环磷酰胺
毒性
嵌合抗原受体
药理学
氟达拉滨
嵌合体(遗传学)
免疫学
医学
体内
生物
T细胞
化疗
免疫系统
内科学
生物技术
基因
生物化学
作者
Shigeki Yagyu,Hidemi Mochizuki,Kumiko Yamashima,Hiroshi Kubo,Shoji Saito,Miyuki Tanaka,Kengo Sakamoto,Akihito Shimoi,Yozo Nakazawa
摘要
Chimeric antigen receptor (CAR)-T cell therapy possesses the potential to cause unexpected on-target toxicities that may be life-threatening. Non-human primates (NHPs) share considerable structural homology and expression profiles of most proteins with humans and are therefore utilised as an animal model for non-clinical safety studies. We have developed a lymphodepleted NHP model by conditioning the animals with immunosuppressive chemotherapy designed to simulate clinical practice conditions, to induce transient mixed chimerism before the administration of human CAR-T cells redirected to target Ephrin type-B receptor 4 (EPHB4-CAR-T cells) to evaluate the toxicity of these cells.We administered 60 mg m-2 day-1 of fludarabine for 4 days and 30 mg kg-1 day-1 of cyclophosphamide for 2 days intravenously to cynomolgus macaques for lymphodepletion; then, 3.3 × 106 kg-1 of non-transduced or EPHB4-CAR-T cells was infused into the macaques, respectively. All macaques were closely monitored and evaluated for potential toxicity for 7 days.Lymphodepletion was successfully achieved on day -1 before T-cell infusion and persisted over 7 days without severe organ toxicities. A single administration of human EPHB4-CAR-T cells did not induce overt organ toxicities, although EPHB4-CAR-T cells were activated in vivo as evidenced by the elevation in copy numbers of the CAR transgene 24 h after infusion.Although this NHP model is limited for the full evaluation of toxicity of human CAR-T cells and the conditioning protocol should be further optimised, this lymphodepleted NHP model could be used to assess acute on-target/off-tumor toxicities of CAR-T cells.
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