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.

[1]  M. A. van der Hoorn,et al.  The progenitor cell inhibition assay to measure the anti-leukemic reactivity of T cell clones against acute and chronic myeloid leukemia. , 2003, Methods.

[2]  Els Goulmy,et al.  Hematopoiesis-restricted minor histocompatibility antigens HA-1- or HA-2-specific T cells can induce complete remissions of relapsed leukemia , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Niels Schaft,et al.  Peptide Fine Specificity of Anti-Glycoprotein 100 CTL Is Preserved Following Transfer of Engineered TCRαβ Genes Into Primary Human T Lymphocytes 1 , 2003, The Journal of Immunology.

[4]  J. Melo,et al.  Allorestricted cytotoxic T cells specific for human CD45 show potent antileukemic activity. , 2003, Blood.

[5]  M. Nishimura,et al.  Transfer of TCR Genes into Mature T Cells Is Accompanied by the Maintenance of Parental T Cell Avidity , 2003, The Journal of Immunology.

[6]  M. Kester,et al.  Generation of minor histocompatibility antigen HA-1-specific cytotoxic T cells restricted by nonself HLA molecules: a potential strategy to treat relapsed leukemia after HLA-mismatched stem cell transplantation. , 2002, Blood.

[7]  Hans J. Stauss,et al.  Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer , 2001, Nature Immunology.

[8]  T. Schumacher,et al.  Immunotherapy through TCR gene transfer , 2001, Nature Immunology.

[9]  F. Koning,et al.  Dual HLA class I and class II restricted recognition of alloreactive T lymphocytes mediated by a single T cell receptor complex , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[10]  G. Nolan,et al.  Retroviral transduction of a T cell receptor specific for an Epstein-Barr virus-encoded peptide. , 2001, Clinical immunology.

[11]  J. Altman,et al.  Peptide-MHC Class I Tetrameric Complexes Display Exquisite Ligand Specificity1 , 2000, The Journal of Immunology.

[12]  T. Kitamura,et al.  Functional Reconstitution of Class II MHC-Restricted T Cell Immunity Mediated by Retroviral Transfer of the αβ TCR Complex1 , 2000, The Journal of Immunology.

[13]  L. de Leij,et al.  Retargeting of a T cell line by anti MAGE-3/HLA-A2 alpha beta TCR gene transfer. , 2000, Anticancer research.

[14]  J. Goldman,et al.  Selective elimination of leukemic CD34(+) progenitor cells by cytotoxic T lymphocytes specific for WT1. , 2000, Blood.

[15]  R. Collins,et al.  Treatment of relapsed leukemia after unrelated donor marrow transplantation with unrelated donor leukocyte infusions. , 2000, Blood.

[16]  W. M. Smit,et al.  Complete remission of accelerated phase chronic myeloid leukemia by treatment with leukemia-reactive cytotoxic T lymphocytes. , 1999, Blood.

[17]  S. Rosenberg,et al.  Efficient transfer of a tumor antigen-reactive TCR to human peripheral blood lymphocytes confers anti-tumor reactivity. , 1999, Journal of immunology.

[18]  P. Moss,et al.  Tetrameric HLA class I–minor histocompatibility antigen peptide complexes demonstrate minor histocompatibility antigen-specific cytotoxic T lymphocytes in patients with graft-versus-host disease , 1999, Nature Medicine.

[19]  H. Rammensee,et al.  Alloreactivity as a source of high avidity peptide-specific human CTL. , 1999, Journal of immunology.

[20]  J. Falkenburg,et al.  T cells recognizing leukemic CD34(+) progenitor cells mediate the antileukemic effect of donor lymphocyte infusions for relapsed chronic myeloid leukemia after allogeneic stem cell transplantation. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[21]  H. Stauss,et al.  Generation of human tumor‐reactive cytotoxic T cells against peptides presented by non‐self HLA class I molecules , 1998, European journal of immunology.

[22]  G. Nolan,et al.  Inhibition of T Cell and Promotion of Natural Killer Cell Development by the Dominant Negative Helix Loop Helix Factor Id3 , 1997, The Journal of experimental medicine.

[23]  C. Bordignon,et al.  Cell-surface marking of CD(34+)-restricted phenotypes of human hematopoietic progenitor cells by retrovirus-mediated gene transfer. , 1997, Human gene therapy.

[24]  J. Falkenburg,et al.  Cytotoxic T‐lymphocyte (CTL) responses against acute or chronic myeloid leukemia , 1997, Immunological reviews.

[25]  Robert H. Collins,et al.  Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  G. Nolan,et al.  Episomal vectors rapidly and stably produce high-titer recombinant retrovirus. , 1996, Human gene therapy.

[27]  David A. Williams,et al.  Colocalization of retrovirus and target cells on specific fibronectin fragments increases genetic transduction of mammalian cells , 1996, Nature Medicine.

[28]  Tak W. Mak,et al.  Human T-cell receptor variable gene segment families , 1995, Immunogenetics.

[29]  A. Bakker,et al.  Tissue distribution of human minor histocompatibility antigens. Ubiquitous versus restricted tissue distribution indicates heterogeneity among human cytotoxic T lymphocyte-defined non-MHC antigens. , 1992, Journal of immunology.

[30]  J. J. Rood,et al.  Immunogenetics of human minor histocompatibility antigens: their polymorphism and immunodominance , 2004, Immunogenetics.

[31]  T. Kitamura,et al.  Functional reconstitution of class II MHC-restricted T cell immunity mediated by retroviral transfer of the alpha beta TCR complex. , 2000, Journal of immunology.

[32]  W. Wilmanns,et al.  Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. , 1990, Blood.

[33]  J. McCubrey,et al.  Transfer of specificity by murine alpha and beta T-cell receptor genes. , 1986, Nature.