肿瘤细胞治疗研究
英文原题：Regeneration of invariant natural killer T (iNKT) cells: application of iPSC technology for iNKT cell-targeted tumor immunotherapy.
恒定自然杀伤T（iNKT）细胞是受主要组织相容性复合体（MHC）I类样分子CD1d限制的先天样T细胞的一个亚群。
恒定自然杀伤T（iNKT）细胞是受主要组织相容性复合体（MHC）I类样分子CD1d限制的先天样T细胞的一个亚群。iNKT细胞表达由小鼠Vα14 Jα18和人类Vα24 Jα18编码的恒定T细胞受体（TCR），并通过识别由CD1d呈递的糖脂抗原（如α-半乳糖神经酰胺（αGalCer））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。尽管靶向iNKT细胞的免疫治疗在概念上是一种有前景的方法，但我们仍发现其临床实施存在技术障碍，这主要是由于iNKT细胞频率低，尤其是在人类中。为弥补这一点，我们提出从诱导多能干细胞（iPSCs）中生成足够数量的具有临床能力的NKT细胞用于癌症免疫治疗。为实现这一目标，我们首先在小鼠中获得了该方法的原理验证（POC）。我们开发了一种将iPSCs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细胞有效排斥了同基因实验性胸腺瘤。在小鼠中实现POC后，我们开发了人类iPSC-iNKT细胞，其基因表达谱与亲本iNKT细胞高度相关。人类iPSC-iNKT细胞在体内还表现出抗肿瘤活性以及对人类NK细胞的佐剂活性。基于这些支持人类iPSC-iNKT细胞抗肿瘤活性的证据，我们开始生成符合良好生产规范（GMP）级别的iPSC-iNKT细胞。截至目前，iPSC-iNKT细胞疗法的首次人体临床试验正在作为单药、剂量递增研究用于晚期头颈癌患者。iPSC-iNKT细胞疗法安全性的证明可能使我们能够通过基因编辑或与树突状细胞等其他免疫细胞产品联合使用，进一步增强iPSC-iNKT细胞的治疗活性，从而改进该策略。在iPSC技术建立16年后，我们正到达评估iPSC衍生免疫细胞临床疗效的第一个检查点。
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.
MEMBER ACCOUNT
登录成功会直接打开下一页。
