@article{ATM32887,
author = {Hairuo Wen and Zhe Qu and Yujing Yan and Chengfei Pu and Chao Wang and Hua Jiang and Tiantian Hou and Yan Huo},
title = {Preclinical safety evaluation of chimeric antigen receptor-modified T cells against CD19 in NSG mice},
journal = {Annals of Translational Medicine},
volume = {7},
number = {23},
year = {2019},
keywords = {},
abstract = {Background: With the increase of chimeric antigen receptor-modified T (CAR-T) cell therapy, serious complications initiated by CAR-T cells have garnered wide attention. We have previously developed a 4-1BB/CD3-ζ-costimulated CAR-T cells against CD19 (CART19) for adult acute lymphoblastic leukemia (ALL). In this study, a preclinical safety assessment of CART19 was performed on NSG mice, to evaluate the preclinical toxicity along with its efficacy and tissue distribution.
Methods: A total of 120 NSG mice were used for a combined pharmacodynamics and toxicity study for 56 days. Ninety-six mice of which were single dosed with Raji-Luc (5×105 per animal, i.p.) and different concentrations of CART19 (0.2×107, 0.6×107 and 1.8×107 per animal, i.v.), while the rest were assigned to the Untreated group. Optical intensity of Raji-Luc in mice, clinical symptoms, body mass, hematological analysis, humanized cytokine, lymphocyte subset counting, necropsy and histopathological examinations were performed. In addition, a single dose of 0.6×107 CART19 was intravenously administered to 48 NSG mice, and the distribution of CART19 in different tissues was analyzed using quantitative PCR.
Results: CART19 is widely distributed in organs well-perfused with blood, including the lungs, blood, bone marrow, liver and spleen. Significant proliferation of CART19 was also found in the blood by through recognition using humanized CD3+ for T lymphocytes. The survival rate and leukemia related clinical symptoms in mice administered CART19 were markedly ameliorated, and the proliferation of Raji cells in mice was effectively inhibited. However, CART19 had no obvious effects on either the mean body mass or the blood cell counts, and no cytokine release syndrome and graft versus host disease were observed.
Conclusions: NSG mice given CART19 treatment demonstrated a longer survival period without significant immunotoxicity, suggesting encouraging clinical prospects for CART19 in patients with R/R ALL. Our study shed light on evaluation and supervision strategies for CAR-T products for the treatment of hematological diseases or leukemia.},
issn = {2305-5847}, url = {https://atm.amegroups.org/article/view/32887}
}