Reprogramming of virus-specific T cells into leukemia-reactive T cells using T cell receptor gene transfer.
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.
Heemskerk
Mirjam H M
MH
Department of Hematology, Leiden University Medical Center, C2-R, P.O. Box 9600, 2300 RC, Netherlands. m.h.m.heemskerk@lumc.nl
Hoogeboom
Manja
M
Hagedoorn
Renate
R
Kester
Michel G D
MG
Willemze
Roel
R
Falkenburg
J H Frederik
JH
D000595:Amino Acid Sequence; D000956:Antigens, Viral / Q000235:genetics; D045744:Cell Line, Tumor; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D018014:Gene Transfer Techniques; D006801:Humans; D007938:Leukemia / Q000276:immunology*; D015778:Minor Histocompatibility Antigens / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology*; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology
D000956:Antigens, Viral; C080145:HA-2 antigen; D015778:Minor Histocompatibility Antigens; D009363:Neoplasm Proteins; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa