Improved Understanding of Chronic Graft Versus Host Disease

Graft versus host disease (GvHD) is a condition that might occur after an allogeneic stem cell transplant (allo-SCT). In GvHD, the donated stem cells view the recipient’s body as foreign, and the donated cells/bone marrow attack the body. A multi-functional team from the University of Helsinki and Helsinki University Hospital has reported an interesting addition to the understanding of the roots of chronic Graft versus host disease (cGvHD) in the most recent issue of the journal Nature Communications.

‘Chronic GvHD (cGvHD) occurs after day 100 post-transplantation and develops in 30–70% of allo-HSCT recipients. The 5-year mortality rate is 30–50% and can be attributable to immune dysregulation and infections. Affected patients frequently need immunosuppressive treatment for years or even for a lifetime.’

In short, cGvHD is a major issue and risk factor for those of us who have taken and/or will be taking the path of allo-SCT.

The team has discovered that around 2% of patients who undergo allo-SCT’s harbor a mutation (called mTOR) in their CD4+ T-cells, that is not found in healthy patients. In depth analysis of this mTOR gene mutation indicates that cells with this mutation proliferate more aggressively and have lower cell death. In addition, these mutated CD4+ T-cells are also more cytotoxic (having a destructive action on other cells). It stands to reason that patients who harbor this mutation in their genes will have a higher likelihood of cGvHD after their allo-SCT.

In addition, the Finnish team screened 527 different drugs at five different concentrations to determine whether these mutated cells could be sensitive to potential drug treatment. These tests were done in their labs using cells from a patient with active cGvHD. The authors state: 

‘… , heat shock protein 90 (HSP90) inhibitors showed an increased killing effect on the index patient’s CD4⁺ T cells as compared to CD4⁺ T cells from both the HSCT donor and healthy control. With regard to other clinically interesting drug classes, both the HSCT donor and the recipient CD4⁺ T cells were sensitive to HDAC inhibitors, CDK-inhibitors, tyrosine kinase inhibitor, and proteosome inhibitors.’

I will not go into a review of these different classes of drugs, some of which are actively used in cancer treatment (e.g., just about all of us will be familiar with proteasome inhibitors such as Velcade, Kyprolis and Ninlaro). 

The authors singled out one specific compound that had superior efficacy against CD4+ cells with the mTOR mutation : the HSP90-inhibitor ganetespib. This is a clinical stage drug that is being or has been tested in a variety of cancers, including multiple myeloma. The website www.clinicaltrials.gov lists one completed Phase I study in MM (NCT 01485835). The fact that this study was completed in September 2015, with no further follow-on studies leaves me to believe that the sponsor company has abandoned pursuing this compound for treatment of myeloma. That does not mean, however, that in the future, this compound cannot be repurposed in the treatment of cGvHD.