Improving T-cell Therapy for Relapsed EBV-Negative Hodgkin Lymphoma by Targeting Upregulated MAGE-A4
- 14 November 2011
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 17 (22), 7058-7066
- https://doi.org/10.1158/1078-0432.ccr-11-1873
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. Clin Cancer Res; 17(22); 7058–66. ©2011 AACR.Keywords
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