Induction of a CD8+ T-cell response to the MAGE cancer testis antigen by combined treatment with azacitidine and sodium valproate in patients with acute myeloid leukemia and myelodysplasia

被引:293
作者
Goodyear, Oliver [2 ]
Agathanggelou, Angelo [2 ]
Novitzky-Basso, Igor [1 ]
Siddique, Shamyla [1 ]
McSkeane, Tina [1 ]
Ryan, Gordon [2 ]
Vyas, Paresh [3 ]
Cavenagh, Jamie [4 ]
Stankovic, Tanja [2 ]
Moss, Paul [1 ,2 ]
Craddock, Charles [1 ,2 ]
机构
[1] Univ Hosp Birmingham Natl Hlth Serv NHS Trust, Queen Elizabeth Hosp, Ctr Clin Haematol, Birmingham B15 2TH, W Midlands, England
[2] Univ Birmingham, CRUK Inst Canc Studies, Birmingham, W Midlands, England
[3] John Radcliffe Hosp NHS Trust, Weatherall Inst Mol Med, Oxford, England
[4] St Bartholomews Hosp, Dept Haematol, London, England
关键词
CHRONIC MYELOGENOUS LEUKEMIA; CLASS-I ANTIGENS; DNA METHYLATION; MULTIPLE-MYELOMA; CANCER/TESTIS ANTIGENS; CUTANEOUS MELANOMA; TUMOR-ANTIGENS; UP-REGULATION; GERM-LINE; EXPRESSION;
D O I
10.1182/blood-2009-11-249474
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Epigenetic therapies, including DNA methyltransferase and histone deacetylase inhibitors, represent important new treatment modalities in hematologic malignancies, but their mechanism of action remains unknown. We reasoned that up-regulation of epigenetically silenced tumor antigens may induce an immunologically mediated antitumor response and contribute to their clinical activity. In this study, we demonstrate that azacitidine (AZA) and sodium valproate (VPA) up-regulate expression of melanoma-associated antigens (MAGE antigens) on acute myeloid leukemia (AML) and myeloma cell lines. In separate studies, we observed that prior exposure to AZA/VPA increased recognition of myeloma cell lines by a MAGE-specific CD8(+) cytotoxic T-lymphocyte (CTL) clone. We therefore measured CTL responses to MAGE antigens in 21 patients with AML or myelodysplasia treated with AZA/VPA. CTL responses to MAGE antigens were documented in only 1 patient before therapy; however, treatment with AZA/VPA induced a CTL response in 10 patients. Eight of the 11 patients with circulating MAGE CTLs achieved a major clinical response after AZA/VPA therapy. This is the first demonstration of a MAGE-specific CTL response in AML. Furthermore, it appears that epigenetic therapies have the capacity to induce a CTL response to MAGE antigens in vivo that may contribute to their clinical activity in AML. This study was registered at http://isrctn.org as #ISCTN68418952. (Blood. 2010; 116(11): 1908-1918)
引用
收藏
页码:1908 / 1918
页数:11
相关论文
共 47 条
  • [1] Cancer-testis antigens are commonly expressed in multiple myeloma and induce systemic immunity following allogeneic stem cell transplantation
    Atanackovic, Djordje
    Arfsten, Julia
    Cao, Yanran
    Gnjatic, Sacha
    Schnieders, Frank
    Bartels, Katrin
    Schilling, Georgia
    Faltz, Christiane
    Wolschke, Christine
    Dierlamm, Judith
    Ritter, Gerd
    Eiermann, Thomas
    Hossfeld, Dieter Kurt
    Zander, Axel R.
    Jungbluth, Achim A.
    Old, Lloyd J.
    Bokemeyer, Carsten
    Kroeger, Nicolaus
    [J]. BLOOD, 2007, 109 (03) : 1103 - 1112
  • [2] Detection and enrichment of antigen-specific CD4+ and CD8+ T cells based on cytokine secretion
    Campbell, JDM
    [J]. METHODS, 2003, 31 (02) : 150 - 159
  • [3] Combination of DNA methylation inhibitor 5-azacytidine and arsenic trioxide has synergistic activity in myeloma
    Chen, Guanghua
    Wang, Yi
    Huang, Haiwen
    Lin, Fengru
    Wu, Depei
    Sun, Aining
    Chang, Huirong
    Feng, Yufeng
    [J]. EUROPEAN JOURNAL OF HAEMATOLOGY, 2009, 82 (03) : 176 - 183
  • [4] Revised recommendations of the international working group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia
    Cheson, BD
    Bennett, JM
    Kopecky, KJ
    Büchner, T
    Willman, CL
    Estey, EH
    Schiffer, CA
    Döhner, H
    Tallman, MS
    Lister, TA
    LoCocco, F
    Willemze, R
    Biondi, A
    Hiddemann, W
    Larson, RA
    Löwenberg, B
    Sanz, MA
    Head, DR
    Ohno, R
    Bloomfield, CD
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 2003, 21 (24) : 4642 - 4649
  • [5] Prolonged upregulation of the expression of HLA class I antigens and costimulatory molecules on melanoma cells treated with 5-aza-2′-deoxycytidine (5-AZA-CdR)
    Coral, S
    Sigalotti, L
    Gasparollo, A
    Cattarossi, I
    Visintin, A
    Cattelan, A
    Altomonte, M
    Maio, M
    [J]. JOURNAL OF IMMUNOTHERAPY, 1999, 22 (01): : 16 - 24
  • [6] De Smet C, 1999, MOL CELL BIOL, V19, P7327
  • [7] Treatment of Chronic Lymphocytic Leukemia with a Hypomethylating Agent Induces Expression of NXF2, an Immunogenic Cancer Testis Antigen
    Dubovsky, Jason A.
    McNeel, Douglas G.
    Powers, John J.
    Gordon, John
    Sotomayor, Eduardo M.
    Pinilla-Ibarz, Javier A.
    [J]. CLINICAL CANCER RESEARCH, 2009, 15 (10) : 3406 - 3415
  • [8] Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies
    Fandy, Tamer E.
    Herman, James G.
    Kerns, Patrick
    Jiemjit, Anchalee
    Sugar, Elizabeth A.
    Choi, Si-Ho
    Yang, Allen S.
    Aucott, Timothy
    Dauses, Tianna
    Odchimar-Reissig, Rosalie
    Licht, Jonathan
    McConnell, Melanie J.
    Nasrallah, Chris
    Kim, Marianne K. H.
    Zhang, Weijia
    Sun, Yezou
    Murgo, Anthony
    Espinoza-Delgado, Igor
    Oteiza, Katharine
    Owoeye, Ibitayo
    Silverman, Lewis R.
    Gore, Steven D.
    Carraway, Hetty E.
    [J]. BLOOD, 2009, 114 (13) : 2764 - 2773
  • [9] Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study
    Fenaux, Pierre
    Mufti, Ghulam J.
    Hellstrom-Lindberg, Eva
    Santini, Valeria
    Finelli, Carlo
    Giagounidis, Aristoteles
    Schoch, Robert
    Gattermann, Norbert
    Sanz, Guillermo
    List, Alan
    Gore, Steven D.
    Seymour, John F.
    Bennett, John M.
    Byrd, John
    Backstrom, Jay
    Zimmerman, Linda
    McKenzie, David
    Beach, C. L.
    Silverman, Lewis R.
    [J]. LANCET ONCOLOGY, 2009, 10 (03) : 223 - 232
  • [10] Functional up-regulation of human leukocyte antigen class I antigens expression by 5-aza-2′-deoxycytidine in cutaneous melanoma:: Immunotherapeutic implications
    Fonsatti, Ester
    Nicolay, Hugues J. M.
    Sigalotti, Luca
    Calabro, Luana
    Pezzani, Laura
    Colizzi, Francesca
    Altomonte, Maresa
    Guidoboni, Massimo
    Marincola, Francesco M.
    Maio, Michele
    [J]. CLINICAL CANCER RESEARCH, 2007, 13 (11) : 3333 - 3338