Our Faculty : Primary Faculty

Thomas Malek, Ph.D.

Current Research Interests
One major aspect of our current research is to better define the mechanisms by which regulatory T cells (Tregs) contribute to self-tolerance, with a focus on the role of IL-2R signaling. Mouse models are used to establish the relevance and inter-relationships of Treg heterogeneity to support self-tolerance and to define the role of IL-2R signaling in the development and homeostasis of Treg subsets. This effort also includes a substantial translational component. A key finding from our group is that IL-2R signaling thresholds differ substantially for Tregs vs. T effector and memory cells. Based on this work, ultra-low-dose IL-2 is now being tested in the clinic and provides a new strategy to treat autoimmune diseases, as the IL-2-dependent increase in Tregs targets the underlying cause rather than the symptoms of autoimmunity. These findings are currently being leveraged in mouse preclinical studies and in human studies to determine: 1) the cellular and molecular basis related to the IL-2-dependent risk that contributes to Type 1 diabetes (T1D); 2) the optimal conditions and mechanisms by which low-dose IL-2 selectively supports Tregs, leading to suppression of autoimmunity; and 3) the effectiveness and mechanism by which ultra-low-dose IL-2 benefits patients with T1D in novel clinical trials. This latter effort depends on a close and extensive collaborative effort with members of the Diabetes Research Institute. We have also developed a patent-pending long-lived novel IL-2-based biologic that shows promise to extensively boost Tregs at low-doses and T memory cells at high doses. This biologic is being advanced for clinical use. The other major aspect of research in our lab is to understand the role of IL-2 in programming T memory responses. A key new finding is that a brief encounter of high levels of a long-lasting IL-2, such as the novel IL-2 biologic, during immunization substantially amplifies the T memory response, including tissue-seeking memory cells. Current work is aimed at understanding the mechanism leading to robust amplified T memory and application of this approach to tumor-immunotherapy, including in the context of checkpoint inhibitors. This research has the potential for application to other vaccines to induced cell-mediated immunity and plans are underway to extend this approach in other areas of need.

Research Profile
Pubmed Link