Modelling CAR T cell signalling using prior knowledge networks

Chimeric antigen receptor (CAR) T cells are a promising new approach in cancer immunotherapy. Their safety, efficacy and phenotype depend heavily on the design of the CAR, which intracellular tail contains up to three domains derived from a range of cellular signalling receptors. Due to its modular design and the multitude of possible domains, there is a vast combinatorial space of CAR designs. There are substantial efforts to improve CAR T cells based on CAR designs. However, testing the effect of each CAR design experimentally is very resource and labour intensive, and not feasible beyond a few hundred different combinations. Therefore, we aim to predict T cell phenotypes upon expression of different CAR designs, informed by single-cell RNA sequencing of a small library of 30 CAR designs using combinations of five different domains. Exploiting a prior knowledge signalling network, we design models of …

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