In a Nature Communications study, scientists at University Health Network and University of Toronto showed that inhibiting histone methyltransferase DOT1L or promoting dual specificity phosphatase 6 (DUSP6; MKP3) could help prevent graft-versus-host disease induced by adoptive T cell therapy.
Adoptive T cell therapies are being developed to treat cancer but can also cause GvHD, in which the transplanted T cells proliferate and damage untargeted host tissues.
As current methods to prevent GvHD systemically suppress the immune system, therapies that prevent GvHD without inhibiting T cell function are needed to avoid limiting the efficacy of adoptive T cell therapies.
To identify inhibitors of T cell responses, the researchers screened 20 compounds known to target epigenetic modulators or effector proteins in CD3+ T cells co-cultured with peripheral blood mononuclear cells (PBMCs) depleted of CD3+ T cells, and identified a tool DOT1L inhibitor known as SGC0946. Transcriptome analysis of CD8+ T cells also showed that SGC0946 increased DUSP6 expression compared with vehicle.
In human CD8+ T cells expressing a T cell receptor (TCR) against a known antigen, cultured with antigen-presenting cells (APCs) loaded with the TCR's cognate antigen to stimulate the T cells, SGC0946 decreased interferon (IFN) gamma secretion and cross-reactivity to other antigens without affecting T cell proliferation and differentiation.
In mice transplanted with xenogeneic CD8+ T cells, SGC0946 pretreatment of the T cells delayed weight loss and onset of GvHD and increased survival compared with vehicle.
In the same model, DUSP6 overexpression in the transferred T cells decreased signs of GvHD, including CD8+ T cell infiltration into colon and liver tissue, compared with normal expression.
The researchers then engineered xenogeneic CAR T cells to overexpress DUSP6, and showed the transplanted cells prevented weight loss and increased survival in a mouse model of leukemia, while preventing leukemia progression. DUSP6 overexpression in T cells showed similar results in a mouse model of lymphoma.
The authors suggested that increasing DUSP6 expression in CAR T cancer therapies could help prevent GvHD.
Pinometostat (EPZ-5676) from Epizyme Inc. (NASDAQ:EPZM) is a DOT1L inhibitor that is in Phase I testing to treat leukemia. In 2012, Epizyme and Celgene Corp. (NASDAQ:CELG) partnered to develop the product. Epizyme entered into a two cooperative research and development agreements (CRADAs) with NCI's Cancer Therapy Evaluation Program (CTEP) in 2016 to evaluate pinometostat to treat cancer (see BioCentury, July 9, 2015).