Alexander von Humboldt Professor for Biochemistry, Institute of Biochemistry I, Medical Faculty, University of Cologne Professor of Cancer Biology, Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute University College London
The Walczak group investigates cell death and ubiquitin in inflammation, immunity to infection, auto-immunity and cancer. A particular emphasis of the group’s work is on harnessing newly gained knowledge on the functional interplay between cell death, ubiquitin and inflammation their role in tumour immunity.
Our research: Research in the Walczak Laboratory is focused on the study of the functional interplay between cell death, ubiquitin and inflammation in immunity, autoimmune and infectious diseases and cancer with a specific focus on tumour immunology. The group is particularly interested in unravelling the roles of different death receptor–ligand systems, whose signaling outputs are determined by ubiquitin-mediated processes, in immunity to infection and cancer but also how these signalling processes and their perturbation can drive cancer, autoimmunity and the pathologic consequences of infection. By gaining a better understanding of this functional interplay, the Walczak lab aims to devise novel therapies for these diseases.
Our successes: In the Fas (CD95) field, Professor Walczak contributed to the elucidation of activation-induced T-cell death (AICD) (Dhein, Walczak et al., Nature 1995). To uncover the role of the Fas–FasL system in AICD, he constructed the first soluble Fas-Fc (CD95-Fc) chimaeric protein. To develop a refined and humanised version of Fas-Fc as a drug, on the basis of a patent on which he is sole inventor and which he outlicenced from his then research group at the DKFZ to Apogenix AG, he founded – and is now scientific advisor of – this biotech company which is focused on the development of drugs in the cell death and immunity space. A successful phase II clinical trial in glioblastoma patients has been conducted with Fas-Fc. On the basis of a scientific rationale developed by Professor Walczak, this biotherapeutic drug is currently tested in two clinical trials as a novel therapy for severe COVID-19. If successful, this therapy may convert this SARS-CoV-2-caused disease which is responsible for the current pandemic and its disastrous effects on human health and the world-wide society as a whole, into a therapeutically manageable disease.
With respect to TRAIL, Professor Walczak identified TRAIL-R2 (Walczak et al., EMBO Journal 1997) and was first to show that TRAIL can kill cancer cells in vivo without killing normal cells (Walczak et al., Nature Medicine 1999). Based thereupon, TRAIL receptor agonists have been developed for the treatment of cancer. Recently, the Walczak group made the unexpected discovery that endogenous TRAIL–TRAIL-R signalling can also act in a pro-tumourigenic manner (von Karstedt, …, Walczak. Cancer Cell 2015; Hartwig et al., …, Walczak. Molecular Cell, 2017). Based on this discovery, Professor Walczak, in collaboration with Apollo Therapeutics (Cambridge, UK), has recently embarked on the development of a TRAIL antagonist for cancer therapy.
Regarding TNF, after first discovering that the linear ubiquitin chain assembly complex (LUBAC) plays a crucial role in immune signalling (Haas, …, Walczak, Molecular Cell 2009), by demonstrating that TNF-induced cell death can be causative for a lethal inflammatory syndrome, the Walczak lab defined a previously unrecognised aetiology for TNF-induced chronic inflammatory disease (Gerlach, …, Walczak, Nature 2011). This discovery resulted in a paradigm shift in the way TNF is thought to be able to cause autoinflammation and autoimmune diseases.
Recently, Professor Walczak and his team discovered that the concept of cell death as the cause for severe inflammatory and autoimmune diseases extends to death ligands beyond TNF (Peltzer, …, Walczak, Nature 2018; Taraborrelli, …, Walczak, Nature Communications, 2018). Rather unexpectedly, only the combined neutralisation of TNF, TRAIL and FasL prevented lethal dermatitis in mice deficient for LUBAC in the skin. The realisation that cell death caused by either of these different death ligands can be sufficient to cause severe, including lethal inflammatory disease also formed the basis for the most recent translational endeavour of the Walczak lab with respect to the treatment of severe COVID-19. Here, the intention is to inhibit the death ligand FasL with the afore-mentioned Fas-Fc protein, a biotherapeutic drug first conceived by Professor Walczak as junior group leader at the DKFZ and developed by Heidelberg-based biotech company Apogenix AG.
Our goals: The overarching goal of the Walczak Laboratory is to provide a better understanding of the physiological interplay between cell death, ubiquitin and inflammation in the generation of immunity and how this functional interplay, on the one hand, controls disease but, on the other, when perturbed can instead become causative for pathologies such as cancer, autoimmune diseases or those that are induced as a consequence of an infection.
Our methods/techniques: The Walczak Laboratory uses state-of-the-art biochemical and biotechnological in-vitro and in-vivo techniques.
Figure 1: Human cancer cells undergoing TRAIL-induced cell death.