Vivianne Malmström

Immune checkpoints are designed to turn off the immune response to prevent autoimmunity and damage to healthy cells, but cancer hijacks these mechanisms by “deactivating” T cells that target cancer cells. Immunological checkpoint inhibitors (ICIs) prevent this deactivation and increase the body’s anti-tumour immune response. Immunotherapy with ICIs has revolutionized cancer treatment during the last years. Despite their high efficacy, ICIs are associated with a new spectrum of adverse events, referred to as immune-related adverse events (irAEs).Arthritis is a common irAE occuring in 7-10% of patients treated with ICI. It is a new rheumatic entity, that differs significantly from other forms of arthritis, in terms of clinical phenotype, pathogenesis and treatment. Current treatment guidelines support cortisone as first line therapy. However, preclinical data suggest that cortisone might reduce the effectiveness of cancer immunotherapy. On the contrary, targeted blockade of pro-inflammatory cytokines such as IL-6 might have excellent anti-inflammatory effect and at the same time not only not interfere with the effectiveness of the ICI but potentially even enhace it. That could support a paradigm shift in the treatment of irAEs. In this randomized, open-label, superiority, controlled, proof-of-concept clinical trial we are going to evaluate the early use of an anti-IL6 receptor inhibitor, tocilizumab,  compared to glucocorticoids, for treatment of ICI-induced arthritis.

The overall purpose of this project is to ‘finger print’ the immune reactions associated with autoimmune rheumatic diseases and use this knowledge for the development of novel and ultimately antigen-specific and curative therapies.We will study disease-associated autoimmunity in rheumatoid arthritis and ANCA-associated vasculitis. We anticipate to identify the most prominent candidate autoantigens (including the precise epitopes recognized by B and T cells) as well as their corresponding lymphocyte repertoires. Next, we will set up immune surveillance panels to screen autoreactive B and T cells and their clonal expansions in patients over time. Ultimately, we aim to dissect the mechanisms by which specific T and B cell clones, alone or in combination cause disease manifestations (symptoms) by creating novel humanized mice to study transition from autoimmunity into autoimmune disease.A caveat to understanding human autoimmune disease has always been their gradual development over a long period of time. An intriguing short cut to inflammatory disease resembling RA is the side effects sometimes developing in cancer patients treated with immune stimulatory check point inhibitors (ICI). We will use our approaches to study to what extent ICI-induced arthritis is characterized by autoimmunity.My track record of identifying and studying candidate autoantigens and the involved B and T cell repertoires in patient samples will form a basis for this translational program.