Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Antigen-specific cellular immunotherapy of leukemia

Abstract

Advances in cellular and molecular immunology have led to the characterization of leukemia-specific T-cell antigens and to the development of strategies for effective augmentation of T-cell immunity in leukemia patients. While several leukemia-related antigens have been identified, this review focuses on the Wilms' tumor 1 (WT1) antigen and the proteinase 3 (Pr3) antigen that are overexpressed in leukemic cells and are already being used in the clinical setting. Moreover, WT1 is also overexpressed in a vast number of nonhematological solid tumors, thereby expanding its use as a promising target for cancer vaccines. Examples of spontaneous immune responses against WT1 and Pr3 in leukemia patients are presented and the potential of WT1 and Pr3 for adoptive T-cell immunotherapy of leukemia is discussed. We also elaborate on the use of professional antigen-presenting cells loaded with mRNA encoding WT1 exploiting the advantage of broad HLA coverage for therapeutic vaccination purposes. Finally, the summarized data underscore the potential of WT1 for the manipulation of T-cell immunity in leukemia and in cancer in general, that will likely pave the way for the development of more effective and generic cancer vaccines.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Ho VT, Soiffer RJ . The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation. Blood 2001; 98: 3192–3204.

    CAS  PubMed  Google Scholar 

  2. Gale RP, Horowitz MM, Ash RC, Champlin RE, Goldman JM, Rimm AA et al. Identical-twin bone marrow transplants for leukemia. Ann Intern Med 1994; 120: 646–652.

    Article  CAS  PubMed  Google Scholar 

  3. Apperley JF, Jones L, Hale G, Waldmann H, Hows J, Rombos Y et al. Bone marrow transplantation for patients with chronic myeloid leukaemia: T-cell depletion with Campath-1 reduces the incidence of graft-versus-host disease but may increase the risk of leukaemic relapse. Bone Marrow Transplant 1986; 1: 53–66.

    CAS  PubMed  Google Scholar 

  4. Goldman JM, Gale RP, Horowitz MM, Biggs JC, Champlin RE, Gluckman E et al. Bone marrow transplantation for chronic myelogenous leukemia in chronic phase. Increased risk for relapse associated with T-cell depletion. Ann Intern Med 1988; 108: 806–814.

    CAS  PubMed  Google Scholar 

  5. Falkenburg JH, Smit WM, Willemze R . Cytotoxic T-lymphocyte (CTL) responses against acute or chronic myeloid leukemia. Immunol Rev 1997; 157: 223–230.

    CAS  PubMed  Google Scholar 

  6. Clark RE, Dodi IA, Hill SC, Lill JR, Aubert G, Macintyre AR et al. Direct evidence that leukemic cells present HLA-associated immunogenic peptides derived from the BCR-ABL b3a2 fusion protein. Blood 2001; 98: 2887–2893.

    CAS  PubMed  Google Scholar 

  7. Clark RE, Christmas SE . BCR-ABL fusion peptides and cytotoxic T cells in chronic myeloid leukaemia. Leuk Lymphoma 2001; 42: 871–880.

    CAS  PubMed  Google Scholar 

  8. Yotnda P, Garcia F, Peuchmaur M, Grandchamp B, Duval M, Lemonnier F et al. Cytotoxic T cell response against the chimeric ETV6-AML1 protein in childhood acute lymphoblastic leukemia. J Clin Invest 1998; 102: 455–462.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Osman Y, Takahashi M, Zheng Z, Toba K, Liu A, Furukawa T et al. Dendritic cells stimulate the expansion of PML-RAR alpha specific cytotoxic T-lymphocytes: its applicability for antileukemia immunotherapy. J Exp Clin Cancer Res 1999; 18: 485–492.

    CAS  PubMed  Google Scholar 

  10. Ohminami H, Yasukawa M, Kaneko S, Yakushijin Y, Abe Y, Kasahara Y et al. Fas-independent and nonapoptotic cytotoxicity mediated by a human CD4(+) T-cell clone directed against an acute myelogenous leukemia-associated DEK-CAN fusion peptide. Blood 1999; 93: 925–935.

    CAS  PubMed  Google Scholar 

  11. Meyerson M, Counter CM, Eaton EN, Ellisen LW, Steiner P, Caddle SD et al. hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell 1997; 90: 785–795.

    CAS  PubMed  Google Scholar 

  12. Nakamura TM, Morin GB, Chapman KB, Weinrich SL, Andrews WH, Lingner J et al. Telomerase catalytic subunit homologs from fission yeast and human. Science 1997; 277: 955–959.

    CAS  PubMed  Google Scholar 

  13. Kelland LR . Overcoming the immortality of tumour cells by telomere and telomerase based cancer therapeutics – current status and future prospects. Eur J Cancer 2005; 41: 971–979.

    CAS  PubMed  Google Scholar 

  14. Arai J, Yasukawa M, Ohminami H, Kakimoto M, Hasegawa A, Fujita S . Identification of human telomerase reverse transcriptase-derived peptides that induce HLA-A24-restricted antileukemia cytotoxic T lymphocytes. Blood 2001; 97: 2903–2907.

    CAS  PubMed  Google Scholar 

  15. Su Z, Dannull J, Yang BK, Dahm P, Coleman D, Yancey D et al. Telomerase mRNA-transfected dendritic cells stimulate antigen-specific CD8+ and CD4+ T cell responses in patients with metastatic prostate cancer. J Immunol 2005; 174: 3798–3807.

    CAS  PubMed  Google Scholar 

  16. Ambrosini G, Adida C, Altieri DC . A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 1997; 3: 917–921.

    CAS  PubMed  Google Scholar 

  17. Andersen MH, Pedersen LO, Becker JC, Straten PT . Identification of a cytotoxic T lymphocyte response to the apoptosis inhibitor protein survivin in cancer patients. Cancer Res 2001; 61: 869–872.

    CAS  PubMed  Google Scholar 

  18. Zeis M, Siegel S, Wagner A, Schmitz M, Marget M, Kuhl-Burmeister R et al. Generation of cytotoxic responses in mice and human individuals against hematological malignancies using survivin-RNA-transfected dendritic cells. J Immunol 2003; 170: 5391–5397.

    CAS  PubMed  Google Scholar 

  19. Schmidt SM, Schag K, Muller MR, Weck MM, Appel S, Kanz L et al. Survivin is a shared tumor-associated antigen expressed in a broad variety of malignancies and recognized by specific cytotoxic T cells. Blood 2003; 102: 571–576.

    CAS  PubMed  Google Scholar 

  20. Maecker B, Sherr DH, Vonderheide RH, Bergwelt-Baildon MS, Hirano N, Anderson KS et al. The shared tumor-associated antigen cytochrome P450 1B1 is recognized by specific cytotoxic T cells. Blood 2003; 102: 3287–3294.

    CAS  PubMed  Google Scholar 

  21. Maecker B, Bergwelt-Baildon MS, Sherr DH, Nadler LM, Schultze JL . Identification of a new HLA-A*0201-restricted cryptic epitope from CYP1B1. Int J Cancer 2005; 115: 333–336.

    CAS  PubMed  Google Scholar 

  22. Siegel S, Wagner A, Kabelitz D, Marget M, Coggin Jr J, Barsoum A et al. Induction of cytotoxic T-cell responses against the oncofetal antigen-immature laminin receptor for the treatment of hematologic malignancies. Blood 2003; 102: 4416–4423.

    CAS  PubMed  Google Scholar 

  23. Fujiwara H, El Ouriaghli F, Grube M, Price DA, Rezvani K, Gostick E et al. Identification and in vitro expansion of CD4+ and CD8+ T cells specific for human neutrophil elastase. Blood 2004; 103: 3076–3083.

    CAS  PubMed  Google Scholar 

  24. Gao L, Bellantuono I, Elsasser A, Marley SB, Gordon MY, Goldman JM et al. Selective elimination of leukemic CD34(+) progenitor cells by cytotoxic T lymphocytes specific for WT1. Blood 2000; 95: 2198–2203.

    CAS  PubMed  Google Scholar 

  25. Gaiger A, Reese V, Disis ML, Cheever MA . Immunity to WT1 in the animal model and in patients with acute myeloid leukemia. Blood 2000; 96: 1480–1489.

    CAS  PubMed  Google Scholar 

  26. Oka Y, Elisseeva OA, Tsuboi A, Ogawa H, Tamaki H, Li H et al. Human cytotoxic T-lymphocyte responses specific for peptides of the wild-type Wilms' tumor gene (WT1 ) product. Immunogenetics 2000; 51: 99–107.

    CAS  PubMed  Google Scholar 

  27. Ohminami H, Yasukawa M, Fujita S . HLA class I-restricted lysis of leukemia cells by a CD8(+) cytotoxic T-lymphocyte clone specific for WT1 peptide. Blood 2000; 95: 286–293.

    CAS  PubMed  Google Scholar 

  28. Molldrem JJ, Clave E, Jiang YZ, Mavroudis D, Raptis A, Hensel N et al. Cytotoxic T lymphocytes specific for a nonpolymorphic proteinase 3 peptide preferentially inhibit chronic myeloid leukemia colony-forming units. Blood 1997; 90: 2529–2534.

    CAS  PubMed  Google Scholar 

  29. Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA et al. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell 1990; 60: 509–520.

    CAS  PubMed  Google Scholar 

  30. Gessler M, Poustka A, Cavenee W, Neve RL, Orkin SH, Bruns GA . Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping. Nature 1990; 343: 774–778.

    CAS  PubMed  Google Scholar 

  31. Pritchard JK, Fleming S, Davidson D, Bickmore W, Porteous D, Gosden C et al. The candidate Wilms' tumour gene is involved in genitourinary development. Nature 1990; 346: 194–197.

    Google Scholar 

  32. Pelletier J, Schalling M, Buckler AJ, Rogers A, Haber DA, Housman D . Expression of the Wilms' tumor gene WT1 in the murine urogenital system. Genes Dev 1991; 5: 1345–1356.

    CAS  PubMed  Google Scholar 

  33. Armstrong JF, Pritchard JK, Bickmore WA, Hastie ND, Bard JB . The expression of the Wilms' tumour gene, WT1, in the developing mammalian embryo. Mech Dev 1993; 40: 85–97.

    CAS  PubMed  Google Scholar 

  34. Miwa H, Beran M, Saunders GF . Expression of the Wilms' tumor gene (WT1) in human leukemias. Leukemia 1992; 6: 405–409.

    CAS  PubMed  Google Scholar 

  35. Miyagi T, Ahuja H, Kubota T, Kubonishi I, Koeffler HP, Miyoshi I . Expression of the candidate Wilms' tumor gene, WT1, in human leukemia cells. Leukemia 1993; 7: 970–977.

    CAS  PubMed  Google Scholar 

  36. Menssen HD, Renkl HJ, Rodeck U, Maurer J, Notter M, Schwartz S et al. Presence of Wilms' tumor gene (wt1) transcripts and the WT1 nuclear protein in the majority of human acute leukemias. Leukemia 1995; 9: 1060–1067.

    CAS  PubMed  Google Scholar 

  37. Oji Y, Ogawa H, Tamaki H, Oka Y, Tsuboi A, Kim EH et al. Expression of the Wilms' tumor gene WT1 in solid tumors and its involvement in tumor cell growth. Jpn J Cancer Res 1999; 90: 194–204.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Yamagami T, Sugiyama H, Inoue K, Ogawa H, Tatekawa T, Hirata M et al. Growth inhibition of human leukemic cells by WT1 (Wilms tumor gene) antisense oligodeoxynucleotides: implications for the involvement of WT1 in leukemogenesis. Blood 1996; 87: 2878–2884.

    CAS  PubMed  Google Scholar 

  39. Inoue K, Ogawa H, Yamagami T, Soma T, Tani Y, Tatekawa T et al. Long-term follow-up of minimal residual disease in leukemia patients by monitoring WT1 (Wilms tumor gene) expression levels. Blood 1996; 88: 2267–2278.

    CAS  PubMed  Google Scholar 

  40. Inoue K, Sugiyama H, Ogawa H, Nakagawa M, Yamagami T, Miwa H et al. WT1 as a new prognostic factor and a new marker for the detection of minimal residual disease in acute leukemia. Blood 1994; 84: 3071–3079.

    CAS  PubMed  Google Scholar 

  41. Inoue K, Tamaki H, Ogawa H, Oka Y, Soma T, Tatekawa T et al. Wilms' tumor gene (WT1) competes with differentiation-inducing signal in hematopoietic progenitor cells. Blood 1998; 91: 2969–2976.

    CAS  PubMed  Google Scholar 

  42. Bergmann L, Miething C, Maurer U, Brieger J, Karakas T, Weidmann E et al. High levels of Wilms' tumor gene (wt1) mRNA in acute myeloid leukemias are associated with a worse long-term outcome. Blood 1997; 90: 1217–1225.

    CAS  PubMed  Google Scholar 

  43. Svedberg H, Chylicki K, Baldetorp B, Rauscher III FJ, Gullberg U . Constitutive expression of the Wilms' tumor gene (WT1) in the leukemic cell line U937 blocks parts of the differentiation program. Oncogene 1998; 16: 925–932.

    CAS  PubMed  Google Scholar 

  44. Silberstein GB, Van Horn K, Strickland P, Roberts Jr CT, Daniel CW . Altered expression of the WT1 Wilms tumor suppressor gene in human breast cancer. Proc Natl Acad Sci USA 1997; 94: 8132–8137.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Loeb DM, Evron E, Patel CB, Sharma PM, Niranjan B, Buluwela L et al. Wilms' tumor suppressor gene (WT1) is expressed in primary breast tumors despite tumor-specific promoter methylation. Cancer Res 2001; 61: 921–925.

    CAS  PubMed  Google Scholar 

  46. Menssen HD, Bertelmann E, Bartelt S, Schmidt RA, Pecher G, Schramm K et al. Wilms' tumor gene (WT1) expression in lung cancer, colon cancer and glioblastoma cell lines compared to freshly isolated tumor specimens. J Cancer Res Clin Oncol 2000; 126: 226–232.

    CAS  PubMed  Google Scholar 

  47. Koesters R, Linnebacher M, Coy JF, Germann A, Schwitalle Y, Findeisen P et al. WT1 is a tumor-associated antigen in colon cancer that can be recognized by in vitro stimulated cytotoxic T cells. Int J Cancer 2004; 109: 385–392.

    CAS  PubMed  Google Scholar 

  48. van der Geld YM, Limburg PC, Kallenberg CG . Proteinase 3, Wegener's autoantigen: from gene to antigen. J Leukoc Biol 2001; 69: 177–190.

    CAS  PubMed  Google Scholar 

  49. Wu CH, Gordon J, Rastegar M, Ogretmen B, Safa AR . Proteinase-3, a serine protease which mediates doxorubicin-induced apoptosis in the HL-60 leukemia cell line, is downregulated in its doxorubicin-resistant variant. Oncogene 2002; 21: 5160–5174.

    CAS  PubMed  Google Scholar 

  50. Muller-Berat N, Minowada J, Tsuji-Takayama K, Drexler H, Lanotte M, Wieslander J et al. The phylogeny of proteinase 3/myeloblastin, the autoantigen in Wegener's granulomatosis, and myeloperoxidase as shown by immunohistochemical studies on human leukemic cell lines. Clin Immunol Immunopathol 1994; 70: 51–59.

    CAS  PubMed  Google Scholar 

  51. Fujiwara H, Melenhorst JJ, El Ouriaghli F, Kajigaya S, Grube M, Sconocchia G et al. In vitro induction of myeloid leukemia-specific CD4 and CD8T cells by CD40 ligand-activated B cells gene modified to express primary granule proteins. Clin Cancer Res 2005; 11: 4495–4503.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Gaiger A, Carter L, Greinix H, Carter D, McNeill PD, Houghton RL et al. WT1-specific serum antibodies in patients with leukemia. Clin Cancer Res 2001; 7: 761s–765s.

    CAS  PubMed  Google Scholar 

  53. Elisseeva OA, Oka Y, Tsuboi A, Ogata K, Wu F, Kim EH et al. Humoral immune responses against Wilms tumor gene WT1 product in patients with hematopoietic malignancies. Blood 2002; 99: 3272–3279.

    CAS  PubMed  Google Scholar 

  54. Wu F, Oka Y, Tsuboi A, Elisseeva OA, Ogata K, Nakajima H et al. Th1-biased humoral immune responses against Wilms tumor gene WT1 product in the patients with hematopoietic malignancies. Leukemia 2005; 19: 268–274.

    CAS  PubMed  Google Scholar 

  55. Stauss HJ . Immunotherapy with CTLs restricted by nonself MHC. Immunol Today 1999; 20: 180–183.

    CAS  PubMed  Google Scholar 

  56. Rezvani K, Grube M, Brenchley JM, Sconocchia G, Fujiwara H, Price DA et al. Functional leukemia-associated antigen-specific memory CD8+ T cells exist in healthy individuals and in patients with chronic myelogenous leukemia before and after stem cell transplantation. Blood 2003; 102: 2892–2900.

    CAS  PubMed  Google Scholar 

  57. Molldrem JJ, Lee PP, Kant S, Wieder E, Jiang W, Lu S et al. Chronic myelogenous leukemia shapes host immunity by selective deletion of high-avidity leukemia-specific T cells. J Clin Invest 2003; 111: 639–647.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Molldrem JJ, Lee PP, Wang C, Felio K, Kantarjian HM, Champlin RE et al. Evidence that specific T lymphocytes may participate in the elimination of chronic myelogenous leukemia. Nat Med 2000; 6: 1018–1023.

    CAS  PubMed  Google Scholar 

  59. Burchert A, Wolfl S, Schmidt M, Brendel C, Denecke B, Cai D et al. Interferon-alpha, but not the ABL-kinase inhibitor imatinib (STI571), induces expression of myeloblastin and a specific T-cell response in chronic myeloid leukemia. Blood 2003; 101: 259–264.

    CAS  PubMed  Google Scholar 

  60. Scheibenbogen C, Letsch A, Thiel E, Schmittel A, Mailaender V, Baerwolf S et al. CD8 T-cell responses to Wilms tumor gene product WT1 and proteinase 3 in patients with acute myeloid leukemia. Blood 2002; 100: 2132–2137.

    CAS  PubMed  Google Scholar 

  61. Oka Y, Tsuboi A, Taguchi T, Osaki T, Kyo T, Nakajima H et al. Induction of WT1 (Wilms' tumor gene)-specific cytotoxic T lymphocytes by WT1 peptide vaccine and the resultant cancer regression. Proc Natl Acad Sci USA 2004; 101: 13885–13890.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Azuma T, Makita M, Ninomiya K, Fujita S, Harada M, Yasukawa M . Identification of a novel WT1-derived peptide which induces human leucocyte antigen-A24-restricted anti-leukaemia cytotoxic T lymphocytes. Br J Haematol 2002; 116: 601–603.

    CAS  PubMed  Google Scholar 

  63. Keilholz U, Menssen HD, Gaiger A, Menke A, Oji Y, Oka Y et al. Wilms' tumour gene 1 (WT1) in human neoplasia. Leukemia 2005; 19: 1318–1323.

    CAS  PubMed  Google Scholar 

  64. Stauss HJ, Xue S, Gillmore R, Gao L, Bendle G, Holler A et al. Exploiting alloreactivity for tumour immunotherapy. Vox Sang 2004; 87 (Suppl 2): 227–229.

    PubMed  Google Scholar 

  65. Sadovnikova E, Stauss HJ . Peptide-specific cytotoxic T lymphocytes restricted by nonself major histocompatibility complex class I molecules: reagents for tumor immunotherapy. Proc Natl Acad Sci USA 1996; 93: 13114–13118.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Bellantuono I, Gao L, Parry S, Marley S, Dazzi F, Apperley J et al. Two distinct HLA-A0201-presented epitopes of the Wilms tumor antigen 1 can function as targets for leukemia-reactive CTL. Blood 2002; 100: 3835–3837.

    CAS  PubMed  Google Scholar 

  67. Sadovnikova E, Parovichnikova EN, Savchenko VG, Zabotina T, Stauss HJ . The CD68 protein as a potential target for leukaemia-reactive CTL. Leukemia 2002; 16: 2019–2026.

    CAS  PubMed  Google Scholar 

  68. Amrolia PJ, Reid SD, Gao L, Schultheis B, Dotti G, Brenner MK et al. Allorestricted cytotoxic T cells specific for human CD45 show potent antileukemic activity. Blood 2003; 101: 1007–1014.

    CAS  PubMed  Google Scholar 

  69. Savage P, Gao L, Vento K, Cowburn P, Man S, Steven N et al. Use of B cell-bound HLA-A2 class I monomers to generate high-avidity, allo-restricted CTLs against the leukemia-associated protein Wilms tumor antigen. Blood 2004; 103: 4613–4615.

    CAS  PubMed  Google Scholar 

  70. Oka Y, Udaka K, Tsuboi A, Elisseeva OA, Ogawa H, Aozasa K et al. Cancer immunotherapy targeting Wilms' tumor gene WT1 product. J Immunol 2000; 164: 1873–1880.

    CAS  PubMed  Google Scholar 

  71. Gao L, Xue SA, Hasserjian R, Cotter F, Kaeda J, Goldman JM et al. Human cytotoxic T lymphocytes specific for Wilms' tumor antigen-1 inhibit engraftment of leukemia-initiating stem cells in non-obese diabetic-severe combined immunodeficient recipients. Transplantation 2003; 75: 1429–1436.

    PubMed  Google Scholar 

  72. Hosen N, Sonoda Y, Oji Y, Kimura T, Minamiguchi H, Tamaki H et al. Very low frequencies of human normal CD34+ haematopoietic progenitor cells express the Wilms' tumour gene WT1 at levels similar to those in leukaemia cells. Br J Haematol 2002; 116: 409–420.

    CAS  PubMed  Google Scholar 

  73. Bonehill A, Heirman C, Thielemans K . Genetic approaches for the induction of a CD4+ T cell response in cancer immunotherapy. J Gene Med 2005; 7: 686–695.

    CAS  PubMed  Google Scholar 

  74. Knights AJ, Muller L, Pawelec G . Immunogenicity of WT-1 peptides. Cancer Immunol Immunother 2002; 51: 349.

    CAS  PubMed  Google Scholar 

  75. Guo Y, Niiya H, Azuma T, Uchida N, Yakushijin Y, Sakai I et al. Direct recognition and lysis of leukemia cells by WT1-specific CD4+ T lymphocytes in an HLA class II-restricted manner. Blood 2005; 106: 1415–1418.

    CAS  PubMed  Google Scholar 

  76. Molldrem JJ, Lee PP, Wang C, Champlin RE, Davis MM . A PR1-human leukocyte antigen-A2 tetramer can be used to isolate low-frequency cytotoxic T lymphocytes from healthy donors that selectively lyse chronic myelogenous leukemia. Cancer Res 1999; 59: 2675–2681.

    CAS  PubMed  Google Scholar 

  77. Dudley ME, Rosenberg SA . Adoptive-cell-transfer therapy for the treatment of patients with cancer. Nat Rev Cancer 2003; 3: 666–675.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Stanislawski T, Voss RH, Lotz C, Sadovnikova E, Willemsen RA, Kuball J et al. Circumventing tolerance to a human MDM2-derived tumor antigen by TCR gene transfer. Nat Immunol 2001; 2: 962–970.

    CAS  PubMed  Google Scholar 

  79. Heemskerk MH, Hoogeboom M, Hagedoorn R, Kester MG, Willemze R, Falkenburg JH . Reprogramming of virus-specific T cells into leukemia-reactive T cells using T cell receptor gene transfer. J Exp Med 2004; 199: 885–894.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Tsuji T, Yasukawa M, Matsuzaki J, Ohkuri T, Chamoto K, Wakita D et al. Generation of tumor-specific, HLA class I-restricted human Th1 and Tc1 cells by cell engineering with tumor peptide-specific T-cell receptor genes. Blood 2005; 106: 470–476.

    CAS  PubMed  Google Scholar 

  81. Xue S, Gao L, Gillmore R, Bendle G, Holler A, Downs AM et al. WT1-targeted immunotherapy of leukaemia. Blood Cells Mol Dis 2004; 33: 288–290.

    CAS  PubMed  Google Scholar 

  82. Xue S, Gillmore R, Downs A, Tsallios A, Holler A, Gao L et al. Exploiting T cell receptor genes for cancer immunotherapy. Clin Exp Immunol 2005; 139: 167–172.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Oka Y, Tsuboi A, Murakami M, Hirai M, Tominaga N, Nakajima H et al. Wilms tumor gene peptide-based immunotherapy for patients with overt leukemia from myelodysplastic syndrome (MDS) or MDS with myelofibrosis. Int J Hematol 2003; 78: 56–61.

    CAS  PubMed  Google Scholar 

  84. Mailander V, Scheibenbogen C, Thiel E, Letsch A, Blau IW, Keilholz U . Complete remission in a patient with recurrent acute myeloid leukemia induced by vaccination with WT1 peptide in the absence of hematological or renal toxicity. Leukemia 2004; 18: 165–166.

    CAS  PubMed  Google Scholar 

  85. Heslop HE, Stevenson FK, Molldrem JJ . Immunotherapy of hematologic malignancy. Hematology (Am Soc Hematol Educ Program) 2003; 1: 331–349.

    Google Scholar 

  86. Seifert U, Maranon C, Shmueli A, Desoutter JF, Wesoloski L, Janek K et al. An essential role for tripeptidyl peptidase in the generation of an MHC class I epitope. Nat Immunol 2003; 4: 375–379.

    CAS  PubMed  Google Scholar 

  87. Vigneron N, Stroobant V, Chapiro J, Ooms A, Degiovanni G, Morel S et al. An antigenic peptide produced by peptide splicing in the proteasome. Science 2004; 304: 587–590.

    CAS  PubMed  Google Scholar 

  88. Dunussi-Joannopoulos K, Dranoff G, Weinstein HJ, Ferrara JL, Bierer BE, Croop JM . Gene immunotherapy in murine acute myeloid leukemia: granulocyte-macrophage colony-stimulating factor tumor cell vaccines elicit more potent antitumor immunity compared with B7 family and other cytokine vaccines. Blood 1998; 91: 222–230.

    CAS  PubMed  Google Scholar 

  89. Dunussi-Joannopoulos K, Weinstein HJ, Arceci RJ, Croop JM . Gene therapy with B7.1 and GM-CSF vaccines in a murine AML model. J Pediatr Hematol Oncol 1997; 19: 536–540.

    CAS  PubMed  Google Scholar 

  90. Gilboa E, Lyerly HK, Vieweg J, Saito S . Immunotherapy of cancer using cytokine gene-modified tumor vaccines. Semin Cancer Biol 1994; 5: 409–417.

    CAS  PubMed  Google Scholar 

  91. Van Tendeloo VF, Van Broeckhoven C, Berneman ZN . Gene-based cancer vaccines: an ex vivo approach. Leukemia 2001; 15: 545–558.

    CAS  PubMed  Google Scholar 

  92. Huang AY, Golumbek P, Ahmadzadeh M, Jaffee E, Pardoll D, Levitsky H . Role of bone marrow-derived cells in presenting MHC class I-restricted tumor antigens. Science 1994; 264: 961–965.

    CAS  PubMed  Google Scholar 

  93. Banchereau J, Steinman RM . Dendritic cells and the control of immunity. Nature 1998; 392: 245–252.

    CAS  PubMed  Google Scholar 

  94. Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ et al. Immunobiology of dendritic cells. Annu Rev Immunol 2000; 18: 767–811.

    CAS  PubMed  Google Scholar 

  95. Banchereau J, Schuler-Thurner B, Palucka AK, Schuler G . Dendritic cells as vectors for therapy. Cell 2001; 106: 271–274.

    CAS  PubMed  Google Scholar 

  96. Gilboa E, Nair SK, Lyerly HK . Immunotherapy of cancer with dendritic-cell-based vaccines. Cancer Immunol Immunother 1998; 46: 82–87.

    CAS  PubMed  Google Scholar 

  97. Vermorken JB, Van Tendeloo VF . Dendritic cell therapy of cancer: can it fulfill its promise? Expert Rev Anticancer Ther 2003; 3: 1–3.

    PubMed  Google Scholar 

  98. Gilboa E, Vieweg J . Cancer immunotherapy with mRNA-transfected dendritic cells. Immunol Rev 2004; 199: 251–263.

    CAS  PubMed  Google Scholar 

  99. Sullenger BA, Gilboa E . Emerging clinical applications of RNA. Nature 2002; 418: 252–258.

    CAS  PubMed  Google Scholar 

  100. Van Tendeloo VF, Ponsaerts P, Lardon F, Nijs G, Lenjou M, Van Broeckhoven C et al. Highly efficient gene delivery by mRNA electroporation in human hematopoietic cells: superiority to lipofection and passive pulsing of mRNA and to electroporation of plasmid cDNA for tumor antigen loading of dendritic cells. Blood 2001; 98: 49–56.

    CAS  PubMed  Google Scholar 

  101. Ponsaerts P, Van Tendeloo VF, Berneman ZN . Cancer immunotherapy using RNA-loaded dendritic cells. Clin Exp Immunol 2003; 134: 378–384.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Dullaers M, Breckpot K, Van Meirvenne S, Bonehill A, Tuyaerts S, Michiels A et al. Side-by-side comparison of lentivirally transduced and MRNA-electroporated dendritic cells: implications for cancer immunotherapy protocols. Mol Ther 2004; 10: 768–779.

    CAS  PubMed  Google Scholar 

  103. Bonehill A, Heirman C, Tuyaerts S, Michiels A, Breckpot K, Brasseur F et al. Messenger RNA-electroporated dendritic cells presenting MAGE-A3 simultaneously in HLA class I and class II molecules. J Immunol 2004; 172: 6649–6657.

    CAS  PubMed  Google Scholar 

  104. Strobel I, Berchtold S, Gotze A, Schulze U, Schuler G, Steinkasserer A . Human dendritic cells transfected with either RNA or DNA encoding influenza matrix protein M1 differ in their ability to stimulate cytotoxic T lymphocytes. Gene Therapy 2000; 7: 2028–2035.

    CAS  PubMed  Google Scholar 

  105. Grunebach F, Muller MR, Nencioni A, Brossart P . Delivery of tumor-derived RNA for the induction of cytotoxic T-lymphocytes. Gene Therapy 2003; 10: 367–374.

    CAS  PubMed  Google Scholar 

  106. Saeboe-Larssen S, Fossberg E, Gaudernack G . mRNA-based electrotransfection of human dendritic cells and induction of cytotoxic T lymphocyte responses against the telomerase catalytic subunit (hTERT). J Immunol Methods 2002; 259: 191–203.

    CAS  PubMed  Google Scholar 

  107. Muller MR, Tsakou G, Grunebach F, Schmidt SM, Brossart P . Induction of chronic lymphocytic leukemia (CLL)-specific CD4- and CD8-mediated T-cell responses using RNA-transfected dendritic cells. Blood 2004; 103: 1763–1769.

    PubMed  Google Scholar 

  108. Schultze JL, Michalak S, Seamon MJ, Dranoff G, Jung K, Daley J et al. CD40-activated human B cells: an alternative source of highly efficient antigen presenting cells to generate autologous antigen-specific T cells for adoptive immunotherapy. J Clin Invest 1997; 100: 2757–2765.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Van den Bosch GA, Ponsaerts P, Nijs G, Lenjou M, Vanham G, Van Bockstaele DR et al. Ex vivo induction of viral antigen-specific CD8T cell responses using mRNA-electroporated CD40-activated B cells. Clin Exp Immunol 2005; 139: 458–467.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Figdor CG, de Vries IJ, Lesterhuis WJ, Melief CJ . Dendritic cell immunotherapy: mapping the way. Nat Med 2004; 10: 475–480.

    CAS  PubMed  Google Scholar 

  111. Michiels A, Tuyaerts S, Bonehill A, Corthals J, Breckpot K, Heirman C et al. Electroporation of immature and mature dendritic cells: implications for dendritic cell-based vaccines. Gene Therapy 2005; 12: 772–782.

    CAS  PubMed  Google Scholar 

  112. Schaft N, Dorrie J, Thumann P, Beck VE, Muller I, Schultz ES et al. Generation of an optimized polyvalent monocyte-derived dendritic cell vaccine by transfecting defined RNAs after rather than before maturation. J Immunol 2005; 174: 3087–3097.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by Grant nos. G.0456.03, G.0313.01 and WO.012.02 of the Fund for Scientific Research – Flanders, Belgium (FWO-Vlaanderen), by grants of the Fortis Bank Verzekeringen – financed Cancer Research, by research grants of the Belgian Federation against Cancer (BFK) and by a grant of the University of Antwerp Concerted Research Action (BOF-GOA) #802. AVD holds a PhD fellowship of the Emmanuel van der Schueren Foundation. VFIVT is a postdoctoral fellow of the Fund for Scientific Research – Flanders, Belgium (FWO-Vlaanderen). The work with the anti-WT1 T-cell clone was supported by the Leukemia Research Fund, UK.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to V F I Van Tendeloo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Van Driessche, A., Gao, L., Stauss, H. et al. Antigen-specific cellular immunotherapy of leukemia. Leukemia 19, 1863–1871 (2005). https://doi.org/10.1038/sj.leu.2403930

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403930

Keywords

This article is cited by

Search

Quick links