The method for assessing the specificity of developing CAR therapies

Abstract

The effectiveness of anti-tumour chimeric antigen receptor (CAR) therapy mainly dealt with an elevated sensitivity of CAR cells to target cells. However, CAR therapies are associated with nonspecific side effects: on-target off-tumour toxicity. Sensitivity and specificity of CAR cells are the most important properties of the recognition process of target cells among other cells. Current developments are mainly concentrated on exploring molecular biology methods for designing CAR cells with the highest sensitivity, while the problem of the CAR cells specificity is rarely considered. For the assessment of CAR cells specificity, we suggest that in addition to an elevated level of CAR-antigen affinity, the ability of CARs for clustering should be taken into account. We assume that the CAR cells cytotoxicity is determined by CAR clustering. The latter is treated within the framework of nucleation theory. The master equation for the probability of CAR cells cytotoxicity is derived. The size of a critical CAR cluster is found to be one of two most essential parameters. The conditions for necessary sensitivity and sufficient specificity are explored. Relevant parametric diagrams are derived. Possible applications of the method for assessing the specificity of developing CAR therapies are discussed.