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Introduction
概述
The immune system evolved to distinguish self and nonself and to effectively protect the individual from microorganisms, many of which cause diseases, and the resulting damage; the immune system also protects us against cancers and toxins, in order to help maintain our normal activities [ 1]. Cancer cells are self-cells with aberrant growth potential, acquired as a result of several gene abnormalities [ 2]. The idea that the immune system could control cancer growth has been discussed for over a century. “Evading immune destruction” has been recently added in the hallmarks of cancer, proposed by Hanahan and Weinberg in [ 2]. We clinically encounter cancer cells that have escaped from immune surveillance. Recent progress in cancer immunity has been answering questions about how the immune system is involved in the process of cancer formation [ 3], and whether immunotherapy eliminates cancer cells that have undergone immune escape.免疫系统的核心作用是通过区分自身和非自身细胞，并有效地保护个体免受微生物的侵害，其中许多微生物会导致疾病，并造成损害；免疫系统还可以保护我们免受癌症和毒素的侵害，以帮助维持我们的正常活动[1]。癌细胞是具有异常生长潜力的自身细胞，由于几种基因突变而产生[2]。一个多世纪以来科学家一直在研究如何让免疫系统可以控制癌症生长的想法。Hanahan和Weinberg在提出在癌症形成中有“逃避免疫系统”因素[2]。我们临床上也遇到了从免疫监视中逃脱的癌细胞。癌症免疫的一直在回答有关免疫系统如何参与癌症形成过程的问题[3]，以及免疫疗法是否能够消除已经过免疫逃逸的癌细胞。The identifi cation of MAGE-A1 in melanoma patients, described as the fi rst cancer antigen by Boon et al. in 1991 [ 4], opened the door to antigen-specifi c cancer immunotherapiesfrom nonspecifi c ones such as immune-adjuvants [ 5, 6] and cytokines [ 7]. During the next two decades, many cancer antigens have been identifi ed, including WT1, leading to the development of more effective cancer immunotherapies [ 8– 10]. Currently, cancer immunotherapyis expected for the fourth most common cancer therapy, behind surgical resection, radiotherapy, and chemotherapies (including molecular target agents).1991年[4]Boon等人在黑色素瘤患者中鉴定第一种癌症抗原被描述为MAGE-A1的，开启了抗原特异性癌症免疫疗法的大门，这些免疫疗法来自免疫佐剂[5,6]和细胞因子等非特异性[7]。在接下来的二十年中，已经鉴定出许多癌抗原，包括WT1，导致更有效的癌症免疫疗法的发展[8-10]。目前，癌症免疫疗法预计是第四种最常见的癌症疗法，仅次于手术切除，放射疗法和化学疗法（包括分子靶向药物）。
Principle of Peptide-Based Cancer Vaccine
基于肽的癌症疫苗原理
In most of cancer immunotherapy , the key process involves exploiting the intrinsic capacity of dendritic cells ( DCs )in vivo or ex vivo in order to induce antigen-specifi c T-cell responses [ 13– 15]. Peptidebased cancer vaccines, which are simple and easily adapted to a variety of cancer patients, are widely used in clinical trials . The principles of peptide-based cancer vaccines, which consist of HLA class I-restricted peptide and immune adjuvant, are as follows (Fig. 1) [ 16, 17].在大多数癌症免疫疗法中，关键过程涉及在体内或离体利用树突细胞（DC）的内在能力以诱导抗原特异性T细胞应答[13-15]。基于肽的癌症疫苗简单且易于适应各种癌症患者，广泛用于临床试验。基于肽的癌症疫苗的原理，其由HLA I类限制性组成肽和免疫佐剂如下（图1）[16,17]。1、HLA class I-restricted peptides are injected intradermally or subcutaneously along with some immune adjuvant. Peptides bind to the HLA class I molecules on the surface of DCs , or are taken up and presented on the cell surface along with HLA class I molecules by immature DCs . Immune adjuvant injected at the same time stimulates immature DCsin peripheral tissues。HLA I类限制性肽与一些免疫佐剂一起皮内或皮下注射。肽与DC表面上的HLA I类分子结合，或被未成熟DC吸收并与HLA I类分子一起呈递在细胞表面上。同时注射的免疫佐剂刺激未成熟的DCsin外周组织2、These activated DCsmigrate via lymphatics to regional lymph nodes, where they arrive as fully mature DCsthat express both antigen/HLA-molecule complexes and costimulatory molecules necessary to stimulate antigen-specifi c T- lymphocytes .这些活化的DC通过淋巴管转移至区域淋巴结，在那里它们作为完全成熟的DC到达，其表达抗原/ HLA-分子复合物和刺激抗原特异性T-淋巴细胞所必需的共刺激分子。3、Antigen-specifi c T-lymphocytes, especially CD8 + cytotoxic T-lymphocytes ( CTLs ), are stimulated to proliferate and differentiate by mature DCsand form a clone of effecter cells.抗原特异性T淋巴细胞，尤其是CD8 +细胞毒性T淋巴细胞（CTL）被成熟DC刺激增殖和分化，并形成有效细胞的克隆。4、Ultimately, antigen-specifi c CTL senter the tumor bed, and kill the targeted cancer cells by inducing apoptosis and releasing specialized cytotoxic granules, such as perforin and granzymes, upon recognition of the antigen on the surfaces of tumor cells.最终，抗原特异性CTL引发肿瘤床，并且在识别肿瘤细胞表面上的抗原后，通过诱导细胞凋亡并释放特异性细胞毒性颗粒（例如穿孔素和颗粒酶）来杀死靶向癌细胞。
Fig. 1 Mechanism of peptide-based cancer vaccines. Cancer cells express some antigens recognized by the host immune system, and present the peptide derived from this antigen/HLA class I complex on the cell surface. Antigen-specifi c cytotoxic lymphocytes that are elicited by peptide-based cancer vaccines recognize peptide/HLA class I complexes via the T-cell receptor (TCR)
图1基于肽的癌症疫苗的机制。癌细胞表达宿主免疫系统识别的一些抗原，并在细胞表面上呈递源自该抗原/ HLA I类复合物的肽。由基于肽的癌症疫苗引发的抗原特异性细胞毒性淋巴细胞通过T细胞受体（TCR）识别肽/ HLA I类复合物
1、Injection of cancer antigen and immune adjuvant
注射癌抗原和免疫佐剂
2、 Migration to lymph node and presentation of cancer antigen to T-cells; antigen-specifi c cytotoxic T-lymphocytes ( CTLs )
迁移至淋巴结并将癌抗原呈递至T细胞; 抗原特异性细胞毒性T淋巴细胞（CTLs）
3、Proliferation and differentiation of T-lymphocytes
T淋巴细胞的增殖和分化
4、Cytotoxicity mediated by antigen-specifi c CTLs
由抗原特异性CTL介导的细胞毒性
Preparation of WT1 Peptide-Based Cancer Vaccine
WT1肽基癌症疫苗的制备
Peptide-based vaccinesgenerally consist of peptides and immune adjuvants. Peptides can be further divided into two groups: HLArestricted short peptides, and non-HLA-restricted long peptides[ 30]. A majority of clinical studies of cancer immunotherapiestargeting WT1 have used HLA-restricted short peptide-based vaccines.基于肽的疫苗通常由肽和免疫佐剂组成。肽可以进一步分为两组：HLA限制性短肽和非HLA限制性长肽[30]。癌症免疫治疗靶向WT1的大多数临床研究使用了HLA限制性短肽基疫苗。Peptides: HLA-restricted short peptides are used; specifi - cally, HLA-A*24:02-restricted modifi ed 9-mer WT1 235 peptide and/or HLA-A*02:01-restricted 9-mer WT1 126 peptide. The doses of peptide are usually 3 mg/body, although the recommended doses (RD) of the peptides have not been determined in dose- escalation studies [ 18, 19].肽：使用HLA限制性短肽; 具体地，HLA-A * 24:02限制性修饰的9-mer WT1 235肽和/或HLA-A * 02:01限制性9-mer WT1 126肽。肽的剂量通常为3毫克/体，尽管肽的推荐剂量（RD）尚未在剂量递增研究中确定[18,19]。Adjuvants: Immune adjuvants are materials that enhance the immune response. Their functions can be broadly divided into two categories: (1) transport medium, by which antigen presenting cells (APCs), including DCs , engulf vaccine antigens effectively; and (2) immune modulator. The latter role is the more important of the two. The activation of DCsthrough the pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), is the most important process and is crucial for initiating the innate immunity response: such signaling makes immature DCs , whose sole function is to capture microbes and the dead cells, differentiate into mature DCs , which can process and present their antigens to T-lymphocytes in regional lymph nodes [ 33– 35]. Immune adjuvants work like pathogenassociated molecular patterns (PAMPs) and damage-associated molecular pattern (DAMPs) to activate DCs .佐剂：免疫佐剂是增强免疫反应的物质。它们的功能大致可分为两类：（1）转运培养基，包括DC在内的抗原呈递细胞（APCs）有效地吞噬疫苗抗原; （2）免疫调节剂。后者的角色是两者中更重要的角色。通过模式识别受体（PRR）激活DC，如Toll样受体（TLRs），是最重要的过程，对于启动先天免疫反应至关重要：这种信号传导使得不成熟的DC，其唯一的功能是捕获微生物和死细胞分化成成熟的DCs，可以处理并将其抗原呈递给区域淋巴结中的T淋巴细胞[33-35]。免疫佐剂的作用类似于病原体相关分子模式（PAMP）和损伤相关分子模式（DAMPs）以激活DC。Products: We describe the vaccine product frequently used in our clinical setting as follows: 3 mg of WT1 peptide is dissolved in a small volume of dimethyl sulfoxide (DMSO), and then the peptide solution is diluted to 400 μl with 5 % glucose. Ultimately, the mixture is emulsifi ed with an equal weight of Montanide ISA51 adjuvant [ 18].产品：我们描述了在我们的临床环境中经常使用的疫苗产品如下：将3mg WT1肽溶解在少量二甲基亚砜（DMSO）中，然后用5％葡萄糖将肽溶液稀释至400μl。最后，用等重量的Montanide ISA51佐剂对混合物进行乳化[18]。
（上图：日本肿瘤医学研究所生产的WT1肿瘤疫苗）
【参考文献】
1、1. Kenneth Murphy et al () Janeway’s immunobiology, 8th edn. Grand Science.
2. Hanahan D, Weinberg RA () Hallmarks of cancer: the next generation. Cell 144:646–674
3. Schreiber RD, Old LJ, Smyth MJ () Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331:1565–1570
4. Van der Bruggen P, Traversari C, Boon T et al (1991) A gene encoding an antigen recognized by cytotoxic T lymphocytes on a human melanoma. Science 254:1643–1647
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12. Van Driessche A, Berneman ZN, Van Tendeloo VF () Active specifi c immunotherapy targeting the Wilms’ tumor protein 1 (WT1) for patients with hematological malignancies and solid tumors: lessons from early clinical trials. Oncologist 17:250–259
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18. Oka Y, Tsuboi A, Taguchi T et al () Induction of WT1 (Wilms’ tumor gene)- specifi c cytotoxic T lymphocytes by WT1 peptide vaccine and the resultant cancer regression. Proc Natl Acad Sci U S A 101:13885–13890
19.Morita S, Oka Y, Tsuboi A et al () A phase I/II trial of a WT1 (Wilms’ tumor gene) peptide vaccine in patients with solid malignancy: safety assessment based on the phase I >
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关键词：KOKOWA ®WT1肿瘤疫苗
KOKOWA ®WT1肿瘤疫苗的搜寻结果
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[最佳回答]KOKOWA ®WT1肿瘤疫苗是获得日本厚生省批准，由日本肿瘤医学研究所株式会社（The Institution of Medical Oncology）生产的预防性广谱肿瘤疫苗（Borad-spectrum tumor vaccine），可有效预防20余种癌症。截至今天，已经超过几十万预防及防复发的患者接受注射。
KOKOWA ®WT1肿瘤疫苗是通过接种WT1等30余种癌症抗原的方式，诱导免疫系统产生识别癌细胞的记忆T细胞。这种记忆T细胞对人体有一生免疫监控作用，并在发现癌细胞时分化效应T细胞靶向攻击癌细胞。
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KOKOWA ®WT1肿瘤疫苗
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