Perera Liyanage P, Zhang Meili, Nakagawa Masao, Petrus Michael N, Maeda Michiyuki, Kadin Marshall E, Waldmann Thomas A, Perera Pin-Yu
Lymphoid Malignancies Branch, National Cancer Institute, Bethesda, Maryland, 20892-1374, USA.
Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto, Japan.
Am J Hematol. 2017 Sep;92(9):892-901. doi: 10.1002/ajh.24794. Epub 2017 Jun 5.
With the emerging success of treating CD19 expressing B cell malignancies with ex vivo modified, autologous T cells that express CD19-directed chimeric antigen receptors (CAR), there is intense interest in expanding this evolving technology to develop effective modalities to treat other malignancies including solid tumors. Exploiting this approach to develop a therapeutic modality for T cell malignancies for which the available regimens are neither curative, nor confer long term survival we generated a lentivirus-based CAR gene transfer system to target the chemokine receptor CCR4 that is over-expressed in a spectrum of T cell malignancies as well as in CD4 CD25 Foxp3 T regulatory cells that accumulate in the tumor microenvironment constituting a barrier against anti-tumor immunity. Ex vivo modified, donor-derived T cells that expressed CCR4 directed CAR displayed antigen-dependent potent cytotoxicity against patient-derived cell lines representing ATL, CTCL, ALCL and a subset of HDL. Furthermore, these CAR T cells also eradicated leukemia in a mouse xenograft model of ATL illustrating the potential utility of this modality in the treatment of a wide spectrum of T cell malignancies.
随着利用表达CD19导向嵌合抗原受体（CAR）的体外修饰自体T细胞治疗表达CD19的B细胞恶性肿瘤取得初步成功，人们对扩展这一不断发展的技术以开发治疗包括实体瘤在内的其他恶性肿瘤的有效方法产生了浓厚兴趣。利用这种方法来开发一种治疗T细胞恶性肿瘤的治疗方式，现有方案对其既无法治愈，也不能带来长期生存，我们构建了一种基于慢病毒的CAR基因转移系统，以靶向趋化因子受体CCR4，该受体在一系列T细胞恶性肿瘤以及肿瘤微环境中积累的CD4 CD25 Foxp3 T调节细胞中过表达，这些调节细胞构成了抗肿瘤免疫的障碍。表达CCR4导向CAR的体外修饰供体来源T细胞对代表成人T细胞白血病（ATL）、皮肤T细胞淋巴瘤（CTCL）、间变性大细胞淋巴瘤（ALCL）和一部分蕈样肉芽肿（HDL）的患者来源细胞系表现出抗原依赖性强细胞毒性。此外，这些CAR T细胞还在ATL小鼠异种移植模型中根除了白血病，说明了这种治疗方式在治疗多种T细胞恶性肿瘤中的潜在效用。
