T cells expressing a KIR-CAR/Dap12 show potent in vivo antitumor activity that is resistant to the tumor-induced T-cell hypofunction observed with CD3ζ-based.

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T cells expressing a KIR-CAR/Dap12 show potent in vivo antitumor activity that is resistant to the tumor-induced T-cell hypofunction observed with CD3ζ-based CARs. A, adult NSG mice were injected subcutaneously with 2 × 106 EM-meso cells as described previo... T cells expressing a KIR-CAR/Dap12 show potent in vivo antitumor activity that is resistant to the tumor-induced T-cell hypofunction observed with CD3ζ-based CARs. A, adult NSG mice were injected subcutaneously with 2 × 106 EM-meso cells as described previously (19). Primary human T cells (5 × 106) transduced with the indicated CARs (80%–90% transduction efficiency) were injected i.v. on day 20 following tumor implantation. Tumor volume was measured by caliper using the formula (π/6) × (length) × (width)2 at the indicated times (n = 7 mice per group). Tumor volume was compared across CAR T-cell treatment groups at day 40 (nadir of tumor regression) and day 52 (end of the experiment) by a one-way ANOVA (P < 0.001) with between-group comparisons performed by a post hoc Scheffe F-test. * indicates statistically different from the mock control at both time points (P < 0.001). B, NSG mice were engrafted with CBG-labeled Nalm6 leukemic cells as described in Materials and Methods. Primary human T cells (2 × 106) transduced with the indicated CAR (70%–90% transduction efficiency) were injected i.v. on day 5 following leukemic cell line injection. Tumor burden was assessed via bioluminescent imaging at the indicated times (n = 5 mice per group). Greater than 50% of the mice treated with mock-transduced and CD19ζ-transduced T cells developed terminal leukemia requiring sacrifice on days 15 and 37, respectively. Greater than 50% of the mice treated with CD19BBζ-transduced T cells developed graft-versus-host disease requiring termination of the experiment on day 72. Total radiance was compared across the CAR T-cell treatment groups at day 37 by a one-way ANOVA (P < 0.001) with between-group comparisons performed by a post hoc Scheffe F-test. CD19BBζ- and CD19KIRS2/DAP12–transduced T-cell groups were statistically different from the CD19ζ-transduced T-cell group (P < 0.001), but no difference could be demonstrated between the CD19BBζ and CD19KIRS2/Dap12 groups (P = 0.748). C, NSG mice were injected subcutaneously with EM-meso cells as described in A. T cells transduced with FAP-BBζ (FAP-CAR) or mock-transduced were injected intravenously on day 20. Tumor volume was measured as in A. FAP-BBζ T-cell–treated mice showed statistically significantly delayed tumor growth compared with mock-treated control tumors (P < 0.026, Student t test). N = 5 animals per group. D, NSG mice were injected subcutaneously with EM-meso cells as described in A. T cells transduced with DAP12 alone, FAP-KIR/DAP12, or mock-transduced were injected intravenously on day 21. Tumor volume was measured as in A. Tumors from FAP-KIR/DAP12 T-cell–treated mice show significantly delayed growth with tumor volume significantly reduced compared with DAP12 and mock controls on day 48 (P < 0.01, ANOVA with post hoc Scheffe F-test). N = 5 animals per group. E, hematocrit was measured on blood collected from mice shown in D on day 48. Treatment conditions were compared using an ANOVA with post hoc Scheffe F-test with the P values shown. F, flow cytometry was performed on tumors harvested on day 48 from 5 animals shown in C. The frequency of CD45−CD90+FAP+ and CD45+FAP+ cells within the tumor was compared by ANOVA with the P values indicated. Enxiu Wang et al. Cancer Immunol Res 2015;3:815-826 ©2015 by American Association for Cancer Research