The efficacy of chimeric antigen receptor (CAR) T cell therapies in solid tumours is still limited by on-target, off-tumour toxicities. Now, Liu, He, Wang et al. have engineered EchoBack-CAR T cells, an ultrasound-activated, genetically modified CAR T cell that enables precise spatiotemporal activation.

To circumvent antigen induced downregulation of CAR expression in T cells, they systematically tested combinations of minimal promoters, CARs and regulatory elements to induce a CAR activation positive feedback loop. They found that the incorporation of CRE-SRE and NF-κB-NFAT elements into the YB-TATA minimal promoter of CD28-containing CARs achieved high induction and sustainability of CAR expression while maintaining low basal leakage; this was named EchoBack-CAR. EchoBack-hGD2CAR T cells exhibited superior glioblastoma (GBM) tumour cell killing in vitro compared with parental CAR T cells that lack promoter optimization.