Molecular Biotechnology and Gene Therapy, Paul-Ehrlich-Institut, Langen, Germany.
Dr. Senckenberg Institute of Pathology, Goethe-University Frankfurt, Frankfurt am Main, Germany.
EMBO Mol Med. 2018 Nov;10(11). doi: 10.15252/emmm.201809158.
Chimeric antigen receptor (CAR) T cells brought substantial benefit to patients with B-cell malignancies. Notwithstanding, CAR T-cell manufacturing requires complex procedures impeding the broad supply chain. Here, we provide evidence that human CD19-CAR T cells can be generated directly using the lentiviral vector CD8-LV specifically targeting human CD8 cells. Administration into mice xenografted with Raji lymphoma cells and human peripheral blood mononuclear cells led to CAR expression solely in CD8 T cells and efficacious elimination of CD19 B cells. Further, upon injection of CD8-LV into mice transplanted with human CD34 cells, induction of CAR T cells and CD19 B-cell depletion was observed in 7 out of 10 treated animals. Notably, three mice showed elevated levels of human cytokines in plasma. Tissue-invading CAR T cells and complete elimination of the B-lymphocyte-rich zones in spleen were indicative of a cytokine release syndrome. Our data demonstrate the feasibility of reprogramming of human CD8 CAR T cells active against CD19 cells, yet with similar adverse effects currently notorious in the clinical practice.
嵌合抗原受体 (CAR) T 细胞为 B 细胞恶性肿瘤患者带来了显著的益处。然而，CAR T 细胞的制造需要复杂的程序，阻碍了广泛的供应链。在这里，我们提供的证据表明，人 CD19-CAR T 细胞可以直接使用针对人 CD8 细胞的慢病毒载体 CD8-LV 产生。将其施用于用 Raji 淋巴瘤细胞和人外周血单核细胞异种移植的小鼠中，导致 CAR 在 CD8 T 细胞中表达，并有效消除 CD19 B 细胞。此外，将 CD8-LV 注入移植有人类 CD34 细胞的小鼠中，在 10 只接受治疗的动物中有 7 只观察到 CAR T 细胞的诱导和 CD19 B 细胞的耗竭。值得注意的是，有 3 只小鼠的血浆中出现了高水平的人细胞因子。组织浸润的 CAR T 细胞和脾脏中富含 B 淋巴细胞区的完全消除表明存在细胞因子释放综合征。我们的数据表明，针对 CD19 细胞的人 CD8 CAR T 细胞的重编程是可行的，但具有类似的不良影响，目前在临床实践中已广为人知。
