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Department of Hematology, Leiden University Medical Center, 2300 RC Leiden, Netherlands

Address correspondence to Mirjam H.M. Heemskerk, Department of Hematology, Leiden University Medical Center, C2-R, P.O. Box 9600, 2300 RC Leiden, Netherlands. Phone: 31-71-5262271; Fax: 31-71-5266755; email: m.h.m.heemskerk{at}lumc.nl

T cells directed against minor histocompatibility antigens (mHags) might be responsible for eradication of hematological malignancies after allogeneic stem cell transplantation. We investigated whether transfer of T cell receptors (TCRs) directed against mHags, exclusively expressed on hematopoietic cells, could redirect virus-specific T cells toward antileukemic reactivity, without the loss of their original specificity. Generation of T cells with dual specificity may lead to survival of these TCR-transferred T cells for prolonged periods of time in vivo due to transactivation of the endogenous TCR of the tumor-reactive T cells by the latent presence of viral antigens. Furthermore, TCR transfer into restricted T cell populations, which are nonself reactive, will minimize the risk of autoimmunity. We demonstrate that cytomegalovirus (CMV)-specific T cells can be efficiently reprogrammed into leukemia-reactive T cells by transfer of TCRs directed against the mHag HA-2. HA-2-TCR–transferred CMV-specific T cells derived from human histocompatibility leukocyte antigen (HLA)-A2⁺ or HLA-A2^– individuals exerted potent antileukemic as well as CMV reactivity, without signs of anti–HLA-A2 alloreactivity. The dual specificity of these mHag-specific, TCR-redirected virus-specific T cells opens new possibilities for the treatment of hematological malignancies of HLA-A2⁺ HA-2–expressing patients transplanted with HLA-A2–matched or –mismatched donors.

Key Words: T cell receptor • gene transfer • minor histocompatibility antigen • virus-specific T cells • leukemia reactive

Abbreviations used in this paper: NGF-R, truncated form of the nerve growth factor receptor; CML, chronic myeloid leukemia; DLI, donor lymphocyte infusion; EBV-LCL, EBV-transformed B cell; eGFP, enhanced green fluorescent protein; HPC, hematopoietic progenitor cell; MFI, mean fluorescence intensity; mHag, minor histocompatibility antigen; MSC, mesenchymal stem cell; PHA, phytohemagglutinin; PIA, progenitor cell inhibition assay.

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