Work

Combined Epigenetic and Immune-Based Therapies for Relapsed Hodgkin'S Lymphoma Post Hematopoietic Stem Cell Transplant

Year: 2011

Type: article

Abstract: Hematopoietic stem cell transplant (HSCT) remains the primary therapy for Hodgkin's Lymphoma (HL) patients who relapse following standard therapies. Those who relapse have limited options for long-term cure. Two approaches have recently shown promise: T cell therapy, and therapy with epigenetic-modifying drugs. As usually seen in cancer, a multimodality approach may work best: we thus hypothesize that a combined immune–based and epigenetic therapy, targeting our antigen of choice MAGEA4, will be an effective approach for treating relapsed HL post HSCT. Success in T cell therapy targeting Epstein Barr virus (EBV) proteins in lymphoma is limited because most are EBV negative. MAGEA4 is expressed in EBV-negative HL, seen only in tumor & immune-privileged germ cells, and immunogenic. We also observed that we can increase MAGE expression by epigenetic modification of the tumor, supporting our hypothesis. To verify whether MAGE T cells can be expanded from different donors, cells from HL patients (n = 4), healthy donors (n = 15) and cord blood (n = 4) were stimulated weekly with autologous DCs pulsed with MAGEA4 peptides. We generated a mixed population of activated T cells with specificity against MAGE from all donor types. These cells recognized different MAGE epitopes, and evaluable T cells demonstrated specific killing against autologous targets and HLA-matched HL cell lines. To explore the effect of combining MAGE T cells with the epigenetic drug decitabine, we first looked at the effects of adding the drug to our T cells – to ensure that the drug does not negatively affect them. We saw no overt effects on or changes in phenotype or specificity when MAGEA4 T cells were cultured with decitabine. We then confirmed that treatment of tumors with decitabine in vitro increased MAGE expression using qPCR. Lastly, we tested our prediction that increases in the frequency of MAGEA4 specific T cells would be seen in HL patients receiving decitabine as therapy. We saw increased MAGEA4 specific T cells in HL patients following treatment (likely reflecting increased antigens in vivo) – manifested as an increase in the epitope repertoire and in the number of IFNγ-secreting cells. We were unable to expand MAGE T cells in all HL patients treated with decitabine, however, highlighting the need for adoptive transfer of these cells. These suggest that MAGEA4-specific T cell immunotherapy, along with epigenetic therapy, is a practical approach for treatment of relapsed HL post-HSCT.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2010.12.303