Abstract 2281: DNA methyl transferase inhibitors (DNMTis) upregulate NY-ESO expression in several human primary cells: implications for co-therapy with engineered adoptive T-cell therapies

The DNA methyl transferase inhibitors 5-aza-2’-deoxycytidine (decitabine or DECI) and 5-azacytidine (azacitidine or AZA) have recently been approved for the treatment of a variety of hematologic malignancies. These cytidine analogues remove repressive epigenetic DNA methyl marks and induce the transcription of numerous genes normally silenced during the processes of cellular differentiation or transformation. DNMTis have a net anti-neoplastic activity through the up-regulation of tumor-suppressor genes involved in the induction of apoptosis, cellular differentiation and cell cycle arrest. In addition, DNMTis promote the expression of several cancer testis antigens (CTAs) by tumor cells, including NY-ESO and MAGE-A1/A3. These observations suggest that the combination of DNMTis with immunotherapeutic modalities may provide some clinical benefit. Adoptive immunotherapies using autologous CD4+ and CD8+ T cells expressing an affinity optimized NY-ESO TCR are in clinical trials and show robust clinical responses in patients across several indications including synovial sarcoma, multiple myeloma or melanoma. DNMTis were previously shown to induce the expression of NY-ESO in antigen-low or -negative tumor cells and consequently enable the activation of NY-ESO-specific T-cells. While there is compelling evidence for the combination of DNMTis with T cells containing engineered affinity-enhanced TCRs recognizing NY-ESO-1, safety data supporting this approach are lacking. Initial tests into the safety of combining these treatments investigated the effects of DECI and AZA on NY-ESO and LAGE-1 expression in a panel of primary adult human cells of different tissue origins. Our data demonstrate that treatment with either compound resulted in a significant up-regulation of NY-ESO transcription in a subset of primary cells tested. The magnitude of increase in transcript expression varied between cell types and, in some cases, was sufficient to activate T cells expressing an affinity-optimized NY-ESO-specific TCR. These findings raise important safety concerns with regards to the potential combination of DNMTi compounds with NY-ESO T-cell therapy and suggest that such co-therapies may result in on-target off-tumor toxicities. Citation Format: Bruno Laugel, Alexandra Sevko, Karen Howe, Zoltan Ferjentsik, Tiago Ferronha, Miguel Maroto, Joanna Brewer, Bent Jakobsen, Gwendolyn Binder-Scholl. DNA methyl transferase inhibitors (DNMTis) upregulate NY-ESO expression in several human primary cells: implications for co-therapy with engineered adoptive T-cell therapies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2281.