Schematic of reverse translational study as described by Shalabi et al. From left to right: participants were treated with CD19.22.BBz CAR T cells in the described clinical trial, demonstrating safety and efficacy but decreased expansion and persistence compared to prior CD22.BBz CAR T trials. Reverse translational (bedside-to-bench) studies revealed CAR design, T-cell phenotype, antigen binding capacity and HAMA-mediated rejection as potential mechanisms to explain the clinical findings. The authors concluded that improved CD22-targeting would enhance the function of dual-targeting CAR T cells, testing this hypothesis in vitro and in an in vivo mouse model. These studies led to the development of an improved dual-targeting CD19.28z/CD22.BBz bicistronic CAR that will be evaluated in participants in an upcoming clinical trial.