Cancer Immunology, Immunotherapy

, Volume 61, Issue 7, pp 1125–1136 | Cite as

Lymphodepletion is permissive to the development of spontaneous T-cell responses to the self-antigen PR1 early after allogeneic stem cell transplantation and in patients with acute myeloid leukemia undergoing WT1 peptide vaccination following chemotherapy

  • Katayoun Rezvani
  • Agnes S. M. Yong
  • Stephan Mielke
  • Bipin N. Savani
  • Behnam Jafarpour
  • Rhoda Eniafe
  • Robert Quan Le
  • Laura Musse
  • Carole Boss
  • Richard Childs
  • A. John Barrett
Original article

Abstract

PR1, an HLA-A*0201 epitope shared by proteinase-3 (PR3) and elastase (ELA2) proteins, is expressed in normal neutrophils and overexpressed in myeloid leukemias. PR1-specific T cells have been linked to graft-versus-leukemia (GVL) effect. We hypothesized that lymphopenia induced by chemo-radiotherapy can enhance weak autoimmune responses to self-antigens such as PR1. We measured PR1-specific responses in 27 patients 30–120 days following allogeneic stem cell transplant (SCT) and correlated these with ELA2 and PR3 expression and minimal residual disease (MRD). Post-SCT 10/13 CML, 6/9 ALL, and 4/5 solid tumor patients had PR1 responses correlating with PR3 and ELA2 expression. At day 180 post-SCT, 8/8 CML patients with PR1 responses were BCR-ABL-negative compared with 2/5 BCR-ABL-positive patients (P = 0.025). In contrast, PR1 responses were detected in 2/4 MRD-negative compared with 4/5 MRD-positive ALL patients (P = 0.76). To assess whether the lymphopenic milieu also exaggerates weak T-cell responses in the autologous setting, we measured spontaneous induction of PR1 responses in 3 AML patients vaccinated with WT1-126 peptide following lymphodepletion. In addition to WT1-specific T cells, we detected PR1-specific T cells in 2 patients during hematopoietic recovery. Our findings suggest that lymphopenia induced by chemo-radiotherapy enhances weak autoimmune responses to self-antigens, which may result in GVL if the leukemia expresses the relevant self-antigen.

Keywords

PR1 WT1 Vaccine Lymphopenia-driven homeostasis Leukemia Immunotherapy 

Notes

Acknowledgments

This study was supported by an NIH bench-to-bedside award. K.R. acknowledges the support of the National Institute for Health Research (NIHR) Biomedical Research Centre. We would like to thank the patients who participated in the study and the nursing and medical staff at the Clinical Centre, NHLBI.

References

  1. 1.
    Williams KM, Hakim FT, Gress RE (2007) T cell immune reconstitution following lymphodepletion. Semin Immunol 19:318–330PubMedCrossRefGoogle Scholar
  2. 2.
    Goldrath AW, Bevan MJ (1999) Low-affinity ligands for the TCR drive proliferation of mature CD8+ T cells in lymphopenic hosts. Immunity 11:183–190PubMedCrossRefGoogle Scholar
  3. 3.
    Clarke SR, Rudensky AY (2000) Survival and homeostatic proliferation of naive peripheral CD4+ T cells in the absence of self peptide:MHC complexes. J Immunol 165:2458–2464PubMedGoogle Scholar
  4. 4.
    Cho BK, Rao VP, Ge Q, Eisen HN, Chen J (2000) Homeostasis-stimulated proliferation drives naive T cells to differentiate directly into memory T cells. J Exp Med 192:549–556PubMedCrossRefGoogle Scholar
  5. 5.
    Mackall CL, Bare CV, Granger LA, Sharrow SO, Titus JA, Gress RE (1996) Thymic-independent T cell regeneration occurs via antigen-driven expansion of peripheral T cells resulting in a repertoire that is limited in diversity and prone to skewing. J Immunol 156:4609–4616PubMedGoogle Scholar
  6. 6.
    Palmer DC, Chan CC, Gattinoni L, Wrzesinski C, Paulos CM, Hinrichs CS et al (2008) Effective tumor treatment targeting a melanoma/melanocyte-associated antigen triggers severe ocular autoimmunity. Proc Natl Acad Sci USA 105:8061–8066PubMedCrossRefGoogle Scholar
  7. 7.
    Ernst B, Lee DS, Chang JM, Sprent J, Surh CD (1999) The peptide ligands mediating positive selection in the thymus control T cell survival and homeostatic proliferation in the periphery. Immunity 11:173–181PubMedCrossRefGoogle Scholar
  8. 8.
    Molldrem J, Dermime S, Parker K, Jiang YZ, Mavroudis D, Hensel N et al (1996) Targeted T-cell therapy for human leukemia: cytotoxic T lymphocytes specific for a peptide derived from proteinase 3 preferentially lyse human myeloid leukemia cells. Blood 88:2450–2457PubMedGoogle Scholar
  9. 9.
    Molldrem JJ, Lee PP, Kant S, Wieder E, Jiang W, Lu S et al (2003) Chronic myelogenous leukemia shapes host immunity by selective deletion of high-avidity leukemia-specific T cells. J Clin Invest 111:639–647PubMedGoogle Scholar
  10. 10.
    Rezvani K, Grube M, Brenchley JM, Sconocchia G, Fujiwara H, Price DA et al (2003) 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 102:2892–2900PubMedCrossRefGoogle Scholar
  11. 11.
    Scheibenbogen C, Letsch A, Thiel E, Schmittel A, Mailaender V, Baerwolf S et al (2002) CD8 T-cell responses to Wilms tumor gene product WT1 and proteinase 3 in patients with acute myeloid leukemia. Blood 100:2132–2137PubMedCrossRefGoogle Scholar
  12. 12.
    Rezvani K, Price D, Brenchley J, Kilical Y, Gostick E, Sconocchia G et al (2007) Transfer of PR1-specific T-cell clones from donor to recipient by stem cell transplantation and association with GvL activity. Cytotherapy 9:245–251PubMedCrossRefGoogle Scholar
  13. 13.
    Gannage M, Abel M, Michallet AS, Delluc S, Lambert M, Giraudier S et al (2005) Ex vivo characterization of multiepitopic tumor-specific CD8 T cells in patients with chronic myeloid leukemia: implications for vaccine development and adoptive cellular immunotherapy. J Immunol 174:8210–8218PubMedGoogle Scholar
  14. 14.
    Scott LM, Civin CI, Rorth P, Friedman AD (1992) A novel temporal expression pattern of three C/EBP family members in differentiating myelomonocytic cells. Blood 80:1725–1735PubMedGoogle Scholar
  15. 15.
    Radomska HS, Huettner CS, Zhang P, Cheng T, Scadden DT, Tenen DG (1998) CCAAT/enhancer binding protein alpha is a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors. Mol Cell Biol 18:4301–4314PubMedGoogle Scholar
  16. 16.
    Zhang P, Nelson E, Radomska HS, Iwasaki-Arai J, Akashi K, Friedman AD et al (2002) Induction of granulocytic differentiation by 2 pathways. Blood 99:4406–4412PubMedCrossRefGoogle Scholar
  17. 17.
    Carvallo C, Geller N, Kurlander R, Srinivasan R, Mena O, Igarashi T et al (2004) Prior chemotherapy and allograft CD34+ dose impact donor engraftment following nonmyeloablative allogeneic stem cell transplantation in patients with solid tumors. Blood 103:1560–1563PubMedCrossRefGoogle Scholar
  18. 18.
    Childs R, Clave E, Contentin N, Jayasekera D, Hensel N, Leitman S et al (1999) Engraftment kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation: full donor T-cell chimerism precedes alloimmune responses. Blood 94:3234–3241PubMedGoogle Scholar
  19. 19.
    Gao L, Bellantuono I, Elsasser A, Marley SB, Gordon MY, Goldman JM et al (2000) Selective elimination of leukemic CD34(+) progenitor cells by cytotoxic T lymphocytes specific for WT1. Blood 95:2198–2203PubMedGoogle Scholar
  20. 20.
    Oka Y, Elisseeva OA, Tsuboi A, Ogawa H, Tamaki H, Li H et al (2000) Human cytotoxic T-lymphocyte responses specific for peptides of the wild-type Wilms’ tumor gene (WT1) product. Immunogenetics 51:99–107PubMedCrossRefGoogle Scholar
  21. 21.
    Rezvani K, Yong AS, Savani BN, Mielke S, Keyvanfar K, Gostick E et al (2007) Graft-versus-leukemia effects associated with detectable Wilms tumor-1 specific T lymphocytes after allogeneic stem-cell transplantation for acute lymphoblastic leukemia. Blood 110:1924–1932PubMedCrossRefGoogle Scholar
  22. 22.
    Diamond DJ, York J, Sun JY, Wright CL, Forman SJ (1997) Development of a candidate HLA A*0201 restricted peptide-based vaccine against human cytomegalovirus infection. Blood 90:1751–1767PubMedGoogle Scholar
  23. 23.
    Rezvani K, Yong AS, Mielke S, Savani BN, Musse L, Superata J et al (2008) Leukemia-associated antigen-specific T-cell responses following combined PR1 and WT1 peptide vaccination in patients with myeloid malignancies. Blood 111:236–242PubMedCrossRefGoogle Scholar
  24. 24.
    Rezvani K, Yong AS, Tawab A, Jafarpour B, Eniafe R, Mielke S et al (2009) Ex vivo characterization of polyclonal memory CD8+ T-cell responses to PRAME-specific peptides in patients with acute lymphoblastic leukemia and acute and chronic myeloid leukemia. Blood 113:2245–2255PubMedCrossRefGoogle Scholar
  25. 25.
    Yong ASM, Keyvanfar K, Eniafe R, Savani BN, Rezvani K, Sloand EM et al (2008) Hematopoietic stem cells and progenitors of chronic myeloid leukemia express leukemia-associated antigens: implications for the graft-versus-leukemia effect and peptide vaccine-based immunotherapy. Leukemia 22:1721–1727PubMedCrossRefGoogle Scholar
  26. 26.
    Appay V, Nixon DF, Donahoe SM, Gillespie GM, Dong T, King A et al (2000) HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function. J Exp Med 192:63–75PubMedCrossRefGoogle Scholar
  27. 27.
    Rezvani K, Yong AS, Mielke S, Jafarpour B, Savani BN, Le RQ et al (2011) Repeated PR1 and WT1 peptide vaccination in Montanide-adjuvant fails to induce sustained high-avidity, epitope-specific CD8+ T cells in myeloid malignancies. Haematologica 96:432–440PubMedCrossRefGoogle Scholar
  28. 28.
    Rezvani K, Mielke S, Ahmadzadeh M, Kilical Y, Savani BN, Zeilah J et al (2006) High donor FOXP3-positive regulatory T-cell (Treg) content is associated with a low risk of GVHD following HLA-matched allogeneic SCT. Blood 108:1291–1297PubMedCrossRefGoogle Scholar
  29. 29.
    Zhang H, Chua KS, Guimond M, Kapoor V, Brown MV, Fleisher TA et al (2005) Lymphopenia and interleukin-2 therapy alter homeostasis of CD4(+)CD25(+) regulatory T cells. Nat Med 11:1238–1243PubMedCrossRefGoogle Scholar
  30. 30.
    Zitvogel L, Kepp O, Kroemer G (2011) Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat Rev Clin Oncol 8:151–160PubMedCrossRefGoogle Scholar
  31. 31.
    Lesterhuis WJ, Punt CJA, Hato SV, Eleveld-Trancikova D, Jansen BJH, Nierkens S et al (2011) Platinum-based drugs disrupt STAT6-mediated suppression of immune responses against cancer in humans and mice. J Clin Invest 121:3100–3108PubMedCrossRefGoogle Scholar
  32. 32.
    Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ et al (2002) Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298:850–854PubMedCrossRefGoogle Scholar
  33. 33.
    Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP et al (2005) Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol 23:2346–2357PubMedCrossRefGoogle Scholar
  34. 34.
    Dummer W, Niethammer AG, Baccala R, Lawson BR, Wagner N, Reisfeld RA et al (2002) T cell homeostatic proliferation elicits effective antitumor autoimmunity. J Clin Invest 110:185–192PubMedGoogle Scholar
  35. 35.
    Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R et al (2008) Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med 358:2698–2703PubMedCrossRefGoogle Scholar
  36. 36.
    Reichardt VL, Okada CY, Liso A, Benike CJ, Stockerl-Goldstein KE, Engleman EG et al (1999) Idiotype vaccination using dendritic cells after autologous peripheral blood stem cell transplantation for multiple myeloma–a feasibility study. Blood 93:2411–2419PubMedGoogle Scholar
  37. 37.
    Bendandi M, Rodriguez-Calvillo M, Inoges S, de Lopez-Diaz CA, Perez-Simon JA, Rodriguez-Caballero A et al (2006) Combined vaccination with idiotype-pulsed allogeneic dendritic cells and soluble protein idiotype for multiple myeloma patients relapsing after reduced-intensity conditioning allogeneic stem cell transplantation. Leuk Lymphoma 47:29–37PubMedCrossRefGoogle Scholar
  38. 38.
    Kitawaki T, Kadowaki N, Kondo T, Ishikawa T, Ichinohe T, Teramukai S et al (2008) Potential of dendritic-cell immunotherapy for relapse after allogeneic hematopoietic stem cell transplantation, shown by WT1 peptide- and keyhole-limpet-hemocyanin-pulsed, donor-derived dendritic-cell vaccine for acute myeloid leukemia. Am J Hematol 83:315–317PubMedCrossRefGoogle Scholar
  39. 39.
    Rousseau RF, Biagi E, Dutour A, Yvon ES, Brown MP, Lin T et al (2006) Immunotherapy of high-risk acute leukemia with a recipient (autologous) vaccine expressing transgenic human CD40L and IL-2 after chemotherapy and allogeneic stem cell transplantation. Blood 107:1332–1341PubMedCrossRefGoogle Scholar
  40. 40.
    Ho VT, Vanneman M, Kim H, Sasada T, Kang YJ, Pasek M et al (2009) Biologic activity of irradiated, autologous, GM-CSF-secreting leukemia cell vaccines early after allogeneic stem cell transplantation. Proc Natl Acad Sci USA 106:15825–15830PubMedCrossRefGoogle Scholar
  41. 41.
    Boublikova L, Kalinova M, Ryan J, Quinn F, O’Marcaigh A, Smith O et al (2006) Wilms’ tumor gene 1 (WT1) expression in childhood acute lymphoblastic leukemia: a wide range of WT1 expression levels, its impact on prognosis and minimal residual disease monitoring. Leukemia 20:254–263PubMedCrossRefGoogle Scholar
  42. 42.
    Cilloni D, Gottardi E, Messa F, Fava M, Scaravaglio P, Bertini M et al (2003) Significant correlation between the degree of WT1 expression and the International Prognostic Scoring System Score in patients with myelodysplastic syndromes. J Clin Oncol 21:1988–1995PubMedCrossRefGoogle Scholar
  43. 43.
    Cilloni D, Renneville A, Hermitte F, Hills RK, Daly S, Jovanovic JV et al (2009) Real-time quantitative polymerase chain reaction detection of minimal residual disease by standardized WT1 assay to enhance risk stratification in acute myeloid leukemia: a European LeukemiaNet study. J Clin Oncol 27:5195–5201PubMedCrossRefGoogle Scholar
  44. 44.
    Ostergaard M, Olesen LH, Hasle H, Kjeldsen E, Hokland P (2004) WT1 gene expression: an excellent tool for monitoring minimal residual disease in 70% of acute myeloid leukaemia patients—results from a single-centre study. Br J Haematol 125:590–600PubMedCrossRefGoogle Scholar
  45. 45.
    Fry TJ, Connick E, Falloon J, Lederman MM, Liewehr DJ, Spritzler J et al (2001) A potential role for interleukin-7 in T-cell homeostasis. Blood 97:2983–2990PubMedCrossRefGoogle Scholar
  46. 46.
    Fry TJ, Mackall CL (2005) The many faces of IL-7: from lymphopoiesis to peripheral T cell maintenance. J Immunol 174:6571–6576PubMedGoogle Scholar
  47. 47.
    Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ et al (2005) Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med 202:907–912PubMedCrossRefGoogle Scholar
  48. 48.
    Goldrath AW, Sivakumar PV, Glaccum M, Kennedy MK, Bevan MJ, Benoist C et al (2002) Cytokine requirements for acute and Basal homeostatic proliferation of naive and memory CD8+ T cells. J Exp Med 195:1515–1522PubMedCrossRefGoogle Scholar
  49. 49.
    Klebanoff CA, Khong HT, Antony PA, Palmer DC, Restifo NP (2005) Sinks, suppressors and antigen presenters: how lymphodepletion enhances T cell-mediated tumor immunotherapy. Trends Immunol 26:111–117PubMedCrossRefGoogle Scholar
  50. 50.
    Mielke S, Rezvani K, Savani BN, Nunes R, Yong AS, Schindler J et al (2007) Reconstitution of FOXP3+ regulatory T cells (Tregs) after CD25-depleted allotransplantation in elderly patients and association with acute graft-versus-host disease. Blood 110:1689–1697PubMedCrossRefGoogle Scholar
  51. 51.
    Krupica T Jr, Fry TJ, Mackall CL (2006) Autoimmunity during lymphopenia: a two-hit model. Clin Immunol 120:121–128PubMedCrossRefGoogle Scholar
  52. 52.
    Keilholz U, Letsch A, Busse A, Asemissen AM, Bauer S, Blau IW et al (2009) A clinical and immunologic phase 2 trial of Wilms tumor gene product 1 (WT1) peptide vaccination in patients with AML and MDS. Blood 113:6541–6548PubMedCrossRefGoogle Scholar
  53. 53.
    Maslak PG, Dao T, Krug LM, Chanel S, Korontsvit T, Zakhaleva V et al (2010) Vaccination with synthetic analog peptides derived from WT1 oncoprotein induces T-cell responses in patients with complete remission from acute myeloid leukemia. Blood 116:171–179PubMedCrossRefGoogle Scholar
  54. 54.
    Oka Y, Tsuboi A, Taguchi T, Osaki T, Kyo T, Nakajima H et al (2004) Induction of WT1 (Wilms’ tumor gene)-specific cytotoxic T lymphocytes by WT1 peptide vaccine and the resultant cancer regression. Proc Natl Acad Sci USA 101:13885–13890PubMedCrossRefGoogle Scholar
  55. 55.
    Schmitt M, Schmitt A, Rojewski MT, Chen J, Giannopoulos K, Fei F et al (2008) RHAMM-R3 peptide vaccination in patients with acute myeloid leukemia, myelodysplastic syndrome, and multiple myeloma elicits immunologic and clinical responses. Blood 111:1357–1365PubMedCrossRefGoogle Scholar
  56. 56.
    Van Tendeloo VF, Van De Velde CJ, Van Driessche A, Cools N, Anguille S et al (2010) Induction of complete and molecular remissions in acute myeloid leukemia by Wilms’ tumor 1 antigen-targeted dendritic cell vaccination. Proc Natl Acad Sci USA 107:13824–13829PubMedCrossRefGoogle Scholar
  57. 57.
    Greiner J, Schmitt A, Giannopoulos K, Rojewski MT, Gotz M, Funk I et al (2010) High-dose RHAMM-R3 peptide vaccination for patients with acute myeloid leukemia, myelodysplastic syndrome and multiple myeloma. Haematologica 95:1191–1197PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag (outside the USA) 2011

Authors and Affiliations

  • Katayoun Rezvani
    • 1
    • 2
  • Agnes S. M. Yong
    • 1
  • Stephan Mielke
    • 1
    • 3
  • Bipin N. Savani
    • 1
    • 4
  • Behnam Jafarpour
    • 1
  • Rhoda Eniafe
    • 1
  • Robert Quan Le
    • 1
  • Laura Musse
    • 1
  • Carole Boss
    • 1
  • Richard Childs
    • 1
  • A. John Barrett
    • 1
  1. 1.Hematology Branch, National Heart, Lung and Blood InstituteNational Institutes of HealthBethesdaUSA
  2. 2.Department of HematologyImperial CollegeLondonUK
  3. 3.Wuerzburg UniversityWuerzburgGermany
  4. 4.Vanderbilt University Medical CenterNashvilleUSA

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