Extended Data Fig. 9: Disabling FAS signaling enhances CAR-T cell persistence and antitumor efficacy in the setting of B cell Non-Hodgkin lymphoma and a solid malignancy.
From: CAR-engineered lymphocyte persistence is governed by a FAS ligand–FAS autoregulatory circuit
(a) Experimental design to compare the in vivo antitumor efficacy and persistence of human T cells expressing a 1928ζ CAR ± a FAS dominant negative receptor (ΔFAS) against four day established Raji-luciferase (Luc) B cell non-Hodgkin lymphoma (B-NHL). (b) Bioluminescence imaging, (c) individual, and (d) summary curves of tumor burden as a function of time using n = 5 (tEGFR), n = 10 mice (tEGFR-1928ζ), or n = 9 (tEGFR-1928ζ-ΔFAS) mice per group. Data in (d) displayed as mean ± standard deviation. Tumor burden at the final time point (d21) was compared using an unpaired one-tailed Mann-Whitney test. (e) Quantification of the absolute number of circulating CAR-T cells (cells mL−1) in the peripheral blood as a function of time in Raji B-NHL bearing mice. Mice received by IV adoptive transfer 5e6 tEGFR-1928ζ or tEGFR-1928ζ-ΔFAS CAR-T cells. Each symbol represents values from individually evaluated mice. P values calculated based on comparison of ΔFAS-expressing Vs. not expressing CAR-T cells at each time point using an unpaired, two-sided, t-test. (f) Experimental design for comparing the in vivo antitumor efficacy of human T cells transduced with a (MSLN)28ζ CAR ± ΔFAS against subcutaneous (s.c.) 14 day established AsPC1-luciferase (Luc) pancreatic cancer tumors. All mice received twice-weekly intraperitoneal (i.p.) injections of 1 μg of IL-15 pre-complexed with IL-15Rα-Fc (1:1 M) and a single intravenous (i.v.) injection of 1e6 human CAR+ T cells. (g) Survival curves and (h) bioluminescent imaging of treated mice. Survival data is plotted as a Kaplan–Meier survival curve with groups statistically compared using a log-rank test. wk = week.
