慢病毒和逆转录病毒嵌合抗原受体整合位点的纵向分析揭示了不同的克隆进化模式

T-cell malignancies following chimeric antigen receptor (CAR) therapies are partly related to insertional mutagenesis, but the longitudinal evolution of CAR-integration sites (IS) remains understudied.

We performed an IS analysis in blood from three tisagenlecleucel (lentiviral), one axicabtagene-ciloleucel and one brexucabtagene-autoleucel (gammaretrovirals) patient at peak expansion and 1-year follow-up. All were complete responders. Peak expansion IS patterns were vector dependent: lentiviral CAR integrated mostly in introns and gammaretrovirals in intergenic regions, closer to transcription start sites.

At 1-year post-infusion, lentiviral CAR showed no major clonal proliferation. Gammaretroviral CARs had divergent outcomes: no detectable CAR (axicabtagene-ciloleucel) or low-level oligoclonal persistence (brexucabtagene-autoleucel). Whether this latter evolution is at risk of further CAR malignancies needs further investigations.