Bai Z, Woodhouse S, Zhao Z, et al. Single-Cell Antigen-Specific Landscape of CAR T Infusion Product Identifies Determinants of CD19-Positive Relapse in Patients with ALL. Science Advances. 2022; 8 (23) (doi: 10.1126/sciadv.abj2820).
Transcriptional profiling helped to pinpoint molecular mechanisms driving relapse or treatment failure in acute lymphoblastic leukemia (ALL) patients who undergo chimeric antigen receptor (CAR) T cell therapy targeting CD19. The research studied the properties of CAR T cell infusion products from 12 children with relapsed/refractory ALL, to determine whether cells' functional makeup influences long-term response. Outcomes upon CD19-specific stimulation or T cell receptor-mediated activation were compared with outcomes in unstimulated controls. Examination of 101,326 single-cell transcriptomes revealed that T cell activation and coinhibitory signatures were similar between patients with durable response and those with relapse. However, patients with CD19-positive relapse lacked sufficient CAR T cells capable of triggering a T helper 2 functional response and of maintaining early memory states. Based on the data, the investigators correlate frequency of early memory T cells to the high ALL relapse rate. The theory was validated in separate functional profiling of 49 patients. The study authors believe bolstering specific CAR T functionality and restoring early memory phenotype are key to prolonging clinical response to CAR T therapy and promoting long-term remission of ALL.