Objective
The overall objective of this proposal is to derive sufficient data that would support clinical testing of combining IL-2/CD25 with anti-CD40L in patients with T1D. To achieve this objective, we have 3 specific goals. First is to assess the effectiveness and safety of this combination approach in stringent pre-clinical models of T1D. The second is to determine how this therapeutic approach alters islet inflammation since this is not easily studied in patients. The third goal is to determine the extent that Tregs and other immune cells that respond to IL-2/CD25 and anti-CD40L are a benefit or limit the effectiveness of this therapeutic approach. Completing these goals will put on firm ground the potential of this combination approach as an immunotherapy for T1D.
Background Rationale
Boosting immune regulation by targeting Treg using IL-2/CD25 has therapeutic value. However, a monotherapy approach for a complex disease such as T1D is unlikely to fully control this disease and some patients may exhibit limited responsiveness to IL-2/CD25 therapy. This proposal is forward-looking and considers a next generation combination approach, IL-2/CD25 plus anti-CD40L. Key signals required for the activation and persistence of autoreactive T cells are blocked by anti-CD40L. Thus, the overall rationale of this proposal is limiting activation of autoreactive T cells with anti-CD40L will make residual autoreactive T cells much more susceptible to inhibition by Tregs, whose numbers and function are boosted by IL-2/CD25. We already know that the combination approach is more effective than either monotherapy to prevent T1D in mice with stage 1 T1D. We also know that the acute effects of the combination therapy result in the increase in several immune cell populations, including Tregs. These supporting data validate the more detailed and rigorous studies proposed here. Past clinical trials revealed severe side effects with anti-CD40L. However, the anti-CD40L we use in this proposal and those being developed for clinical applications have been modified to eliminate this problem. We choose these two biologics because IL-2/CD25 is in clinical development by BMS and blocking the CD40L pathway as a therapeutic target for autoimmunity is being developed by several companies, including BMS. Thus, there is a clear pathway for clinical translation of the findings from the proposed study.
Description of Project
Over 8 million people world-wide are afflicted with type 1 diabetes (T1D). Current therapies are to provide insulin or more recently anti-CD3 immunotherapy (Teplizumab), the latter to limit continued damage to insulin-producing β-cells by autoreactive T cells, i.e. those cells that destroy β-cells. An ideal therapy is to re-regulate the immune system to physiologically silence these autoreactive T cells. Regulatory T cells (Tregs) represent a major mechanism by which autoreactive T cells are normally kept silent and are dysfunctional in some patients with T1D and other autoimmune diseases. Tregs are highly dependent on IL-2, a critical hormone-like substance of the immune system. Given this central role of Tregs to monitor and suppress autoreactive T cells, intensive research is ongoing to enhance the Treg compartment in the context of autoimmunity and other inflammatory disorders. One major approach is administering low-dose (LD) IL-2, because at low doses, IL-2 selectively enhances Tregs. Another attractive feature of LD IL-2 is that can be readily delivered to many patients with T1D. Numerous early-stage clinical trials using LD IL-2 have been completed and others are ongoing in a diverse set of autoimmune diseases, including T1D. These trials have established that LD IL-2 is safe, while Tregs increase in the blood of essentially all patients. Clinical improvement often occurs. Despite this promise, these trials point to some limitations. First, although clinical symptoms often improve, symptoms return once patients no longer receive LD IL-2. Second, clear indication of clinical efficacy has not been robustly established in larger phase 2 trials, including T1D. Perhaps a fundamental concern with these trials is that IL-2 does not have ideal properties and requires frequent administration to maintain Treg increases.
An important goal of my research program is to develop improved treatments for T1D and other autoimmune diseases by immunomodulation and enhancement of Tregs. In this regard we have developed a novel IL-2-based drug called IL-2/CD25. This drug is much more effective than IL-2 to limit T1D in mouse pre-clinical studies. We have both a mouse and human version of IL-2/CD25, where the latter has been licensed to Bristol Myers Squibb (BMS) for clinical development. In a phase 1 clinical trial in healthy volunteers, a single administration of human IL-2/CD25 was shown to be safe while selectively increasing Tregs for more than 2 months. This contrasts with LD IL-2 that would need to be injected daily to achieve the same effect.
Although IL-2/CD25 is much more effective than IL-2 in pre-clinical studies, we have also found in our model of T1D that only about half of the mice are diabetes free long-term. My lab is now intensively working on identifying optimal combination approaches that will enhance the efficacy achieved with IL-2/CD25 monotherapy. We have identified another biologic, anti-CD40L, that is highly effective in preventing T1D in mice with stage 1 T1D (normal blood sugar levels but anti-insulin autoantibody positive), when combined with IL-2/CD25. What we plan to do next, as outlined in this proposal, is assess the effectiveness and safety of this combination approach in pre-clinical studies where mice have more severe disease, i.e. stage 2 T1D (abnormal blood glucose levels) and stage 3 T1D (newly diagnosed T1D). We also wish to learn why this approach works so well, as this may provide clues on how to improve upon this approach. Overall, we plan to develop a robust data set in our pre-clinical studies that will pave the way for clinical trials in patients with T1D.
Anticipated Outcome
The following represents key points that we will learn from this proposal. First, we will learn whether the high efficacy of IL-2/CD25 plus anti-CD40L in controlling stage 1 T1D also occurs in setting of more progressive attack of β-cells by autoreactive T cells. Second, we will learn the extent the inflammatory response attacking islets is reorganized after therapy with IL-2/CD25 plus anti-CD40L, including how therapy affects autoreactive T cells. Lastly, we will find out the degree that each cell population that is enhanced by the combination therpy contributes to a beneficial therapeutic effect. The anticipated outcome of this research is that the combination therapy will show high efficacy at all stages of T1D. This result will be accompanied by a distinctive immune landscape that protect islets and β-cells through highly effective inhibition of autoreactive T cells though the aggregated effects of IL-2/CD25 and anti-CD40L that may also promote β-cell function. Such an outcome would be highly favorable to support design and implementation of clinical trials for patients with T1D.
Relevance to T1D
Patients with T1D are faced with limited treatment options when they are diagnosed with T1D. New therapies are needed that effectively silence the immune response to protect the remaining functional β-cells. Ideally, β-cells could be replaced. However, in this setting, autoimmune attack will eventually reoccur. This proposal is directly relevant to the goal of the JDRF to devise new and more effective therapies to prevent and/or limit T1D progression. We focus on physiological immune regulation rather than broad based immunosuppression to limit the autoimmune attack, where that latter is associated with recurrent infections and non-specific toxicities with chronic use. Our combination therapy targets complementary pathways that are designed to enhance immune regulation by Tregs (IL-2/CD25) while limiting the activation of autoreactive T cells (anti-CD40L). Our supporting data suggest that this may be viable option, where the combination leads to unique changes in the immune cells associated with islets. As these biologics have human equivalents, a pathway exists to move this approach toward clinical testing in T1D.