With this model, we have recently demonstrated the superior efficacy and safety profile of CAR-T cells generated from naïve/stem memory subsets rather than total T lymphocytes, supporting the robustness of this model to profile human CAR-T cell performances in mice.28 In this study, toxicity assessment in HuSGM3 mice engrafted with the B-ALL cell line NALM-6 revealed that CD4 CAR-T cells targeting CD19 play a crucial role during CRS development, which was more severe when they included the CD28 endodomain rather than 4-1BB. This evidence concerns the gene CD28 and acute lymphoblastic leukemia.