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CMV-Specific TCR-Transgenic T Cells for Immunotherapy¹

Andrea Schub,^* Ingrid G. Schuster, Wolfgang Hammerschmidt,^* and Andreas Moosmann^2*

^*Department of Gene Vectors, Helmholtz Zentrum München, Munich, Germany; Institute of Molecular Immunology, Helmholtz Zentrum München, Munich, Germany; and Clinical Cooperation Group Molecular Oncology, Helmholtz Zentrum München and Ludwig-Maximilians-Universität München, Munich, Germany

Reactivation of CMV can cause severe disease after allogeneic hemopoietic stem cell transplantation. Adoptive T cell therapy was successfully used for patients who had received transplants from CMV-positive donors. However, patients with transplants from CMV-negative donors are at highest risk, and an adoptive therapy is missing because CMV-specific T cells are not available from such donors. To address this problem, we used retroviral transfer of CMV-specific TCR genes. We generated CMV-specific T cell clones of several HLA restrictions recognizing the endogenously processed Ag pp65. The genes of four TCRs were cloned and transferred to primary T cells from CMV-negative donors. These CMV-TCR-transgenic T cells displayed a broad spectrum of important effector functions (secretion of IFN- and IL-2, cytotoxicity, proliferation) in response to endogenously processed pp65 and could be enriched and expanded by strictly Ag-specific stimulation. Expansion of engineered T cells was accompanied by an increase in specific effector functions, indicating that the transferred specificity is stable and fully functional. Hence, we expect these CMV-TCR-transgenic T cells to be effective in controlling acute CMV disease and establishing an antiviral memory.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Deutsche Forschungsgemeinschaft Grants SFB-Transregio 36 and SFB 455 and by the Helmholtz Alliance on Immunotherapy of Cancer funded by the Initiative and Networking Fund of the Helmholtz Association.

² Address correspondence and reprint requests to Dr. Andreas Moosmann, Clinical Cooperation Group Molecular Oncology, Helmholtz Zentrum München, Marchioninistrasse 25, 81377 Munich, Germany. E-mail address: andreas.moosmann{at}helmholtz-muenchen.de

³ Abbreviations used in this paper: allo-HSCT, allogeneic hemopoietic stem cell transplantation; mLCL, mini-lymphoblastoid cell line; BBL, CD40-activated B blast; J76, Jurkat 76; J76CD8, Jurkat 76 stably expressing human CD8; MLV, murine leukemia virus; D, donor; R, recipient; CD62L, L-selectin.