Figure 5.

CD19-specific CAR⁺ human T cells display significant antileukemic activity in an immunodeficient mouse model of human pre-B ALL. (a) Xenograft model using human CD19-specific CAR⁺ T cells to treat a primary human pre-B ALL in immunodeficient mice. After establishment of ALL, mice were randomized to treatment with the indicated T cell populations. (b and c) Hematoxylin & Eosin stained section of a NOD-SCID-β₂^−/− mouse calvarium (b) and spleen (c) 7–8 weeks following injection of pre-B ALL. Arrows indicate areas of bone marrow infiltrated by malignant ALL cells. The asterisk indicates leukemic cells that have invaded the leptomeningeal membranes. (d) Dose dependent antileukemic effect of CAR⁺ T cells given 2 weeks after establishing leukemia. Peripheral blood CD19⁺ B-ALL blast cell counts were measured at weekly intervals in mice (>4 mice/group) that were injected with the indicated numbers of αCD19-ζ CAR⁺ T cells or mock-transduced T cells The blast count in the 5 × 10⁶ CAR⁺ T cell group is significantly lower than the count in the Mock and no T cell groups (ANOVA on the log-transformed blast counts, F-test P = 0.008) (e) Leukemia-free survival over time in animals described in panel D receiving no T cells, mock-transduced T cells, or αCD19 -ζ CAR⁺ T cells (5 × 10⁶). Animals were assessed for leukemia at weekly intervals. Survival curves for the indicated groups were compared using the log-rank test. The group receiving αCD19 -ζ CAR⁺ T cells show a significantly increased median survival (log-rank test, P < 0.001) compared to animals receiving mock-transduced or no T cells. (f) Increased antileukemic effect of CAR⁺ T cells expressing costimulatory domains given 2 weeks after establishing leukemia. Peripheral blood CD19⁺ ALL blast cell counts were measured in leukemic mice (≥7 mice/group) that were injected with 2 × 10⁶ CAR T cells or mock-transduced T cells. At week 5, animals in all CAR⁺ T cell groups expressing costimulatory domains have significantly lower blast counts than Mock and no T cell groups by ANOVA (using Scheffe, P < 0.01). Results represent mean and standard error of mean in d and f.