Regeneration of invariant natural killer T (iNKT) cells: application of iPSC technology for iNKT cell-targeted tumor immunotherapy.

IF 5 3区 医学 Q2 IMMUNOLOGY
Takahiro Aoki, Shinichiro Motohashi, Haruhiko Koseki
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引用次数: 2

Abstract

Invariant natural killer T (iNKT) cells are a subset of innate-like T cells restricted by a major histocompatibility complex (MHC) class I-like molecule, CD1d. iNKT cells express an invariant T cell receptor (TCR) encoded by Vα14 Jα18 in mice and Vα24 Jα18 in humans and are activated by recognizing glycolipid antigens, such as α-galactosylceramide (αGalCer), presented by CD1d. iNKT cells exhibit anti-tumor activity via their NK-like cytotoxicity and adjuvant activity. Although iNKT cell-targeted immunotherapy is a conceptually promising approach, we still found a technical hurdle for its clinical implementation which is mainly due to the low frequency of iNKT cells, particularly in humans. To compensate for this, we proposed to generate adequate numbers of clinically competent NKT cells from induced pluripotent stem cells (iPSCs) for cancer immunotherapy. Toward this goal, we first obtained the proof of concept (POC) for this approach in mice. We developed a technology to differentiate iPSCs into iNKT cells (iPSC-iNKT cells) and found iPSC-iNKT cells efficiently rejected a syngeneic experimental thymoma by inducing antigen-specific CD8 T cells. After achieving the POC in mice, we developed human iPSC-iNKT cells, which had a high correlation in their gene expression profiles with parental iNKT cells. Human iPSC-iNKT cells also exhibited anti-tumor activity and adjuvant activity for human NK cells in vivo. Based on this supporting evidence for the anti-tumor activity of human iPSC-iNKT cells, we began to generate good manufacturing practice (GMP)-grade iPSC-iNKT cells. As of now, the first-in-human clinical trial of iPSC-iNKT cell therapy is ongoing as a single-agent, dose-escalation study for patients with advanced head and neck cancer. Demonstration of the safety of iPSC-iNKT cell therapy may allow us to improve the strategy by further reinforcing the therapeutic activity of iPSC-iNKT, cells either by gene-editing or combinatorial use with other immune cell products such as dendritic cells. Sixteen years after the establishment of the iPSC technology, we are reaching the first checkpoint to evaluate the clinical efficacy of iPSC-derived immune cells.

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不变性自然杀伤T细胞的再生:iPSC技术在iNKT细胞靶向肿瘤免疫治疗中的应用
不变性自然杀伤T细胞(iNKT)是先天样T细胞的一个亚群,受主要组织相容性复合体(MHC) i类分子CD1d的限制。iNKT细胞表达一种由小鼠Vα14 Jα18和人Vα24 Jα18编码的不变T细胞受体(invariant T cell receptor, TCR),通过识别CD1d呈递的α-半乳糖神经酰胺(αGalCer)等糖脂抗原而被激活。iNKT细胞通过其nk样细胞毒性和佐剂活性表现出抗肿瘤活性。尽管iNKT细胞靶向免疫疗法在概念上是一种很有前景的方法,但我们仍然发现其临床实施的技术障碍,这主要是由于iNKT细胞的低频率,特别是在人类中。为了弥补这一点,我们建议从诱导多能干细胞(iPSCs)中产生足够数量的临床胜任的NKT细胞用于癌症免疫治疗。为了实现这一目标,我们首先在小鼠身上获得了这种方法的概念验证(POC)。我们开发了一种将ipsc分化为iNKT细胞(iPSC-iNKT细胞)的技术,并发现iPSC-iNKT细胞通过诱导抗原特异性CD8 T细胞有效地排斥了同基因的实验性胸腺瘤。在小鼠中实现POC后,我们开发了人类iPSC-iNKT细胞,其基因表达谱与亲代iNKT细胞高度相关。人iPSC-iNKT细胞在体内也表现出抗肿瘤活性和对人NK细胞的佐剂活性。基于这一支持iPSC-iNKT细胞抗肿瘤活性的证据,我们开始生产GMP级iPSC-iNKT细胞。截至目前,iPSC-iNKT细胞治疗的首个人体临床试验正在进行中,作为一项单药、剂量递增的研究,用于晚期头颈癌患者。iPSC-iNKT细胞治疗的安全性证明可能使我们能够通过基因编辑或与其他免疫细胞产品(如树突状细胞)组合使用进一步增强iPSC-iNKT细胞的治疗活性,从而改进策略。在iPSC技术建立16年后,我们正在达到评估iPSC衍生免疫细胞临床疗效的第一个检查点。
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来源期刊
CiteScore
11.10
自引率
1.20%
发文量
45
审稿时长
11 weeks
期刊介绍: Inflammation and Regeneration is the official journal of the Japanese Society of Inflammation and Regeneration (JSIR). This journal provides an open access forum which covers a wide range of scientific topics in the basic and clinical researches on inflammation and regenerative medicine. It also covers investigations of infectious diseases, including COVID-19 and other emerging infectious diseases, which involve the inflammatory responses. Inflammation and Regeneration publishes papers in the following categories: research article, note, rapid communication, case report, review and clinical drug evaluation.
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