Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia.
Elena J OrlandoXia HanCatherine TribouleyPatricia A WoodRebecca J LearyMarkus RiesterJohn E LevineMuna QayedStephan A GruppMichael BoyerBarbara De MoerlooseEneida R NemecekHenrique BittencourtHidefumi HiramatsuJochen BuechnerStella M DaviesMichael R VernerisKevin NguyenJennifer L BrogdonHans BitterMichael MorrisseyPiotr L PierogSerafino PantanoJeffrey A EngelmanWendy WincklerPublished in: Nature medicine (2018)
We identified genetic mutations in CD19 and loss of heterozygosity at the time of CD19- relapse to chimeric antigen receptor (CAR) therapy. The mutations are present in the vast majority of resistant tumor cells and are predicted to lead to a truncated protein with a nonfunctional or absent transmembrane domain and consequently to a loss of surface antigen. This irreversible loss of CD19 advocates for an alternative targeting or combination CAR approach.