Engineered yeast cells simulating CD19+ cancers to control CAR T cell activation

Abstract

Chimeric antigen receptor (CAR) T cells have become an established immunotherapy and show promising results for the treatment of hematological cancers. However, modulation of surface levels of the targeted antigen in cancer cells affects the quality and safety of CAR T cell therapy. Here we present the Synthetic Cellular Advanced Signal Adapter (SCASA) system, based on successful engineering of yeast to simulate cancer cells with tunable surface-antigen densities, as a tool for controlled activation of CAR T cell responses and assessment of antigen density effects. Specifically, we demonstrate I) controllable antigen-densities of CD19 on yeast using G protein-coupled receptors (GPCRs), II) a customizable system allowing choice of signal input and modular pathway engineering for precise fine-tuning of the output, III) synthetic cell-cell communication with CAR T cells and the application of CD19-displaying yeast in the characterization of CAR designs, and IV) more efficient and robust activational control of clinically-derived CAR T cells in comparison to the NALM6 cancer cell line. Based on this yeast-based antigen-presenting cell system, we envision efficient assessment of how varying antigen densities in cancer cells affect CAR T cell responses and ultimately support development of safer and better quality of personalized cancer therapies.