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

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*

*Corresponding author for this work

Research output: Contribution to journalArticle

55 Scopus citations

Abstract

Purpose: Patients with Hodgkin lymphoma (HL) relapsing after hematopoietic stem cell transplant have limited options for long-term cure.Wehave 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 inHL-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.

Original languageEnglish (US)
Pages (from-to)7058-7066
Number of pages9
JournalClinical Cancer Research
Volume17
Issue number22
DOIs
StatePublished - Nov 15 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Cruz, C. R., Gerdemann, U., Leen, A. M., Shafer, J. A., Ku, S., Tzou, B., Horton, T. M., Sheehan, A., Copeland, A., Younes, A., Rooney, C. M., Heslop, H. E., & Bollard, C. M. (2011). Improving T-cell therapy for relapsed EBV-negative Hodgkin lymphoma by targeting upregulated MAGE-A4. Clinical Cancer Research, 17(22), 7058-7066. https://doi.org/10.1158/1078-0432.CCR-11-1873