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

Abstract

AbstractChimeric antigen receptor (CAR) T cells have become an established form of immunotherapy and continue to show promising results for the treatment of hematological cancers in most patients. While this immunotherapy continues to generate excitement in the clinic, antigen modulation in cancer cells affects the quality and safety of CAR T cell therapy. Here we present the engineering of yeast to robustly and dynamically modulate antigen densities, hence establishing a novel tool for assessing antigen-density thresholds in CAR T cell responses. Using a synthetic biology approach, we successfully engineer yeast to simulate cancer cells and demonstrate i) controllable antigen densities of CD19 through the use of G protein-coupled receptors (GPCRs), ii) a customizable system for tuning antigen densities through the employment of heterologous GPCRs for defining signal input types and signal pathway engineering for adapting intensities, and iii) activational control of clinically-derived CAR T cells within a physiologically relevant range compared to the activation elicited by a NALM6 cancer cell line. Based on this yeast-based antigen-presenting cell system, we envision an efficient assessment of how varying antigen densities in cancer cells from patients affect CAR T cell responses and ultimately support safer and better quality of personalized cancer therapies.