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

Author:

Goodyear Oliver1,Agathanggelou Angelo1,Novitzky-Basso Igor2,Siddique Shamyla2,McSkeane Tina2,Ryan Gordon1,Vyas Paresh3,Cavenagh Jamie4,Stankovic Tanja1,Moss Paul12,Craddock Charles12

Affiliation:

1. CRUK Institute for Cancer Studies, University of Birmingham, Birmingham;

2. Centre for Clinical Haematology, Queen Elizabeth Hospital, University Hospital Birmingham National Health Service (NHS) Trust, Birmingham;

3. Weatherall Institute of Molecular Medicine, John Radcliffe Hospital NHS Trust, Oxford; and

4. Department of Haematology, St Bartholomew's Hospital, London, United Kingdom

Abstract

Abstract 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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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