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Minor histocompatibility Ags: identification strategies, clinical results and translational perspectives

Bone Marrow Transplantation volume 51, pages 163–171 (2016)Cite this article

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Abstract

Allogeneic stem cell transplantation (allo-SCT) and donor lymphocyte infusion are effective treatment modalities for various hematological malignancies. Their therapeutic effect, the graft-versus-tumor (GvT) effect, is based mainly on an alloimmune response of donor T cells directed at tumor cells, in which differences in the expression of minor histocompatibility Ags (mHags) on the cells of the patient and donor have a crucial role. However, these differences are also responsible for induction of sometimes detrimental GvHD. As relapse and development of GvHD pose major threats for a large proportion of allotransplanted patients, additional therapeutic strategies are required. To augment the GvT response without increasing the risk of GvHD, specific mHag-directed immunotherapeutic strategies have been developed. Over the past years, much effort has been put into the identification of therapeutically relevant mHags to enable these strategies for a substantial proportion of patients. Currently, the concept of mHag-directed immunotherapy is tested in clinical trials on feasibility, safety and efficacy. In this review, we will summarize the recent developments in mHag identification and the clinical data on mHag-specific immune responses and mHag-directed therapies in patients with hematological malignancies. Finally, we will outline the current challenges and future prospectives in the field.

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References

  1. Goulmy E . Minor histocompatibility antigens: allo target molecules for tumor-specific immunotherapy. Cancer J 2004; 10: 1–7.

    Article  CAS  PubMed  Google Scholar 

  2. de Bueger M, Bakker A, Van Rood JJ, Van der Woude F, Goulmy E . Tissue distribution of human minor histocompatibility antigens. Ubiquitous versus restricted tissue distribution indicates heterogeneity among human cytotoxic T lymphocyte-defined non-MHC antigens. J Immunol 1992; 149: 1788–1794.

    CAS  PubMed  Google Scholar 

  3. van Loenen MM, de Boer R, Hagedoorn RS, van Egmond EH, Falkenburg JH, Heemskerk MH . Optimization of the HA-1-specific T-cell receptor for gene therapy of hematologic malignancies. Haematologica 2011; 96: 477–481.

    Article  CAS  PubMed  Google Scholar 

  4. Goulmy E . Minor histocompatibility antigens: from transplantation problems to therapy of cancer. Hum Immunol 2006; 67: 433–438.

    Article  CAS  PubMed  Google Scholar 

  5. Spaapen R, Mutis T . Targeting haematopoietic-specific minor histocompatibility antigens to distinguish graft-versus-tumour effects from graft-versus-host disease. Best Pract Res Clin Haematol 2008; 21: 543–557.

    Article  CAS  PubMed  Google Scholar 

  6. Spaapen RM, Lokhorst HM, van den Oudenalder K, Otterud BE, Dolstra H, Leppert MF et al. Toward targeting B cell cancers with CD4+ CTLs: identification of a CD19-encoded minor histocompatibility antigen using a novel genome-wide analysis. J Exp Med 2008; 205: 2863–2872.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mutis THY . Antibodies as biomarkers for chronic GVHD. Blood 2015; 125: 3046–3047.

    Article  PubMed  Google Scholar 

  8. Nakasone H, Tian L, Sahaf B, Kawase T, Schoenrock K, Perloff S et al. Allogeneic HY antibodies detected 3 months after female-to-male HCT predict chronic GVHD and nonrelapse mortality in humans. Blood 2015; 125: 3193–3201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Brickner AG, Warren EH, Caldwell JA, Akatsuka Y, Golovina TN, Zarling AL et al. The immunogenicity of a new human minor histocompatibility antigen results from differential antigen processing. J Exp Med 2001; 193: 195–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. den Haan JM, Sherman NE, Blokland E, Huczko E, Koning F, Drijfhout JW et al. Identification of a graft versus host disease-associated human minor histocompatibility antigen. Science 1995; 268: 1476–1480.

    Article  CAS  PubMed  Google Scholar 

  11. Dolstra H, Fredrix H, Maas F, Coulie PG, Brasseur F, Mensink E et al. A human minor histocompatibility antigen specific for B cell acute lymphoblastic leukemia. J Exp Med 1999; 189: 301–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Murata M, Warren EH, Riddell SR . A human minor histocompatibility antigen resulting from differential expression due to a gene deletion. J Exp Med 2003; 197: 1279–1289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Spierings E, Brickner AG, Caldwell JA, Zegveld S, Tatsis N, Blokland E et al. The minor histocompatibility antigen HA-3 arises from differential proteasome-mediated cleavage of the lymphoid blast crisis (Lbc) oncoprotein. Blood 2003; 102: 621–629.

    Article  CAS  PubMed  Google Scholar 

  14. Dausset J, Cann H, Cohen D, Lathrop M, Lalouel JM, White R . Centre d'etude du polymorphisme humain (CEPH): collaborative genetic mapping of the human genome. Genomics 1990; 6: 575–577.

    Article  CAS  PubMed  Google Scholar 

  15. Van Bergen CA, Rutten CE, Van Der Meijden ED, Van Luxemburg-Heijs SA, Lurvink EG, Houwing-Duistermaat JJ et al. High-throughput characterization of 10 new minor histocompatibility antigens by whole genome association scanning. Cancer Res 2010; 70: 9073–9083.

    Article  CAS  PubMed  Google Scholar 

  16. Warren EH, Otterud BE, Linterman RW, Brickner AG, Engelhard VH, Leppert MF et al. Feasibility of using genetic linkage analysis to identify the genes encoding T cell-defined minor histocompatibility antigens. Tissue Antigens 2002; 59: 293–303.

    Article  CAS  PubMed  Google Scholar 

  17. Akatsuka Y, Nishida T, Kondo E, Miyazaki M, Taji H, Iida H et al. Identification of a polymorphic gene, BCL2A1, encoding two novel hematopoietic lineage-specific minor histocompatibility antigens. J Exp Med 2003; 197: 1489–1500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. de Rijke B, van Horssen-Zoetbrood A, Beekman JM, Otterud B, Maas F, Woestenenk R et al. A frameshift polymorphism in P2X5 elicits an allogeneic cytotoxic T lymphocyte response associated with remission of chronic myeloid leukemia. J Clin Invest 2005; 115: 3506–3516.

    Article  CAS  PubMed  Google Scholar 

  19. Gubarev MI, Jenkin JC, Leppert MF, Buchanan GS, Otterud BE, Guilbert DA et al. Localization to chromosome 22 of a gene encoding a human minor histocompatibility antigen. J Immunol 1996; 157: 5448–5454.

    CAS  PubMed  Google Scholar 

  20. Gubarev MI, Jenkin JC, Otterrud BE, Leppert MF, Schallheim JM, Beatty PG . Localization to chromosome 11 of a gene encoding a human minor histocompatibility antigen. Exp Hematol 1998; 26: 976–981.

    CAS  PubMed  Google Scholar 

  21. Kamei M, Nannya Y, Torikai H, Kawase T, Taura K, Inamoto Y et al. HapMap scanning of novel human minor histocompatibility antigens. Blood 2009; 113: 5041–5048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Oostvogels R, Minnema MC, van Elk M, Spaapen RM, te Raa GD, Giovannone B et al. Towards effective and safe immunotherapy after allogeneic stem cell transplantation: identification of hematopoietic-specific minor histocompatibility antigen UTA2-1. Leukemia 2013; 27: 642–649.

    Article  CAS  PubMed  Google Scholar 

  23. Spaapen RM, de Kort RA, van den Oudenalder K, van Elk M, Bloem AC, Lokhorst HM et al. Rapid identification of clinical relevant minor histocompatibility antigens via genome-wide zygosity–genotype correlation analysis. Clin Cancer Res 2009; 15: 7137–7143.

    Article  CAS  PubMed  Google Scholar 

  24. Oostvogels R, Lokhorst HM, Minnema MC, van Elk M, van den Oudenalder K, Spierings E et al. Identification of minor histocompatibility antigens based on the 1000 Genomes Project. Haematologica 2014; 99: 1854–1859.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bleakley M, Riddell SR . Exploiting T cells specific for human minor histocompatibility antigens for therapy of leukemia. Immunol Cell Biol 2011; 89: 396–407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wenandy L, Kollgaard T, Letsch A, Andersen RS, Stather D, Seremet T et al. The 1170 A-P single-nucleotide polymorphism (SNP) in the Her-2/neu protein (HER2) as a minor histocompatibility antigen (mHag). Leukemia 2009; 23: 1926–1929.

    Article  CAS  PubMed  Google Scholar 

  27. Hambach L, Goulmy E . Immunotherapy of cancer through targeting of minor histocompatibility antigens. Curr Opin Immunol 2005; 17: 202–210.

    Article  CAS  PubMed  Google Scholar 

  28. Hombrink P, Hadrup SR, Bakker A, Kester MG, Falkenburg JH, von dem Borne PA et al. High-throughput identification of potential minor histocompatibility antigens by MHC tetramer-based screening: feasibility and limitations. PLoS ONE 2011; 6: e22523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hombrink P, Hassan C, Kester MG, de Ru AH, van Bergen CA, Nijveen H et al. Discovery of T cell epitopes implementing HLA-peptidomics into a reverse immunology approach. J Immunol 2013; 190: 3869–3877.

    Article  CAS  PubMed  Google Scholar 

  30. Hombrink P, Hassan C, Kester MG, Jahn L, Pont MJ, de Ru AH et al. Identification of biological relevant minor histocompatibility antigens within the B-lymphocyte-derived HLA-ligandome using a reverse immunology approach. Clin Cancer Res 2015; 21: 2177–2186.

    Article  CAS  PubMed  Google Scholar 

  31. Sampson JK, Sheth NU, Koparde VN, Scalora AF, Serrano MG, Lee V et al. Whole exome sequencing to estimate alloreactivity potential between donors and recipients in stem cell transplantation. Br J Haematol 2014; 166: 566–570.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jameson-Lee M, Koparde V, Griffith P, Scalora AF, Sampson JK, Khalid H et al. In silico derivation of HLA-specific alloreactivity potential from whole exome sequencing of stem-cell transplant donors and recipients: understanding the quantitative immunobiology of allogeneic transplantation. Front Immunol 2014; 5: 529.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Hambach L, Vermeij M, Buser A, Aghai Z, van der Kwast T, Goulmy E . Targeting a single mismatched minor histocompatibility antigen with tumor-restricted expression eradicates human solid tumors. Blood 2008; 112: 1844–1852.

    Article  CAS  PubMed  Google Scholar 

  34. Spaapen RM, Groen RW, van den Oudenalder K, Guichelaar T, van Elk M, Aarts-Riemens T et al. Eradication of medullary multiple myeloma by CD4+ cytotoxic human T lymphocytes directed at a single minor histocompatibility antigen. Clin Cancer Res 2010; 16: 5481–5488.

    Article  CAS  PubMed  Google Scholar 

  35. Marijt WA, Heemskerk MH, Kloosterboer FM, Goulmy E, Kester MG, van der Hoorn MA et al. Hematopoiesis-restricted minor histocompatibility antigens HA-1- or HA-2-specific T cells can induce complete remissions of relapsed leukemia. Proc Natl Acad Sci USA 2003; 100: 2742–2747.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Akatsuka Y, Warren EH, Gooley TA, Brickner AG, Lin MT, Hansen JA et al. Disparity for a newly identified minor histocompatibility antigen, HA-8, correlates with acute graft-versus-host disease after haematopoietic stem cell transplantation from an HLA-identical sibling. Br J Haematol 2003; 123: 671–675.

    Article  CAS  PubMed  Google Scholar 

  37. Gallardo D, Arostegui JI, Balas A, Torres A, Caballero D, Carreras E et al. Disparity for the minor histocompatibility antigen HA-1 is associated with an increased risk of acute graft-versus-host disease (GvHD) but it does not affect chronic GvHD incidence, disease-free survival or overall survival after allogeneic human leucocyte antigen-identical sibling donor transplantation. Br J Haematol 2001; 114: 931–936.

    Article  CAS  PubMed  Google Scholar 

  38. 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  PubMed  Google Scholar 

  39. Mutis T, Gillespie G, Schrama E, Falkenburg JH, Moss P, Goulmy E . Tetrameric HLA class I-minor histocompatibility antigen peptide complexes demonstrate minor histocompatibility antigen-specific cytotoxic T lymphocytes in patients with graft-versus-host disease. Nat Med 1999; 5: 839–842.

    Article  CAS  PubMed  Google Scholar 

  40. Tseng LH, Lin MT, Hansen JA, Gooley T, Pei J, Smith AG et al. Correlation between disparity for the minor histocompatibility antigen HA-1 and the development of acute graft-versus-host disease after allogeneic marrow transplantation. Blood 1999; 94: 2911–2914.

    Article  CAS  PubMed  Google Scholar 

  41. Perez-Garcia A, De la Camara R, Torres A, Gonzalez M, Jimenez A, Gallardo D . Minor histocompatibility antigen HA-8 mismatch and clinical outcome after HLA-identical sibling donor allogeneic stem cell transplantation. Haematologica 2005; 90: 1723–1724.

    CAS  PubMed  Google Scholar 

  42. Gratwohl A, Hermans J, Niederwieser D, van Biezen A, van Houwelingen HC, Apperley J . Female donors influence transplant-related mortality and relapse incidence in male recipients of sibling blood and marrow transplants. Hematol J 2001; 2: 363–370.

    Article  CAS  PubMed  Google Scholar 

  43. Markiewicz M, Siekiera U, Karolczyk A, Szymszal J, Helbig G, Wojnar J et al. Immunogenic disparities of 11 minor histocompatibility antigens (mHAs) in HLA-matched unrelated allogeneic hematopoietic SCT. Bone Marrow Transplant 2009; 43: 293–300.

    Article  CAS  PubMed  Google Scholar 

  44. Mutis T, Brand R, Gallardo D, van Biezen A, Niederwieser D, Goulmy E . Graft-versus-host driven graft-versus-leukemia effect of minor histocompatibility antigen HA-1 in chronic myeloid leukemia patients. Leukemia 2010; 24: 1388–1392.

    Article  CAS  PubMed  Google Scholar 

  45. Spierings E, Kim YH, Hendriks M, Borst E, Sergeant R, Canossi A et al. Multicenter analyses demonstrate significant clinical effects of minor histocompatibility antigens on GvHD and GvL after HLA-matched related and unrelated hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2013; 19: 1244–1253.

    Article  CAS  PubMed  Google Scholar 

  46. Heinemann FM, Ferencik S, Ottinger HD, Beelen DW, Grosse-Wilde H . Impact of disparity of minor histocompatibility antigens HA-1, CD31, and CD49b in hematopoietic stem cell transplantation of patients with chronic myeloid leukemia with sibling and unrelated donors. Transplantation 2004; 77: 1103–1106.

    Article  CAS  PubMed  Google Scholar 

  47. Lin MT, Gooley T, Hansen JA, Tseng LH, Martin EG, Singleton K et al. Absence of statistically significant correlation between disparity for the minor histocompatibility antigen-HA-1 and outcome after allogeneic hematopoietic cell transplantation. Blood 2001; 98: 3172–3173.

    Article  CAS  PubMed  Google Scholar 

  48. Spellman S, Warden MB, Haagenson M, Pietz BC, Goulmy E, Warren EH et al. Effects of mismatching for minor histocompatibility antigens on clinical outcomes in HLA-matched, unrelated hematopoietic stem cell transplants. Biol Blood Marrow Transplant 2009; 15: 856–863.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hobo W, Broen K, van der Velden WJ, Greupink-Draaisma A, Adisty N, Wouters Y et al. Association of disparities in known minor histocompatibility antigens with relapse-free survival and graft-versus-host disease after allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2013; 19: 274–282.

    Article  CAS  PubMed  Google Scholar 

  50. Kongtim P, Di Stasi A, Rondon G, Chen J, Adekola K, Popat U et al. Can a female donor for a male recipient decrease the relapse rate for patients with acute myeloid leukemia treated with allogeneic hematopoietic stem cell transplantation? Biol Blood Marrow Transplant 2015; 21: 713–719.

    Article  PubMed  Google Scholar 

  51. Warren EH, Fujii N, Akatsuka Y, Chaney CN, Mito JK, Loeb KR et al. Therapy of relapsed leukemia after allogeneic hematopoietic cell transplantation with T cells specific for minor histocompatibility antigens. Blood 2010; 115: 3869–3878.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Meij P, Jedema I, van der Hoorn MA, Bongaerts R, Cox L, Wafelman AR et al. Generation and administration of HA-1-specific T-cell lines for the treatment of patients with relapsed leukemia after allogeneic stem cell transplantation: a pilot study. Haematologica 2012; 97: 1205–1208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Inaguma Y, Akahori Y, Murayama Y, Shiraishi K, Tsuzuki-Iba S, Endoh A et al. Construction and molecular characterization of a T-cell receptor-like antibody and CAR-T cells specific for minor histocompatibility antigen HA-1H. Gene Ther 2014; 21: 575–584.

    Article  CAS  PubMed  Google Scholar 

  54. Palucka K, Banchereau J . Cancer immunotherapy via dendritic cells. Nat Rev Cancer 2012; 12: 265–277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. van der Waart AB, van de Weem NM, Maas F, Kramer CS, Kester MG, Falkenburg JH et al. Inhibition of Akt signaling promotes the generation of superior tumor-reactive T cells for adoptive immunotherapy. Blood 2014; 124: 3490–3500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Colonna M, Trinchieri G, Liu YJ . Plasmacytoid dendritic cells in immunity. Nat Immunol 2004; 5: 1219–1226.

    Article  CAS  PubMed  Google Scholar 

  57. Morelli AE, Thomson AW . Dendritic cells: regulators of alloimmunity and opportunities for tolerance induction. Immunol Rev 2003; 196: 125–146.

    Article  CAS  PubMed  Google Scholar 

  58. Romani N, Gruner S, Brang D, Kampgen E, Lenz A, Trockenbacher B et al. Proliferating dendritic cell progenitors in human blood. J Exp Med 1994; 180: 83–93.

    Article  CAS  PubMed  Google Scholar 

  59. 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 alpha. J Exp Med 1994; 179: 1109–1118.

    Article  CAS  PubMed  Google Scholar 

  60. Reichardt VL, Brossart P, Kanz L . Dendritic cells in vaccination therapies of human malignant disease. Blood Rev 2004; 18: 235–243.

    Article  PubMed  Google Scholar 

  61. Syme R, Bajwa R, Robertson L, Stewart D, Gluck S . Comparison of CD34 and monocyte-derived dendritic cells from mobilized peripheral blood from cancer patients. Stem Cells 2005; 23: 74–81.

    Article  PubMed  Google Scholar 

  62. Banchereau J, Palucka AK, Dhodapkar M, Burkeholder S, Taquet N, Rolland A et al. Immune and clinical responses in patients with metastatic melanoma to CD34(+) progenitor-derived dendritic cell vaccine. Cancer Res 2001; 61: 6451–6458.

    CAS  PubMed  Google Scholar 

  63. Di Nicola M, Carlo-Stella C, Mortarini R, Baldassari P, Guidetti A, Gallino GF et al. Boosting T cell-mediated immunity to tyrosinase by vaccinia virus-transduced, CD34(+)-derived dendritic cell vaccination: a phase I trial in metastatic melanoma. Clin Cancer Res 2004; 10: 5381–5390.

    Article  CAS  PubMed  Google Scholar 

  64. Bloy N, Pol J, Aranda F, Eggermont A, Cremer I, Fridman WH et al. Trial watch: dendritic cell-based anticancer therapy. Oncoimmunology 2014; 3: e963424.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Anguille S, Smits EL, Lion E, van Tendeloo VF, Berneman ZN . Clinical use of dendritic cells for cancer therapy. Lancet Oncol 2014; 15: e257–e267.

    Article  CAS  PubMed  Google Scholar 

  66. Di Nicola M, Zappasodi R, Carlo-Stella C, Mortarini R, Pupa SM, Magni M et al. Vaccination with autologous tumor-loaded dendritic cells induces clinical and immunologic responses in indolent B-cell lymphoma patients with relapsed and measurable disease: a pilot study. Blood 2009; 113: 18–27.

    Article  CAS  PubMed  Google Scholar 

  67. Mapara MY, Kim YM, Wang SP, Bronson R, Sachs DH, Sykes M . Donor lymphocyte infusions mediate superior graft-versus-leukemia effects in mixed compared to fully allogeneic chimeras: a critical role for host antigen-presenting cells. Blood 2002; 100: 1903–1909.

    Article  CAS  PubMed  Google Scholar 

  68. Sykes M, Sheard MA, Sachs DH . Graft-versus-host-related immunosuppression is induced in mixed chimeras by alloresponses against either host or donor lymphohematopoietic cells. J Exp Med 1988; 168: 2391–2396.

    Article  CAS  PubMed  Google Scholar 

  69. Anderson BE, McNiff JM, Jain D, Blazar BR, Shlomchik WD, Shlomchik MJ . Distinct roles for donor- and host-derived antigen-presenting cells and costimulatory molecules in murine chronic graft-versus-host disease: requirements depend on target organ. Blood 2005; 105: 2227–2234.

    Article  CAS  PubMed  Google Scholar 

  70. Duffner UA, Maeda Y, Cooke KR, Reddy P, Ordemann R, Liu C et al. Host dendritic cells alone are sufficient to initiate acute graft-versus-host disease. J Immunol 2004; 172: 7393–7398.

    Article  CAS  PubMed  Google Scholar 

  71. Levenga H, Woestenenk R, Schattenberg AV, Maas F, Jansen JH, Raymakers R et al. Dynamics in chimerism of T cells and dendritic cells in relapsed CML patients and the influence on the induction of alloreactivity following donor lymphocyte infusion. Bone Marrow Transplant 2007; 40: 585–592.

    Article  CAS  PubMed  Google Scholar 

  72. Matte CC, Liu J, Cormier J, Anderson BE, Athanasiadis I, Jain D et al. Donor APCs are required for maximal GVHD but not for GVL. Nat Med 2004; 10: 987–992.

    Article  CAS  PubMed  Google Scholar 

  73. Shlomchik WD, Couzens MS, Tang CB, McNiff J, Robert ME, Liu J et al. Prevention of graft versus host disease by inactivation of host antigen-presenting cells. Science 1999; 285: 412–415.

    Article  CAS  PubMed  Google Scholar 

  74. Auffermann-Gretzinger S, Lossos IS, Vayntrub TA, Leong W, Grumet FC, Blume KG et al. Rapid establishment of dendritic cell chimerism in allogeneic hematopoietic cell transplant recipients. Blood 2002; 99: 1442–1448.

    Article  CAS  PubMed  Google Scholar 

  75. Giralt S, Thall PF, Khouri I, Wang X, Braunschweig I, Ippolitti C et al. Melphalan and purine analog-containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation. Blood 2001; 97: 631–637.

    Article  CAS  PubMed  Google Scholar 

  76. Kottaridis PD, Milligan DW, Chopra R, Chakraverty RK, Chakrabarti S, Robinson S et al. In vivo CAMPATH-1H prevents graft-versus-host disease following nonmyeloablative stem cell transplantation. Blood 2000; 96: 2419–2425.

    Article  CAS  PubMed  Google Scholar 

  77. McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 2001; 97: 3390–3400.

    Article  CAS  PubMed  Google Scholar 

  78. Parmiani G, Russo V, Maccalli C, Parolini D, Rizzo N, Maio M . Peptide-based vaccines for cancer therapy. Hum Vaccin Immunother 2014; 10: 3175–3178.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Hoppes R, Oostvogels R, Luimstra JJ, Wals K, Toebes M, Bies L et al. Altered peptide ligands revisited: vaccine design through chemically modified HLA-A2-restricted T cell epitopes. J Immunol 2014; 193: 4803–4813.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Parmiani G, Castelli C, Dalerba P, Mortarini R, Rivoltini L, Marincola FM et al. Cancer immunotherapy with peptide-based vaccines: what have we achieved? Where are we going? J Natl Cancer Inst 2002; 94: 805–818.

    Article  CAS  PubMed  Google Scholar 

  81. Mutis T, Ghoreschi K, Schrama E, Kamp J, Heemskerk M, Falkenburg JH et al. Efficient induction of minor histocompatibility antigen HA-1-specific cytotoxic T-cells using dendritic cells retrovirally transduced with HA-1-coding cDNA. Biol Blood Marrow Transplant 2002; 8: 412–419.

    Article  CAS  PubMed  Google Scholar 

  82. Overes IM, Fredrix H, Kester MG, Falkenburg JH, van der Voort R, de Witte TM et al. Efficient activation of LRH-1-specific CD8+ T-cell responses from transplanted leukemia patients by stimulation with P2X5 mRNA-electroporated dendritic cells. J Immunother 2009; 32: 539–551.

    Article  CAS  PubMed  Google Scholar 

  83. Hambach L, Aghai Z, Pool J, Kroger N, Goulmy E . Peptide length extension skews the minor HA-1 antigen presentation toward activated dendritic cells but reduces its presentation efficiency. J Immunol 2010; 185: 4582–4589.

    Article  CAS  PubMed  Google Scholar 

  84. Palucka K, Banchereau J . Human dendritic cell subsets in vaccination. Curr Opin Immunol 2013; 25: 396–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Schadendorf D, Ugurel S, Schuler-Thurner B, Nestle FO, Enk A, Brocker EB et al. Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG. Ann Oncol 2006; 17: 563–570.

    Article  CAS  PubMed  Google Scholar 

  86. Small EJ, Schellhammer PF, Higano CS, Redfern CH, Nemunaitis JJ, Valone FH et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol 2006; 24: 3089–3094.

    Article  CAS  PubMed  Google Scholar 

  87. Wimmers F, Schreibelt G, Skold AE, Figdor CG, De Vries IJ . Paradigm shift in dendritic cell-based immunotherapy: from in vitro generated monocyte-derived DCs to naturally circulating DC subsets. Front immunol 2014; 5: 165.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Tel J, Aarntzen EH, Baba T, Schreibelt G, Schulte BM, Benitez-Ribas D et al. Natural human plasmacytoid dendritic cells induce antigen-specific T-cell responses in melanoma patients. Cancer Res 2013; 73: 1063–1075.

    Article  CAS  PubMed  Google Scholar 

  89. Lou Y, Liu C, Kim GJ, Liu YJ, Hwu P, Wang G . Plasmacytoid dendritic cells synergize with myeloid dendritic cells in the induction of antigen-specific antitumor immune responses. J Immunol 2007; 178: 1534–1541.

    Article  CAS  PubMed  Google Scholar 

  90. Bonifaz LC, Bonnyay DP, Charalambous A, Darguste DI, Fujii S, Soares H et al. In vivo targeting of antigens to maturing dendritic cells via the DEC-205 receptor improves T cell vaccination. J Exp Med 2004; 199: 815–824.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Tacken PJ, Figdor CG . Targeted antigen delivery and activation of dendritic cells in vivo: steps towards cost effective vaccines. Semin Immunol 2011; 23: 12–20.

    Article  CAS  PubMed  Google Scholar 

  92. Asakura S, Hashimoto D, Takashima S, Sugiyama H, Maeda Y, Akashi K et al. Alloantigen expression on non-hematopoietic cells reduces graft-versus-leukemia effects in mice. J Clin Invest 2010; 120: 2370–2378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Palucka K, Banchereau J . Dendritic-cell-based therapeutic cancer vaccines. Immunity 2013; 39: 38–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Makkouk A, Weiner GJ . Cancer immunotherapy and breaking immune tolerance: new approaches to an old challenge. Cancer Res 2015; 75: 5–10.

    Article  CAS  PubMed  Google Scholar 

  95. Vasaturo A, Di Blasio S, Peeters DG, de Koning CC, de Vries JM, Figdor CG et al. Clinical implications of co-inhibitory molecule expression in the tumor microenvironment for DC vaccination: a game of stop and go. Front Immunol 2013; 4: 417.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Hobo W, Maas F, Adisty N, de Witte T, Schaap N, van der Voort R et al. siRNA silencing of PD-L1 and PD-L2 on dendritic cells augments expansion and function of minor histocompatibility antigen-specific CD8+ T cells. Blood 2010; 116: 4501–4511.

    Article  CAS  PubMed  Google Scholar 

  97. Norde WJ, Maas F, Hobo W, Korman A, Quigley M, Kester MG et al. PD-1/PD-L1 interactions contribute to functional T-cell impairment in patients who relapse with cancer after allogeneic stem cell transplantation. Cancer Res 2011; 71: 5111–5122.

    Article  CAS  PubMed  Google Scholar 

  98. van der Waart AB, Fredrix H, van der Voort R, Schaap N, Hobo W, Dolstra H . siRNA silencing of PD-1 ligands on dendritic cell vaccines boosts the expansion of minor histocompatibility antigen-specific CD8(+) T cells in NOD/SCID/IL2Rg(null) mice. Cancer Immunol Immunother 2015; 64: 645–654.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. de Haart SJ, van de Donk NW, Minnema MC, Huang JH, Aarts-Riemens T, Bovenschen N et al. Accessory cells of the microenvironment protect multiple myeloma from T-cell cytotoxicity through cell adhesion-mediated immune resistance. Clin Cancer Res 2013; 19: 5591–5601.

    Article  CAS  PubMed  Google Scholar 

  100. Kawase T, Nannya Y, Torikai H, Yamamoto G, Onizuka M, Morishima S et al. Identification of human minor histocompatibility antigens based on genetic association with highly parallel genotyping of pooled DNA. Blood 2008; 111: 3286–3294.

    Article  CAS  PubMed  Google Scholar 

  101. Torikai H, Akatsuka Y, Miyazaki M, Tsujimura A, Yatabe Y, Kawase T et al. The human cathepsin H gene encodes two novel minor histocompatibility antigen epitopes restricted by HLA-A*3101 and -A*3303. Br J Haematol 2006; 134: 406–416.

    Article  CAS  PubMed  Google Scholar 

  102. Kawase T, Akatsuka Y, Torikai H, Morishima S, Oka A, Tsujimura A et al. Alternative splicing due to an intronic SNP in HMSD generates a novel minor histocompatibility antigen. Blood 2007; 110: 1055–1063.

    Article  CAS  PubMed  Google Scholar 

  103. Tykodi SS, Fujii N, Vigneron N, Lu SM, Mito JK, Miranda MX et al. C19orf48 encodes a minor histocompatibility antigen recognized by CD8+ cytotoxic T cells from renal cell carcinoma patients. Clin Cancer Res 2008; 14: 5260–5269.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. 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  PubMed  Google Scholar 

  105. Dolstra H, de Rijke B, Fredrix H, Balas A, Maas F, Scherpen F et al. Bi-directional allelic recognition of the human minor histocompatibility antigen HB-1 by cytotoxic T lymphocytes. Eur J Immunol 2002; 32: 2748–2758.

    Article  CAS  PubMed  Google Scholar 

  106. Bleakley M, Otterud BE, Richardt JL, Mollerup AD, Hudecek M, Nishida T et al. Leukemia-associated minor histocompatibility antigen discovery using T-cell clones isolated by in vitro stimulation of naive CD8+ T cells. Blood 2010; 115: 4923–4933.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. van Bergen CA, Kester MG, Jedema I, Heemskerk MH, van Luxemburg-Heijs SA, Kloosterboer FM et al. Multiple myeloma-reactive T cells recognize an activation-induced minor histocompatibility antigen encoded by the ATP-dependent interferon-responsive (ADIR) gene. Blood 2007; 109: 4089–4096.

    Article  CAS  PubMed  Google Scholar 

  108. Stumpf AN, van der Meijden ED, van Bergen CA, Willemze R, Falkenburg JH, Griffioen M . Identification of 4 new HLA-DR-restricted minor histocompatibility antigens as hematopoietic targets in antitumor immunity. Blood 2009; 114: 3684–3692.

    Article  CAS  PubMed  Google Scholar 

  109. Griffioen M, Honders MW, van der Meijden ED, van Luxemburg-Heijs SA, Lurvink EG, Kester MG et al. Identification of 4 novel HLA-B*40:01 restricted minor histocompatibility antigens and their potential as targets for graft-versus-leukemia reactivity. Haematologica 2012; 97: 1196–1204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Griffioen M, van der Meijden ED, Slager EH, Honders MW, Rutten CE, van Luxemburg-Heijs SA et al. Identification of phosphatidylinositol 4-kinase type II beta as HLA class II-restricted target in graft versus leukemia reactivity. Proc Natl Acad Sci USA 2008; 105: 3837–3842.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Warren EH, Vigneron NJ, Gavin MA, Coulie PG, Stroobant V, Dalet A et al. An antigen produced by splicing of noncontiguous peptides in the reverse order. Science 2006; 313: 1444–1447.

    Article  CAS  PubMed  Google Scholar 

  112. Armistead PM, Liang S, Li H, Lu S, Van Bergen CA, Alatrash G et al. Common minor histocompatibility antigen discovery based upon patient clinical outcomes and genomic data. PLoS ONE 2011; 6: e23217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Wolfel C, Lennerz V, Lindemann E, Hess G, Derigs HG, Huber C et al. Dissection and molecular analysis of alloreactive CD8+ T cell responses in allogeneic haematopoietic stem cell transplantation. Cancer Immunol Immunother 2008; 57: 849–857.

    Article  PubMed  CAS  Google Scholar 

  114. Broen K, Levenga H, Vos J, van Bergen K, Fredrix H, Greupink-Draaisma A et al. A polymorphism in the splice donor site of ZNF419 results in the novel renal cell carcinoma-associated minor histocompatibility antigen ZAPHIR. PLoS ONE 2011; 6: e21699.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Dr Lokhorst reports grants from Janssen Research and Development, LLC; from Genmab, Utrecht, and from Cellgene, all outside the submitted work. Dr Mutis reports grants from Janssen Research and Development, LLC and grants from Genmab, Utrecht, both outside the submitted work.

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  1. Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, The Netherlands

    R Oostvogels & T Mutis

  2. Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands

    R Oostvogels

  3. Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands

    R Oostvogels, H M Lokhorst & T Mutis

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  1. R Oostvogels
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Oostvogels, R., Lokhorst, H. & Mutis, T. Minor histocompatibility Ags: identification strategies, clinical results and translational perspectives. Bone Marrow Transplant 51, 163–171 (2016). https://doi.org/10.1038/bmt.2015.256

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