim, et al. Tim-3+ T-bet+ Tumor-Specific Th1 Cells Colocalize with and Inhibit Development and Growth of Murine Neoplasms J. Immunol., February 1, 2005; 174(3): 1405 - 1415. [Abstract] [Full Text] [PDF] H. E. Heslop Biology and Treatment of Epstein-Barr Virus-Associated Non-Hodgkin Lymphomas Hematology, January 1, 2005; 2005(1): 260 - 266. [Abstract] [Full Text] [PDF] E. G. M. Berkhoff, A. C. M. Boon, N. J. Nieuwkoop, R. A. M. Fouchier, K. Sintnicolaas, A. D. M. E. Osterhaus, and G. F. Rimmelzwaan A Mutation in the HLA-B*2705-Restricted NP383-391 Epitope Affects the Human Influenza A Virus-Specific Cytotoxic T-Lymphocyte Response In Vitro J. Virol., May 15, 2004; 78(10): 5216 - 5222. [Abstract] [Full Text] [PDF] R. H. Edwards, D. Sitki-Green, D. T. Moore, and N. Raab-Traub Potential Selection of LMP1 Variants in Nasopharyngeal Carcinoma J. Virol., January 15, 2004; 78(2): 868 - 881. [Abstract] [Full Text] [PDF] J. D. Roback, M. S. Hossain, L. Lezhava, J. W. Gorechlad, S. A. Alexander, D. L. Jaye, S. Mittelstaedt, S. Talib, J. E. Hearst, C. D. Hillyer, et al. Allogeneic T Cells Treated with Amotosalen Prevent Lethal Cytomegalovirus Disease without Producing Graft-versus-Host Disease Following Bone Marrow Transplantation J. Immunol., December 1, 2003; 171(11): 6023 - 6031. [Abstract] [Full Text] [PDF] K. Matsui, L. A. O'Mara, and P. M. Allen Successful elimination of large established tumors and avoidance of antigen-loss variants by aggressive adoptive T cell immunotherapy Int. Immunol., July 1, 2003; 15(7): 797 - 805. [Abstract] [Full Text] [PDF] S. Gottschalk, O. L. Edwards, U. Sili, M. H. Huls, T. Goltsova, A. R. Davis, H. E. Heslop, and C. M. Rooney Generating CTLs against the subdominant Epstein-Barr virus LMP1 antigen for the adoptive immunotherapy of EBV-associated malignancies Blood, March 1, 2003; 101(5): 1905 - 1912. [Abstract] [Full Text] [PDF] K. Kuzushima, N. Hayashi, A. Kudoh, Y. Akatsuka, K. Tsujimura, Y. Morishima, and T. Tsurumi Tetramer-assisted identification and characterization of epitopes recognized by HLA A*2402-restricted Epstein-Barr virus-specific CD8+ T cells Blood, February 15, 2003; 101(4): 1460 - 1468. [Abstract] [Full Text] [PDF] K. C.M. Straathof, C. M. Bollard, C. M. Rooney, and H. E. Heslop Immunotherapy for Epstein-Barr Virus-Associated Cancers in Children Oncologist, February 1, 2003; 8(1): 83 - 98. [Abstract] [Full Text] [PDF] H. E. Heslop, F. K. Stevenson, and J. J. Molldrem Immunotherapy of Hematologic Malignancy Hematology, January 1, 2003; 2003(1): 331 - 349. [Abstract] [Full Text] [PDF] J. W. J. van Esser, H. G. M. Niesters, B. van der Holt, E. Meijer, A. D. M. E. Osterhaus, J. W. Gratama, L. F. Verdonck, B. Lowenberg, and J. J. Cornelissen Prevention of Epstein-Barr virus-lymphoproliferative disease by molecular monitoring and preemptive rituximab in high-risk patients after allogeneic stem cell transplantation Blood, May 29, 2002; 99(12): 4364 - 4369. [Abstract] [Full Text] [PDF] Q. Tao, J. Yang, H. Huang, L. J. Swinnen, and R. F. Ambinder Conservation of Epstein-Barr Virus Cytotoxic T-Cell Epitopes in Posttransplant Lymphomas : Implications for Immune Therapy Am. J. Pathol., May 1, 2002; 160(5): 1839 - 1845. [Abstract] [Full Text] [PDF] C. M. Bollard, C. Rossig, M. J. Calonge, M. H. Huls, H.-J. Wagner, J. Massague, M. K. Brenner, H. E. Heslop, and C. M. Rooney Adapting a transforming growth factor beta -related tumor protection strategy to enhance antitumor immunity Blood, May 1, 2002; 99(9): 3179 - 3187. [Abstract] [Full Text] [PDF] C. Rossig, C. M. Bollard, J. G. Nuchtern, C. M. Rooney, and M. K. Brenner Epstein-Barr virus-specific human T lymphocytes expressing antitumor chimeric T-cell receptors: potential for improved immunotherapy Blood, March 15, 2002; 99(6): 2009 - 2016. [Abstract] [Full Text] [PDF] A. C. M. Boon, G. de Mutsert, Y. M. F. Graus, R. A. M. Fouchier, K. Sintnicolaas, A. D. M. E. Osterhaus, and G. F. Rimmelzwaan Sequence Variation in a Newly Identified HLA-B35-Restricted Epitope in the Influenza A Virus Nucleoprotein Associated with Escape from Cytotoxic T Lymphocytes J. Virol., March 1, 2002; 76(5): 2567 - 2572. [Abstract] [Full Text] [PDF] B. Savoldo, M. L. Cubbage, A. G. Durett, J. Goss, M. H. Huls, Z. Liu, L. Teresita, A. P. Gee, P. D. Ling, M. K. Brenner, et al. Generation of EBV-Specific CD4+ Cytotoxic T Cells from Virus Naive Individuals J. Immunol., January 15, 2002; 168(2): 909 - 918. [Abstract] [Full Text] [PDF]

	Blood Online is supported in part by Genentech BioOncology and Biogen Idec
	Copyright © 2001 by American Society of Hematology         Online ISSN: 1528-0020