Inflammasome as a new potential target in cytokine release syndrome management during chimeric antigen receptor T cell therapy

In these last two decades, CD19-redirected Chimeric Antigen Receptor (CAR) T cells have achieved an impressive clinical success for the treatment of B-cell origin hematologic malignancies. However, most patients treated with CAR T cells experience severe toxicities, such as Cytokine Release Syndrome (CRS) and neurotoxicity, which require extreme attention in patient monitoring and management. Despite the years of research, the pathophysiology of these adverse events is still partially unknown. In the same decades, another field of immunology research has brought important news since the discovery of a multimeric complex in activated macrophage cells, which was ultimately called inflammasome. The inflammasome family is composed by a multitude of cytosolic molecular sensors, which respond to potential damage factors, an adaptor protein and an effector, the Caspase-1 (Cas-1). Once inflammasome is triggered and Cas-1 activated, the proteolytic maturation of IL1β and IL-18 allows their release, while the cleavage of gasdermin D leads to pyroptotic cell death. The aim of this project was to investigate the implication of inflammasome complex in the development of CRS, by means of an in vitro model consisting in tripartite coculture with CD19 CAR T cells, CD19+ NALM6 and macrophage-like cells. Then, we showed that IL1β release was blocked by VX-765, a Cas-1 inhibitor, but not by MCC950, which inhibits NLRP3 sensor, suggesting a different inflammasome type involvement

Out of specification Tisagenlecleucel is associated with outcomes comparable to standard of care product in relapsed or refractory diffuse large B-cell lymphoma

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