Engineering Improved CAR T Cell Products with A Multi‐Cytokine Particle Platform for Hematologic and Solid Tumors

Abstract

Despite the remarkable clinical efficacy of chimeric antigen receptor (CAR) T cells in hematological malignancies, only a subset of patients achieves a durable complete response (dCR). DCR has been correlated with CAR T cell products enriched with T cells memory phenotypes. Therefore, reagents that consistently promote memory phenotypes during the manufacturing of CAR T cells have the potential to significantly improve clinical outcomes. A novel modular multi‐cytokine particle (MCP) platform is developed that combines the signals necessary for activation, costimulation, and cytokine support into a single “all‐in‐one” stimulation reagent for CAR T cell manufacturing. This platform allows for the assembly and screening of compositionally diverse MCP libraries to identify formulations tailored to promote specific phenotypes with a high degree of flexibility. The approach is leveraged to identify unique MCP formulations that manufacture CAR T cell products from diffuse large B cell patients   with increased proportions of memory‐like phenotypes MCP‐manufactured CAR T cells demonstrate superior anti‐tumor efficacy in mouse models of lymphoma and ovarian cancer through enhanced persistence. These findings serve as a proof‐of‐principle of the powerful utility of the MCP platform to identify “all‐in‐one” stimulation reagents that can improve the effectiveness of cell therapy products through optimal manufacturing.