Engineering Improved Car T Cell Products with A Multi-Cytokine Particle Platform for Hematologic and Solid Tumors.

Despite the remarkable clinical efficacy of chimeric antigen receptor (CAR) T cells in hematological malignancies, only a subset of patients achieve a durable complete response (dCR). DCR has been correlated with CAR T cell products enriched with T cells of memory phenotypes. Therefore, reagents that consistently promote memory phenotypes during the manufacturing of CAR T cell products have the potential to significantly improve clinical outcomes. We have developed a novel modular multi-cytokine particle (MCP) platform 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 assembly and screening of compositionally diverse MCP libraries to identify formulations tailored to promote specific phenotypes with a high degree of flexibility. We leveraged this platform to identify unique MCP formulations that increase the proportion of memory phenotype CAR T cells. MCP-manufactured CAR T cell products exhibit increased proportions of memory-like phenotypes in diffuse large B cell lymphoma (DLBCL) patient CAR T cells and demonstrate superior anti-tumor efficacy in mouse models of lymphoma and ovarian cancer through enhanced persistence. Our 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. This article is protected by copyright. All rights reserved.