Novel strategies to assess cytokine release mediated by chimeric antigen receptor T cells based on the adverse outcome pathway concept.

The success of cellular immunotherapies such as chimeric antigen receptor (CAR) T cell therapy has led to their implementation as a revolutionary treatment option for cancer patients. However, the safe translation of such novel immunotherapies, from non-clinical assessment to first-in-human studies is still hampered by the lack of suitable in vitro and in vivo models recapitulating the complexity of the human immune system. Additionally, using cells derived from human healthy volunteers in such test systems may not adequately reflect the altered state of the patient's immune system thus potentially underestimating the risk of life-threatening conditions, such as cytokine release syndrome (CRS) following CAR T cell therapy. The IMI2/EU project imSAVAR (immune safety avatar: non-clinical mimicking of the immune system effects of immunomodulatory therapies) aims at creating a platform for novel tools and models for enhanced non-clinical prediction of possible adverse events associated with immunomodulatory therapies. This platform shall in the future guide early non-clinical safety assessment of novel immune therapeutics thereby also reducing the costs of their development. Therefore, we review current opportunities and challenges associated with non-clinical in vitro and in vivo models for the safety assessment of CAR T cell therapy ranging from organ-on-chip models up to advanced biomarker screening.