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
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
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DOI：
10.1182/blood-2009-11-249474
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发表时间：
2010-09-16
期刊：
影响因子：
20.3
通讯作者：
Craddock, Charles
中科院分区：
文献类型：
--
作者：
Goodyear, Oliver;Agathanggelou, Angelo;Craddock, Charles
表观遗传疗法，包括DNA甲基转移酶和组蛋白脱乙酰酶抑制剂，代表了血液恶性肿瘤的重要新治疗方式，但其作用机制仍不清楚。我们推测，表观遗传沉默的肿瘤抗原的上调可能会诱导免疫介导的抗肿瘤反应并有助于其临床活性。在这项研究中，我们证明，阿扎胞苷（AZA）和丙戊酸钠（VPA）上调表达的黑色素瘤相关抗原（法师抗原）的急性髓性白血病（AML）和骨髓瘤细胞系。在单独的研究中，我们观察到预先暴露于AZA/VPA增加了MAGE特异性CD 8（+）细胞毒性T淋巴细胞（CTL）克隆对骨髓瘤细胞系的识别。因此，我们测量了21例AML或骨髓增生异常患者接受AZA/VPA治疗后对法师抗原的CTL应答。治疗前仅1例患者记录了对法师抗原的CTL应答;然而，AZA/VPA治疗诱导了10例患者的CTL应答。11例循环法师CTL患者中有8例在AZA/VPA治疗后获得了主要临床应答。这是AML中MAGE特异性CTL应答的首次证明。此外，表观遗传疗法似乎具有在体内诱导对法师抗原的CTL应答的能力，这可能有助于其在AML中的临床活性。本研究在http://isrctn.org注册为#ISCTN68418952。（血。2010; 116（11）：1908-1918）
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)