Broadly neutralizing antibody derived CAR T cells reduce viral reservoir in individuals infected with HIV-1
Broadly neutralizing antibody derived CAR T cells reduce viral reservoir in individuals infected with HIV-1
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广泛中和抗体衍生的 CAR-T 细胞可减少 HIV-1 感染者的病毒库
DOI：
10.1172/jci150211
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发表时间：
2021-10-01
影响因子：
15.9
通讯作者：
Zhang, Hui
中科院分区：
文献类型：
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作者：
Liu, Bingfeng;Zhang, Wanying;Zhang, Hui
背景嵌合抗原受体（CAR）T细胞已经成为治疗恶性肿瘤的方法。该策略也被提议用于治疗HIV-1感染。我们已经开发了一种广泛中和的抗体衍生（bNAb衍生）CAR T细胞疗法，其可以对HIV-1感染的细胞发挥特异性细胞毒性活性。我们在正在接受抗逆转录病毒治疗（ART）分析中断的HIV-1感染者中进行了一项开放标签试验，研究bNAb衍生的CAR T细胞疗法的安全性、副作用特征、药代动力学特性和抗病毒活性。总共14名参与者仅完成了bNAb衍生的CART细胞的单次施用。CAR T细胞疗法施用是安全的且耐受性良好。6名参与者停止ART，所有人都发生了病毒血症反弹，中位时间为5.3周。值得注意的是，CAR T细胞处理后，细胞相关病毒RNA和完整的前病毒显著减少。对CART细胞给药前后HIV-1变异体的分析表明，CART细胞对反弹病毒施加压力，导致选择的病毒具有较少的多样性和针对CART细胞介导的细胞毒性的突变。未发现bNAb衍生的CAR T细胞过继转移的安全性问题。他们减少了病毒库。所有的反弹都是由于预先存在或出现的病毒逃逸突变。
BACKGROUND. Chimeric antigen receptor (CAR) T cells have emerged as an approach to treat malignant tumors. This strategy has also been proposed for the treatment of HIV-1 infection. We have developed a broadly neutralizing antibody-derived (bNAb-derived) CAR T cell therapy that can exert specific cytotoxic activity against HIV-1-infected cells.METHODS. We conducted an open-label trial of the safety, side-effect profile, pharmacokinetic properties, and antiviral activity of bNAb-derived CAR T cell therapy in individuals infected with HIV-1 who were undergoing analytical interruption of antiretroviral therapy (ART).RESULTS. A total of 14 participants completed only a single administration of bNAb-derived CART cells. CAR T cell therapy administration was safe and well tolerated. Six participants discontinued ART, and viremia rebound occurred in all of them, with a 5.3-week median time. Notably, the cell-associated viral RNA and intact proviruses decreased significantly after CAR T cell treatment. Analyses of HIV-1 variants before or after CART cell administration suggested that CART cells exerted pressure on rebound viruses, resulting in a selection of viruses with less diversity and mutations against CART cell-mediated cytotoxicity.CONCLUSION. No safety concerns were identified with adoptive transfer of bNAb-derived CAR T cells. They reduced viral reservoir. All the rebounds were due to preexisting or emergence of viral escape mutations.