Improving T-cell therapy for relapsed EBV-negative Hodgkin lymphoma by targeting upregulated MAGE-A4

Clin Cancer Res. 2011 Nov 15;17(22):7058-66. doi: 10.1158/1078-0432.CCR-11-1873. Epub 2011 Sep 9.


Purpose: Patients with Hodgkin lymphoma (HL) relapsing after hematopoietic stem cell transplant have limited options for long-term cure. We have shown that infused cytotoxic T cells (CTL) targeting Epstein Barr virus (EBV)-derived proteins induced complete remissions in EBV(+) HL patients. A limitation of this approach is that up to 70% of relapsed HL tumors are EBV-negative. For these patients, an alternative is to target the cancer/testis antigen MAGE-A4 present in EBV antigen-negative HL tumors. Furthermore, epigenetic modification by clinically available demethylating agents can enhance MAGE-A4 expression in previously MAGE-negative tumors.

Experimental design: We explored the feasibility of combining adoptive T cell therapy with epigenetic modification of tumor antigen expression. We further characterized MAGE-A4-specific T-cell phenotype and function, and examined the effects of the epigenetic modifying drug decitabine on these T cells.

Results: Cytotoxic T cells were generated specifically recognizing MAGE-A4 expressed by autologous HL targets and tumor cell lines. Decitabine-previously shown to increase tumor antigen expression in HL-did not compromise MAGE-A4-specific T-cell phenotype and function. In patients treated with decitabine, expanded MAGE-A4-specific T cells had a broader antitumor T cell repertoire, consistent with increased antigen stimulation in vivo.

Conclusions: Adoptive transfer of MAGE-A4-specific T cells, combined with epigenetic modifying drugs to increase expression of the protein, may improve treatment of relapsed HL.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Neoplasm / metabolism*
  • Antimetabolites, Antineoplastic / therapeutic use*
  • Azacitidine / analogs & derivatives*
  • Azacitidine / pharmacology
  • Azacitidine / therapeutic use
  • Cell Line, Tumor
  • Decitabine
  • Epigenesis, Genetic
  • Epitopes
  • Feasibility Studies
  • Herpesvirus 4, Human / isolation & purification
  • Hodgkin Disease / immunology
  • Hodgkin Disease / therapy*
  • Hodgkin Disease / virology
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Molecular Targeted Therapy
  • Neoplasm Proteins / metabolism*
  • Recurrence
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / transplantation*
  • Up-Regulation


  • Antigens, Neoplasm
  • Antimetabolites, Antineoplastic
  • Epitopes
  • MAGEA4 protein, human
  • Neoplasm Proteins
  • Decitabine
  • Azacitidine