Cellular avidity as a novel biomarker for candidate selection of cell-based immunotherapies

Abstract Cellular immunotherapies are increasingly complex in design. Affinity readouts, i.e., the measurements of the strength of single receptor-ligand interactions, are frequently used to assess the binding of chimeric antigen receptors (CARs) or T cell receptors (TCRs) to their ligand. However, affinity is a poor predictor of effector function of the engineered downstream product. Therefore, new tools are needed to evaluate the binding strength of CAR and TCR-transgenic cells to their cognate targets in a more biologically relevant context. Recent studies demonstrated the utility of measuring cellular avidity as a novel biomarker for identifying and developing potent and safe immunotherapies. Unlike affinity, cellular avidity is driven by the overall strength of dynamic surface interactions between effector cells and their targets by integrating receptor density, the sum of individual affinities, and engagement of the multitude of co-receptors within the immunological synapse. Here, we show that increased specific avidity, i.e., TCRs with the strongest antigen binding and the lowest background, correlated with improved effector function both in vitro and in vivo. For CAR-T, higher cellular avidity was significantly correlated with improved tumor control in in vivo murine models, but also associated with toxicities in patients, suggesting fine-tuning of cell therapies to the desired avidity for ideal function is needed.