Efficacy and Safety of CD28- or 4-1BB-based CD19 CAR-T cells in B Cell Acute Lymphoblastic Leukemia

Abstract CD19-directed chimeric antigen receptor-T (CAR-T) cells with 4-1BB or CD28 co-stimulatory domain have shown impressive antitumor activity against relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). However, a parallel comparison of their performances in r/r B-ALL therapy has not been sufficiently reported. Here we manufactured 4-1BB- and CD28-based CD19 CAR-T cells using the same process technology, and evaluated their efficacy and safety in r/r B-ALL therapy based on pre-clinical and exploratory clinical investigations. In B-ALL-bearing mice, similar antitumor effect and CAR-T kinetics in peripheral blood were observed at the CAR-T dose of 1×107 /mouse. However, when the dose was decreased to 1×106/mouse, 4-1BB CAR-T cells were more potent in eradicating tumor cells and showed longer persistence than CD28 CAR-T cells. Retrospective analysis of an exploratory clinical study that used 4-1BB- or CD28-based CAR-T cells to treat r/r B-ALL was performed. Compared with CD28 CAR-T cells, 4-1BB CAR-T cells resulted in higher antitumor efficacy and less severe adverse events. This study demonstrated that the performance of 4-1BB CAR-T cells was superior to that of CD28 CAR-T cells in suppressing CD19+ B-ALL, at least under our manufacture process.