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

Abstract

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.

• Authors: Conrad R Cruz, Ulrike Gerdemann, Ann M Leen, Jessica A Shafer, Stephanie Ku, Benjamin Tzou, Terzah M Horton, Andrea Sheehan, Amanda Copeland, Anas Younes, Cliona M Rooney, Helen E Heslop, Catherine M Bollard
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 22 Pg. 7058-66 (Nov 15 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21908573 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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