An in vivo humanized mouse model for determining donor-dependent cytokine release syndrome in response to checkpoint and bispecific antibody therapy

Abstract

Abstract Although immuno-oncology therapies such as checkpoint inhibitors, bispecific antibodies and CAR-T cells have been successfully used as cancer treatments, they can have severe adverse effects such as cytokine release syndrome (CRS). The animal models and in vitro human PBMC assays presently in use do not reliably predict CRS in patients. Currently, the only widely accepted predictors of CRS are cancer burden and therapeutic dose. Despite this, most pre-clinical assays used to evaluate CRS do not incorporate cancer cells. A predictive assay that can screen for patient/cancer/therapy combinations at risk for developing CRS would improve the safety of immuno-oncology drug development. We have developed a novel, rapid, sensitive and reproducible in vivo PBMC humanized mouse model that is able to differentiate human PBMC donors based on individual cytokine release response. Using this model, we evaluated cytokine release in response to immune checkpoint inhibitors and bispecific T-cell engaging antibodies. Additionally, this mouse model uses luciferase labelled cell lines to allow the measurement of tumor burden at the time of treatment as well as assess short term tumor response. We have ongoing efforts to further develop this assay in order to evaluate efficacy and CRS of at the same time, and progress will be discussed. This mouse model has immediate utility in current and future drug development.