Coordinators: Prof. K. F. Rabe, Prof. G. Riemekasten, Prof. S. Schreiber, Prof. S. Weidinger, Prof. D. Zillikens
In CD-5 a randomized, placebo-controlled, clinical “proof-of concept” study (Phase 2a) is conducted to investigate the safety and clinical efficacy of low-dose therapy with the cytokine interleukin-2 (IL-2) in five different chronic inflammatory diseases from the fields of dermatology (atopic dermatitis, pemphigus vulgaris, mucous membrane pemphigoid), gastroenterology (ulcerative colitis) and rheumatology (polymyositis/dermatomyositis). In cooperation with the RTFs, the clinical study will be accompanied by an extensive scientific program aimed at gaining new insights into the pathomechanisms of these diseases as well as the mechanisms of action of low-dose IL-2 therapy.
Low-dose IL-2 therapy induces the selective expansion of regulatory T cells (Treg), which are indispensable for the suppression of excessive immune responses and for the control inflammatory processes. The restoration or strengthening of Treg acitivity may alleviate the clinical symptoms of inflammatory and immunological diseases. First phase 1 and 2 clinical studies, some of which were carried out by cluster members, were able to prove the safety and very good tolerance of low-dose IL-2 therapy in patients with different inflammatory and immunological diseases, such as systemic lupus erythematosus (SLE), and to provide preliminary evidence for the clinical efficacy of this treatment.
The main aim of this clinical study is to use a standardized master protocol to investigate and compare the safety and efficacy of low-dose IL-2 therapy in patients with different chronic inflammatory diseases in order to create the scientific basis for more comprehensive studies (what is known as a “disease-finding basket trial”). In addition to the detailed analyses of Treg sub-populations, the accompanying scientific investigations include extensive studies of relevant immune cells, cytokines and intracellular signaling pathways in order to gain decisive insights into both general as well as disease-specific modes of action of the treatment. Suitable biomarkers for the treatment response and follow-up checks are also to be identified and complex models are to be developed for predicting an individual treatment response.
The concept of the low-dose IL-2 therapy was developed by participating scientists of CD-5 from animal model-based pre-clinical research through to clinical application. There is internationally recognized and leading German expertise in the field of low-dose IL-2 therapy of chronic inflammatory diseases. The clinical introduction of low-dose IL-2 therapy can therefore be regarded as a prime example of a successful “bench-to-bedside” approach within translational immunology and medicine.
Low-dose IL-2 therapy and its associated reconstitution and enhancement of immunological tolerance mechanisms interferes directly with the immunopathogenesis of many chronic inflammatory diseases and therefore represents a promising and selective biological treatment approach with a unique and physiological mode of action. The establishment of such a targeted approach would be an important advance in the treatment of numerous chronic inflammatory diseases for which there exist currently no specific or only inadequately effective treatment options.
Detailed phenotypic analyses of Treg sub-populations, including antigen specificity, TCR repertoire and epigenetic changes, are to be carried out in cooperation with RTF I, RTF VI, TI-2 and TI-4. The identification of biomarkers and development of models for the treatment response will be supported by RTF VIII by way of integrated analyses of proteomes, transcriptomes, epigenomes and metabolomes.