Development of a Unique T Cell Receptor Gene-Transferred Tax-Redirected T Cell Immunotherapy for Adult T Cell Leukemia
Development of a Unique T Cell Receptor Gene-Transferred Tax-Redirected T Cell Immunotherapy for Adult T Cell Leukemia
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DOI：
10.1016/j.bbmt.2020.04.006
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发表时间：
2020-08-01
影响因子：
4.3
通讯作者：
Kanda, Yoshinobu
中科院分区：
文献类型：
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作者：
Kawamura, Koji;Tanaka, Yukie;Kanda, Yoshinobu
成人T细胞白血病/淋巴瘤（ATL）是一种侵袭性外周T细胞肿瘤，由人类T细胞嗜淋巴细胞病毒1型（HTLV-1）感染引起。其预后仍然极差。Tax是HTLV-1最重要的调节蛋白，与宿主细胞的侵袭性增殖相关，也是CD8（+）细胞毒性T细胞（CTL）的主要靶抗原。基于我们先前的研究结果，即具有含有独特氨基酸序列基序的T细胞受体（TCR）的Tax特异性CTL对HTLV-1表现出强烈的HLA-A * 24：02限制性Tax（301 - 309）特异性活性，我们旨在开发针对ATL的Tax重定向T细胞免疫疗法。从先前建立的CTL克隆中克隆TCR-α/β基因，并使用逆转录病毒siTCR载体将其转导到健康志愿者的外周血单核细胞（PBMC）中。然后在体外和体内评估针对HTLV-1感染的T细胞或原代ATL细胞的细胞毒性功效。重定向的CTL（Tax-siCTL）产生大量细胞因子，并在体外对ATL/HTLV-1感染的T细胞显示出强的杀伤活性，尽管它们对ATL细胞不具有普遍活性。接下来，在使用HTLV-1感染的T细胞系（MT-2）的异种移植小鼠模型中，在所有用Tax-siCTL治疗的小鼠中，肿瘤迅速减小并最终消失，而没有正常组织损伤，尽管所有未治疗或用非基因修饰的PBMC治疗的小鼠都因肿瘤进展而死亡。我们的研究结果证实，Tax-siCTL可以发挥强大的抗ATL/HTLV-1作用，而对正常细胞没有显着反应，并有可能成为ATL患者的新型免疫疗法。(C)2020年美国移植和细胞治疗学会。爱思唯尔公司出版
Adult T cell leukemia/lymphoma (ATL) is an aggressive peripheral T cell neoplasm caused by infection with human T cell lymphotropic virus type-1 (HTLV-1). Its prognosis remains extremely poor. Tax, the most important regulatory protein for HTLV-1, is associated with the aggressive proliferation of host cells and is also a major target antigen for CD8(+) cytotoxic T cells (CTLs). Based on our previous findings that Tax-specific CTLs with a T cell receptor (TCR) containing a unique amino-acid sequence motif exhibit strong HLA-A*24:02-restricted, Tax(301-309) -specific activity against HTLV-1, we aimed to develop a Tax-redirected T cell immunotherapy for ATL. TCR-alpha/beta genes were cloned from a previously established CTL clone and transduced into peripheral blood mononuclear cells (PBMCs) of healthy volunteers using a retroviral siTCR vector. Then the cytotoxic efficacy against HTLV-1-infected T cells or primary ATL cells was assessed both in vitro and in vivo. The redirected CTLs (Tax-siCTLs) produced a large amount of cytokines and showed strong killing activity against ATL/HTLV-1-infected T cells in vitro, although they did not have universal activity against ATL cells. Next, in a xenograft mouse model using an HTLV-1-infected T cell line (MT-2), in all mice treated with Tax-siCTLs, the tumor rapidly diminished and finally disappeared without normal tissue damage, although all mice that were untreated or treated with non-gene-modified PBMCs died because of tumor progression. Our findings confirm that Tax-siCTLs can exert strong anti-ATL/HTLV-1 effects without a significant reaction against normal cells and have the potential to be a novel immunotherapy for ATL patients. (C) 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.