In silico study of heterogeneous tumour-derived organoid response to CAR T-cell therapy

Abstract

Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapy for treating cancers. This method consists in modifying the patients’ T-cells to directly target antigen-presenting cancer cells. One of the barriers to the development of this type of therapies, is target antigen heterogeneity. It is thought that intratumour heterogeneity is one of the leading determinants of therapeutic resistance and treatment failure. While understanding antigen heterogeneity is important for efective therapeutics, a good therapy strategy could enhance the therapy efciency. In this work we introduce an agent-based model (ABM), built upon a previous ABM, to rationalise the outcomes of diferent CAR T-cells therapies strategies over heterogeneous tumour-derived organoids. We found that one dose of CAR T-cell therapy should be expected to reduce the tumour size as well as its growth rate, however it may not be enough to completely eliminate it. Moreover, the amount of free CAR T-cells (i.e. CAR T-cells that did not kill any cancer cell) increases as we increase the dosage, and so does the risk of side efects. We tested diferent strategies to enhance smaller dosages, such as enhancing the CAR T-cells long-term persistence and multiple dosing. For both approaches an appropriate dosimetry strategy is necessary to produce “efective yet safe” therapeutic results. Moreover, an interesting emergent phenomenon results from the simulations, namely the formation of a shield-like structure of cells with low antigen expression. This shield turns out to protect cells with high antigen expression. Finally we tested a multi-antigen recognition therapy to overcome antigen escape and heterogeneity. Our studies suggest that larger dosages can completely eliminate the organoid, however the multiantigen recognition increases the risk of side efects. Therefore, an appropriate small dosages dosimetry strategy is necessary to improve the outcomes. Based on our results, it is clear that a proper therapeutic strategy could enhance the therapies outcomes. In that direction, our computational approach provides a framework to model treatment combinations in diferent scenarios and to explore the characteristics of successful and unsuccessful treatments.