Jain MD, Ziccheddu B, Coughlin CA, et al. Whole-Genome Sequencing Reveals Complex Genomic Features Underlying Anti-CD19 CAR T-Cell Treatment Failures in Lymphoma. Blood. 2022; (doi: 10.1182/blood.2021015008).
Tumor-intrinsic genomic changes appear to contribute significantly to treatment failure in persons with large B-cell lymphomas who undergo CD19-directed chimeric antigen receptor (CAR-19) therapy. Researchers used whole-genome sequencing to study 51 tumor samples from 49 individuals matching this patient profile. Reduced expression or loss of CD19 prior to treatment had no impact on responses, raising the probability that more than one mechanism is implicated in CAR-19 treatment success or failure. In fact, the analysis identified several predictors of CAR-19 resistance — including the presence of complex structural variants, certain mutational processes, and genomic damage from reactive oxygen species. Deletion of the RHOA tumor suppressor also was associated with CAR-19 clinical failure.