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.

  • Original Article
  • Published:

Allografting

CD8+ T-cell responses to tumor-associated antigens correlate with superior relapse-free survival after allo-SCT

Bone Marrow Transplantation volume 43, pages 399–410 (2009)Cite this article

Abstract

The GVL effect following allo-SCT is one of the most prominent examples showing the ability of the immune system to eliminate malignant hematological diseases. Tumor-associated Ags (TAA), for instance WT1 and proteinase-3, have been proposed as targets for T cells to establish a GVL effect. Here, we examined an additional TAA (MUC1) as a possible T-cell target of GVL-related immune responses. We have defined new peptide epitopes from the MUC1 Ag to broaden patients’ screening and to expand the repertoire of immunologic monitoring as well as for therapeutic approaches in the future. Twenty-eight patients after allo-SCT have been screened for T-cell responses toward TAA (proteinase-3, WT1, MUC1). We could detect a significant relationship between relapse and the absence of a TAA-specific T-cell response, whereby only 2/13 (15%) patients with TAA-specific CTL relapsed, in contrast to 9/15 (60%) patients without TAA-specific CTL responses (P<0.05). In conclusion, CD8+ T-cell responses directed to TAA might contribute to the GVL effect. These observations highlight both the importance and the potential of immunotherapeutic approaches after allo-SCT.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. 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.

    Article  CAS  Google Scholar 

  2. 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.

    Article  CAS  Google Scholar 

  3. Mutis T, Verdijk R, Schrama E, Esendam B, Brand A, Goulmy E . Feasibility of immunotherapy of relapsed leukemia with ex vivo-generated cytotoxic T lymphocytes specific for hematopoietic system-restricted minor histocompatibility antigens. Blood 1999; 93: 2336–2341.

    CAS  PubMed  Google Scholar 

  4. Yotnda P, Firat H, Garcia-Pons F, Garcia Z, Gourru G, Vernant JP et al. Cytotoxic T-cell response against the chimeric p210 BCR-ABL protein in patients with chronic myelogenous leukemia. J Clin Invest 1998; 101: 2290–2296.

    Article  CAS  Google Scholar 

  5. Rezvani K, Yong AS, Savani BN, Mielke S, Keyvanfar K, Gostick E et al. Graft-versus-leukemia effects associated with detectable Wilms tumor-1 specific T lymphocytes following allogeneic stem cell transplantation for acute lymphoblastic leukemia (ALL). Blood 2007; 110: 1924–1932.

    Article  CAS  Google Scholar 

  6. Gendler S, Taylor-Papadimitriou J, Duhig T, Rothbard J, Burchell J . A highly immunogenic region of a human polymorphic epithelial mucin expressed by carcinomas is made up of tandem repeats. J Biol Chem 1988; 263: 12820–12823.

    CAS  PubMed  Google Scholar 

  7. Girling A, Bartkova J, Burchell J, Gendler S, Gillett C, Taylor-Papadimitriou J . A core protein epitope of the polymorphic epithelial mucin detected by the monoclonal antibody SM-3 is selectively exposed in a range of primary carcinomas. Int J Cancer 1989; 43: 1072–1076.

    Article  CAS  Google Scholar 

  8. Brossart P, Schneider A, Dill P, Schammann T, Grünebach F, Wirths S et al. The epithelial tumor antigen MUC1 is expressed in hematological malignancies and is recognized by MUC1-specific cytotoxic T-lymphocytes. Cancer Res 2001; 61: 6846–6850.

    CAS  PubMed  Google Scholar 

  9. Brossart P, Wirths S, Stuhler G, Reichardt VL, Kanz L, Brugger W . Induction of cytotoxic T-lymphocyte responses in vivo after vaccination with peptide-pulsed dendritic cells. Blood 2000; 96: 3102–3108.

    CAS  PubMed  Google Scholar 

  10. Brossart P, Heinrich KS, Stuhler G, Behnke L, Reichardt VL, Stevanović S et al. Identification of HLA-A2-restricted T-cell epitopes derived from the MUC1 tumor antigen for broadly applicable vaccine therapies. Blood 1999; 93: 4309–4317.

    CAS  Google Scholar 

  11. Celis E, Tsai V, Crimi C, DeMars R, Wentworth PA, Chesnut RW et al. Induction of anti-tumor cytotoxic T lymphocytes in normal humans using primary cultures and synthetic peptide epitopes. Proc Natl Acad Sci USA 1994; 91: 2105–2109.

    Article  CAS  Google Scholar 

  12. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood 1998; 92: 2322–2333.

    CAS  PubMed  Google Scholar 

  13. Moorman AV, Harrison CJ, Buck GA, Richards SM, Secker-Walker LM, Martineau M et al. Adult Leukaemia Working Party, Medical Research Council/National Cancer Research Institute: Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood 2007; 109: 3189–3197.

    Article  CAS  Google Scholar 

  14. Badros A, Barlogie B, Siegel E, Cottler-Fox M, Zangari M, Fassas A et al. Improved outcome of allogeneic transplantation in high-risk multiple myeloma patients after nonmyeloablative conditioning. J Clin Oncol 2002; 20: 1295–1303.

    Article  Google Scholar 

  15. Rammensee HG, Bachmann J, Emmerich NP, Bachor OA, Stevanović S . SYFPEITHI: database for MHC ligands and peptide motifs. Immunogenetics 1999; 50: 213–219.

    Article  CAS  Google Scholar 

  16. Hebart H, Daginik S, Stevanović S, Grigoleit U, Dobler A, Baur M et al. Sensitive detection of human cytomegalovirus peptide-specific cytotoxic T-lymphocyte responses by interferon-gamma-enzyme-linked immunospot assay and flow cytometry in healthy individuals and in patients after allogeneic stem cell transplantation. Blood 2002; 99: 3830–3837.

    Article  CAS  Google Scholar 

  17. Sallusto F, Lanzavecchia A . Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor α. J Exp Med 1994; 179: 1109–1118.

    Article  CAS  Google Scholar 

  18. Zhou LJ, Tedder TF . CD14+ blood monocytes can differentiate into functionally mature CD83+ dendritic cells. Proc Natl Acad Sci USA 1996; 93: 2588–2592.

    Article  CAS  Google Scholar 

  19. 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.

    Article  CAS  Google Scholar 

  20. Kammula US, Lee KH, Riker AI, Wang E, Ohnmacht GA, Rosenberg SA et al. Functional analysis of antigen-specific T lymphocytes by serial measurement of gene expression in peripheral blood mononuclear cells and tumor specimens. J Immunol 1999; 163: 6867–6875.

    CAS  PubMed  Google Scholar 

  21. Loeffler J, Swatoch P, Akhawi-Araghi D, Hebart H, Einsele H . Automated RNA extraction followed by rapid quantification of cytokine and chemokine gene expression using fluorescence resonance energy transfer. Clinical Chemistry 2003; 49: 985–988.

    Article  Google Scholar 

  22. Nakamura R, Battiwalla M, Solomon S, Follmann D, Chakrabarti S, Cortez K et al. Persisting posttransplantation cytomegalovirus antigenemia correlates with poor lymphocyte proliferation to cytomegalovirus antigen and predicts for increased late relapse and treatment failure. Biol Blood Marrow Transplant 2004; 10: 49–57.

    Article  Google Scholar 

  23. Appelbaum FR . Hematopoietic cell transplantation as immunotherapy. Nature 2001; 411: 385–389.

    Article  CAS  Google Scholar 

  24. Wu CJ, Ritz J . Induction of tumor immunity following allogeneic stem cell transplantation. Adv Immunol 2006; 90: 133–173.

    Article  CAS  Google Scholar 

  25. Zittoun RA, Mandelli F, Willemze R, de Witte T, Labar B, Resegotti L et al. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. European Organization for Research and Treatment of cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) Leukemia Cooperative Groups. N Engl J Med 1995; 332: 217–223.

    Article  CAS  Google Scholar 

  26. Ljungman P, de Witte T, Verdonck L, Gahrton G, Freycon F, Gravett P et al. Bone marrow transplantation for acute myeloblastic leukemia: an EBMT Leukemia Working Party prospective analysis from HLA-typing. Br J Haematol 1993; 84: 61–66.

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  28. Sullivan KM, Weiden PL, Storb R, Witherspoon RP, Fefer A, Fisher L et al. Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia. Blood 1989; 73: 1720–1728.

    CAS  PubMed  Google Scholar 

  29. Stevanović S . Identification of tumor-associated T-cell epitopes for vaccine development. Nat Rev Cancer 2002; 2: 514–520.

    Article  Google Scholar 

  30. van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, Van den Eynde B et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science 1991; 254: 1643–1647.

    Article  CAS  Google Scholar 

  31. Rosenberg SA, Yang JC, Schwartzentruber DJ, Hwu P, Marincola FM, Topalian SL et al. Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 1998; 4: 321–327.

    Article  CAS  Google Scholar 

  32. Nestle FO, Alijagic S, Gilliet M, Sun Y, Grabbe S, Dummer R et al. Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. Nat Med 1998; 4: 328–332.

    Article  CAS  Google Scholar 

  33. Scheibenbogen C, Sun Y, Keilholz U, Song M, Stevanović S, Asemissen AM et al. Identification of known and novel immunogenic T-cell epitopes from tumor antigens recognized by peripheral blood T-cells from patients responding to IL-2- based treatment. Int J Cancer 2002; 98: 409–414.

    Article  CAS  Google Scholar 

  34. Gückel B, Rentzsch C, Nastke MD, Marmé A, Gruber I, Stevanović S et al. Pre-existing T-cell immunity against mucin-1 in breast cancer patients and healthy volunteers. J Cancer Res Clin Oncol 2006; 132: 265–274.

    Article  Google Scholar 

  35. 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.

    Article  CAS  Google Scholar 

  36. Tsuboi A, Oka Y, Nakajima H, Fukuda Y, Elisseeva OA, Yoshihara S et al. Wilms tumor gene WT1 peptide-based immunotherapy induced a minimal response in a patient with advanced therapy-resistant multiple myeloma. Int J Hematol 2007; 86: 414–417.

    Article  Google Scholar 

  37. Rezvani K, Yong AS, Mielke S, Savani BN, Musse L, Superata J et al. Leukemia-associated antigen-specific T-cell responses following combined PR1 and WT1 peptide vaccination in patients with myeloid malignancies. Blood 2008; 111: 236–242.

    Article  CAS  Google Scholar 

  38. Grigoleit GU, Kapp M, Hebart H, Fick K, Beck R, Jahn G et al. Dendritic cell Vaccination in allogeneic stem cell recipients: induction of HCMV-specific CTL responses even in patients receiving a transplant from an HCMV-seronegative donor. J Inf Dis 2007; 196: 699–704.

    Article  Google Scholar 

  39. den Haan JM, Meadows LM, Wang W, Pool J, Blokland E, Bishop TL et al. The minor histocompatibility antigen HA-1: a diallelic gene with a single amino acid polymorphism. Science 1998; 279: 1054–1057.

    Article  CAS  Google Scholar 

  40. Goulmy E, Schipper R, Pool J, Blokland E, Falkenburg JH, Vossen J et al. Mismatches of minor histocompatibility antigens between HLA-identical donors and recipients and the development of graft-versus-host disease after bone marrow transplantation. N Engl J Med 1996; 334: 281–285.

    Article  CAS  Google Scholar 

  41. Wills MR, Carmichael AJ, Mynard K, Jin X, Weekes MP, Plachter B et al. The human cytotoxic (CTL) response to cytomegalovirus is dominated by structural protein pp65: frequency, specificity, and T-cell receptor usage of pp65-specific CTL. Journal of Virology 1996; 70: 7569–7579.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Walker BD, Flexner C, Birch-Limberger K, Fisher L, Paradis TJ, Aldovini A et al. Long-term culture and fine specificity of human cytotoxic T-lymphocyte clones reactive with human immunodeficiency virus type 1. Proc Natl Acad Sci USA 1989; 86: 9514–9518.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by grants from the IZKF Würzburg, project D-57-N (MK, GS and GUG), and the Deutsche Forschungsgemeinschaft, SFB 685 (SS)

Author information

Authors and Affiliations

  1. Medizinische Klinik und Poliklinik II, Julius-Maximilians-Universität, Würzburg, Germany

    M Kapp, K Fick, S M Tan, J Loeffler, G Stuhler, H Einsele & G U Grigoleit

  2. Abteilung Immunologie, Interfakultäres Institut für Zellbiologie, Eberhard-Karls-Universität, Tübingen, Germany

    S Stevanović

  3. Hospital Ampang, Selangor Darul Ehsan, Malaysia

    S M Tan

  4. Institut für Klinische Transfusionsmedizin und Hämotherapie, Julius-Maximilians-Universität, Würzburg, Germany

    A Opitz

  5. Institut für Transfusionsmedizin und Immunhämatologie, Johann-Wolfgang-Goethe-Universität, Frankfurt am Main, Germany

    T Tonn

Authors
  1. M Kapp
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Stevanović
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K Fick
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S M Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Loeffler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A Opitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T Tonn
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. G Stuhler
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. H Einsele
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. G U Grigoleit
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G U Grigoleit.

Additional information

Supplementary Information accompanies the paper on Bone Marrow Transplantation website (http://www.nature.com/bmt)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kapp, M., Stevanović, S., Fick, K. et al. CD8+ T-cell responses to tumor-associated antigens correlate with superior relapse-free survival after allo-SCT. Bone Marrow Transplant 43, 399–410 (2009). https://doi.org/10.1038/bmt.2008.426

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2008.426

Keywords

This article is cited by

Search

Advanced search

Quick links