Reprogramming of virus-specific T cells into leukemia-reactive T cells using T cell receptor gene transfer
MHM Heemskerk, M Hoogeboom… - The Journal of …, 2004 - rupress.org
MHM Heemskerk, M Hoogeboom, R Hagedoorn, MGD Kester, R Willemze, JHF Falkenburg
The Journal of experimental medicine, 2004•rupress.orgT 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 …
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 …
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.
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