Mechanisms of Resistance to CAR-T cell Immunotherapy: Insights from a Mathematical Model

Abstract

Chimeric Antigen Receptor (CAR)-T cell therapy long-term follow-up studies revealed non-durable remissions in a significant number of patients. Some of the mechanisms underlying these relapses include poor CAR T cell cytotoxicity or persistence, as well as antigen loss or lineage switching in tumor cells. In order to investigate how antigen-mediated resistance mechanisms affect therapy outcomes, we develop a mathematical model based on a set of integral-partial differential equations. Using a continuous variable to describe the level of antigen expression of tumor cells, we recapitulated important cellular mechanisms across patients with different therapeutic responses. Fitted with clinical data, the model successfully captured the dynamics of tumor and CAR-T cells for several hematological cancers. Furthermore, the role played by these mechanisms are explored with regard to different biological scenarios, such as pre-existing or acquired mutations, providing a deeper understanding of key factors underlying resistance to CAR-T cell immunotherapy. Statement of significanceOur study introduces the first mathematical model to characterize the influence of a continuous level of antigen expression on the interplay between Chimeric Antigen Receptor (CAR)-T cells and cancer cells. We examine various cellular mechanisms across different hematologic cancers, taking into account both antigen-positive and antigen-negative relapses. Our findings shed light on the role of antigen density in CAR-T cell therapies and provide a valuable framework to investigate resistance with potential to improve patients outcomes.