Antitumor activity of CAR-T cells targeting the intracellular oncoprotein WT1 can be enhanced by vaccination
Antitumor activity of CAR-T cells targeting the intracellular oncoprotein WT1 can be enhanced by vaccination
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DOI：
10.1182/blood-2017-08-802926
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发表时间：
2018-09-13
期刊：
影响因子：
20.3
通讯作者：
Shiku, Hiroshi
中科院分区：
文献类型：
--
作者：
Akahori, Yasushi;Wang, Linan;Shiku, Hiroshi
最近嵌合抗原受体(CAR)-T细胞治疗血液恶性肿瘤的成功支持了液体和实体肿瘤治疗的进一步发展。然而，CAR-T细胞疗法的扩展受到肿瘤特异性表面抗原的可用性的限制，同时保留了正常细胞。来自细胞内表达蛋白的肿瘤抗原具有丰富的多样性，这是当前和传统CAR-T细胞无法靶向的。此外，过继性转移的T细胞经常遭受衰竭和扩张不足，部分原因是在荷瘤宿主中运行的免疫抑制机制。因此，有必要开发在体内进一步激活和扩增这些CAR-T细胞的手段。Wilms tumor 1 （WT1）是一种细胞内致癌转录因子，是肿瘤免疫治疗的一个有吸引力的靶点，因为它在广泛的白血病和实体瘤中过表达，而在正常成人组织中低水平表达。在本研究中，我们开发了由WT1235-243/HLAA* 2402复合物特异性单链可变片段（scFv）组成的CART细胞。我们的CAR-T细胞的治疗效果在异种移植模型中得到了证明，通过接种装载相应抗原的树突状细胞（dc）进一步增强了治疗效果。这种增强的疗效至少部分是由CAR-T细胞的扩增和激活介导的。本研究中显示的CAR-T细胞不仅展示了扩大CAR-T细胞可用靶标范围的潜力，而且还提供了一个概念证明，即靶向肽/主要组织相容性复合体的CAR-T细胞的功效可以通过接种疫苗来提高。
The recent success of chimeric antigen receptor (CAR)-T cell therapy for treatment of hematologic malignancies supports further development of treatments for both liquid and solid tumors. However, expansion of CAR-T cell therapy is limited by the availability of surface antigens specific for the tumor while sparing normal cells. There is a rich diversity of tumor antigens from intracellularly expressed proteins that current and conventional CAR-T cells are unable to target. Furthermore, adoptively transferred T cells often suffer from exhaustion and insufficient expansion, in part, because of the immunosuppressive mechanisms operating in tumor-bearing hosts. Therefore, it is necessary to develop means to further activate and expand those CAR-T cells in vivo. The Wilms tumor 1 (WT1) is an intracellular oncogenic transcription factor that is an attractive target for cancer immunotherapy because of its overexpression in a wide range of leukemias and solid tumors, and a low level of expression in normal adult tissues. In the present study, we developed CART cells consisting of a single chain variable fragment (scFv) specific to the WT1235-243/HLAA* 2402 complex. The therapeutic efficacy of our CAR-T cells was demonstrated in a xenograft model, which was further enhanced by vaccination with dendritic cells (DCs) loaded with the corresponding antigen. This enhanced efficacy was mediated, at least partly, by the expansion and activation of CAR-T cells. CAR-T cells shown in the present study not only demonstrate the potential to expand the range of targets available to CAR-T cells, but also provide a proof of concept that efficacy of CAR-T cells targeting peptide/major histocompatibility complex can be boosted by vaccination.