Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is associated with a remarkably poor prognosis and with no treatment consensus. The identification of relevant therapeutic targets is challenging. Here, we investigated the immune functions, antileukemia efficacy and safety of CD28/4-1BB CAR T cells targeting CD123 the interleukin (IL)-3 receptor alpha chain which is overexpressed on BPDCN. We demonstrated that both retroviral and lentiviral engineering CD28/4-1BB CD123 CAR T cells exhibit effector functions against BPDCN cells through CD123 antigen recognition and that they efficiently kill BPDCN cell lines and BPDCN-derived PDX cells. In vivo, CD28/4-1BB CD123 CAR T-cell therapy displayed strong efficacy by promoting a decrease of BPDCN blast burden. Furthermore we showed that T cells from BPDCN patient transduced with CD28/4-1BB CD123 CAR successfully eliminate autologous BPDCN blasts in vitro. Finally, we demonstrated in humanized mouse models that these effector CAR T cells exert low or no cytotoxicity against various subsets of normal cells with low CD123 expression, indicating a potentially low on-target/off-tumor toxicity effect. Collectively, our data support the further evaluation for clinical assessment of CD28/4-1BB CD123 CAR T cells in BPDCN neoplasm.

中文翻译：

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原生质浆样树突状细胞瘤中的CD28 / 4-1BB CD123 CAR T细胞。

弹性浆细胞样树突状细胞瘤（BPDCN）与预后显着差且没有治疗共识有关。相关治疗靶标的鉴定具有挑战性。在这里，我们调查了针对CD123的CD28 / 4-1BB CAR T细胞的免疫功能，抗白血病功效和安全性，该CD123是在BPDCN上过表达的白介素（IL）-3受体α链。我们证明，逆转录病毒和慢病毒工程CD28 / 4-1BB CD123 CAR T细胞均通过CD123抗原识别表现出针对BPDCN细胞的效应子功能，并且它们有效杀死BPDCN细胞系和BPDCN衍生的PDX细胞。在体内，CD28 / 4-1BB CD123 CAR T细胞疗法通过促进BPDCN blast负担的减少显示出强大的疗效。此外，我们显示，从CD28 / 4-1BB CD123 CAR转导的BPDCN患者的T细胞在体外成功消除了自体BPDCN母细胞。最后，我们在人源化小鼠模型中证明了这些效应CAR T细胞对CD123低表达的正常细胞的各种亚群均具有低毒性或无细胞毒性，表明潜在的低靶点/肿瘤外毒性作用。总之，我们的数据支持对BPDCN肿瘤中CD28 / 4-1BB CD123 CAR T细胞进行临床评估的进一步评估。