mTOR Inhibition for Transplantation: More May Not Be Better
In this issue, Fantus et al7 presented intriguing results of their study to comprehensively investigate the impacts of a TORKinib, AZD2014 that has been in clinical trial for antitumor therapy, on resting immune cell populations and on alloantigen-induced T- and B cell responses. The inclusion of RAPA as the control in this study made it possible to compare the effects of these 2 drugs side-by-side, which revealed important clinically relevant results. In vitro, AZD2014 inhibited the development of dendritic cells and CD3/CD28-induced T cell proliferation in vitro, although a higher concentration was required compared to RAPA. When given to naive mice in vivo, AZD2014 depleted thymocytes in the thymus and T and B cells in secondary lymphoid tissues while sparing the naturally occurring CD4+CD25+Foxp3+ regulatory T cells in the thymus but not in the secondary lymphoid tissues. However, it wasn’t determined whether certain subsets of T and B cells (ie naive or memory) were more prone to the effects of AZD2014 and RAPA. In addition, other immune cell populations, such as dendritic cells, natural killer, natural killer T and follicular helper T cells, were also depleted by AZD2014 and RAPA, demonstrating that mTOR activities are important for the survival of these cells in the steady state. These results call for researchers' attention to monitor the effects of TORKinibs on the normal immune cells, in addition to those on malignant cells, in clinical trials to investigate the antitumor effects of TORKinibs.
They then studied the impacts of AZD2014 on alloresponses using a heart transplant model, in which AZD2014 was transiently administered from day 3 to day 11 after transplantation. Although AZD2014 was able to prolong the survival of heart allografts, its suppressive effects were less potent than RAPA, despite the fact that AZD2014 inhibited both mTORC1 and mTORC2. These data confirmed those from their earlier study to investigate the impacts of a similar TORKinib AZD8055 on allograft survival using the same model.