title: Improving T-cell therapy for relapsed EBV-negative Hodgkin lymphoma by targeting upregulated MAGE-A4.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.
authors: Conrad R
authors: CR
authors: Cruz
authors: Ulrike
authors: U
authors: Gerdemann
authors: Ann M
authors: AM
authors: Leen
authors: Jessica A
authors: JA
authors: Shafer
authors: Stephanie
authors: S
authors: Ku
authors: Benjamin
authors: B
authors: Tzou
authors: Terzah M
authors: TM
authors: Horton
authors: Andrea
authors: A
authors: Sheehan
authors: Amanda
authors: A
authors: Copeland
authors: Anas
authors: A
authors: Younes
authors: Cliona M
authors: CM
authors: Rooney
authors: Helen E
authors: HE
authors: Heslop
authors: Catherine M
authors: CM
authors: Bollard
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism*; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D000077209:Decitabine; D044127:Epigenesis, Genetic; D000939:Epitopes; D005240:Feasibility Studies; D004854:Herpesvirus 4, Human / Q000302:isolation & purification; D006689:Hodgkin Disease / Q000276:immunology / Q000628:therapy* / Q000821:virology; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000378:metabolism*; D012008:Recurrence; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000637:transplantation*; D015854:Up-Regulation
chemical_list: D000951:Antigens, Neoplasm; D000964:Antimetabolites, Antineoplastic; D000939:Epitopes; C095204:MAGEA4 protein, human; D009363:Neoplasm Proteins; D000077209:Decitabine; D001374:Azacitidine