The Malek lab has a long-standing interest in the basic mechanisms that control T cell development and function with a focus on the role of IL-2 family cytokines in this process. We extensively study Tregs and have established that IL-2 influences several steps in mouse thymic Treg development while also acting as a dominant contributor to Treg peripheral homeostasis. More recent work shows that Blimp-1 and CEACAM1 control a regulatory loop that impacts the function and homeostasis of human Tregs. Low levels of IL-2R signaling readily support mouse Treg development and homeostasis while more extensive signaling is required for Teff development and memory programming. Correspondingly, low amounts of IL-2 readily induce IL-2R signaling in human Tregs but not CD4+ and CD8+ Teff cells. These findings provide mechanistic support that underpins low-dose IL-2 as a Treg-selective agent in the context of autoimmunity and high-dose IL-2 as a means to boost anti-cancer responses.

More recently, we developed a novel IL-2-based biologic, a fusion protein of IL-2 linked to CD25, that exhibits pharmacokinetics and pharmacodynamics that is superior to recombinant IL-2, while being selective toward the high affinity IL-2R. Our pre-clinical studies showed that low-dose IL-2/CD25 prevents diabetes in NOD mice by expanding a highly suppressive Treg subset in the inflamed pancreas. Currently, low-dose IL-2/CD25 is being tested as a therapy for autoimmunity in phase 1 clinical trials. In other pre-clinical studies, high-dose IL-2/CD25 was shown to be highly effective in limiting tumor growth for immunogenic tumors, particularly when administered with checkpoint blockade, by lowering T cell exhaustion.

Unexpectedly, these IL-2/CD25-dependent anti-cancer responses through targeting the high affinity IL-2R were much more effective than the “gold-standard” using an IL-2R agonist with selectivity toward the intermediate affinity IL-2R. Ongoing studies seek to determine the molecular and cellular mechanisms underlying the effectiveness of IL-2/CD25 to boost Tregs at low-doses and to enhance cancer immunotherapy at high-doses.

We are also developing next-generation combination strategies that show more effective control of autoimmunity than IL-2/CD25 monotherapy using the NOD mouse model of type 1 diabetes.