CN113597430A - 激活t细胞用于癌症治疗的方法 - Google Patents
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Abstract
本发明提供的负载癌特异性肿瘤抗原表位的抗原呈递细胞,即树突状细胞,能够快速有效地诱导癌抗原特异性T细胞,优选记忆性T细胞的分化和增殖,由此激活的记忆性T细胞能够治疗癌症或肿瘤性疾病或防止癌症的复发、进展或转移,同时避免癌细胞的防御机制。
Description
技术领域
本发明涉及癌症特异性肿瘤抗原表位、负载该表位的抗原呈递细胞,以及使用该抗原呈递细胞激活T细胞用于癌症治疗的方法。
背景技术
胃癌是世界上发病率较高的恶性肿瘤,尤其是在亚洲地区。胃癌的发展有许多已知的原因;然而,胃癌可以典型地分为EB病毒相关胃癌和胃癌细胞抗原相关胃癌,前者是由EB病毒(EBV)感染引起的,后者是由胃肠道细胞遗传突变积累引起的。对于目前胃癌的治疗,癌组织切除一直被认为是最有效的方法,化疗和放疗也被采用。然而,如果没有及时发现,胃癌似乎是一种难以治愈的疾病。此外,尽管使用几种生物制剂(抗体、小分子)进行了临床试验,但临床效果良好的治疗剂尚未见报道。
近期,利用患者来源的自体T细胞进行癌细胞特异性靶向治疗已在多家机构开展研究,利用嵌合抗原受体(CAR)T细胞进行淋巴瘤临床试验已在多家机构开展研究。由于其良好的临床疗效和较低的副作用,该疗法已作为一种抗癌治疗新领域受到广泛关注。
患者来源的T细胞的使用降低了免疫反应的诱导(这是细胞治疗剂最大的副作用),并消除了对捐赠者HLA类型的限制。因此,这类T细胞被认为是有效且无副作用的治疗剂。目前,CD8+T细胞、CD4+T细胞、NK细胞、树突状细胞和CAR T细胞是在抗癌治疗领域应用最广泛的细胞治疗剂。NK细胞具有细胞杀伤作用,但由于不具有抗原特异性而产生多种副作用。树突状细胞是属于疫苗概念的治疗剂,因为它们没有直接杀死细胞的功能,并且能够将抗原特异性传递给患者体内的T细胞,从而将癌细胞特异性高效地传递给T细胞。此外,CD4+T细胞通过抗原特异性帮助其他细胞,而CD8+T细胞已知具有最佳的抗原特异性和细胞杀伤作用。
然而,迄今为止使用或开发的大多数细胞治疗药物都有局限性,因此没有临床效果。具体地说,癌细胞自身分泌抑制人体内免疫反应的物质,或者不呈递产生针对这种癌细胞的抗体所必需的抗原,从而阻止适当的免疫反应的发生。
同时,树突状细胞不仅充当监督者来检测来自人体外部或体内产生的抗原,而且携带这些被识别和吸收的抗原迅速到达次级淋巴器官,从而充当特异性抗原呈递细胞,将抗原提呈给免疫细胞,包括与抗原发生反应的T细胞。使用树突状细胞的抗癌免疫治疗疫苗已经通过几种方法开发出来,大致可以分为离体生成的树突状细胞疫苗和体内树突状细胞疫苗。体内树突状细胞疫苗的工作方式是将抗原直接传递给存在于体内的树突状细胞。此外,使用离体产生的树突状细胞疫苗的方式是:从患者的外周血单个核细胞(PBMCs)中分离树突状细胞,并将待呈递的抗原递送到分离的树突状细胞,通过该抗原,树突状细胞被激活,然后将树突状细胞注射回患者体内,从而将抗原从注射的树突状细胞递送到T细胞。在后者中,离体树突状细胞培养方法和抗原递送方法是重要的,目前使用的抗原递送方法包括使用病毒或核转染将要呈递的抗原的DNA转染,或靶向树突状细胞的抗原递送,其中抗原结合至靶向树突状细胞的抗体。
目前,树突状细胞疫苗最大的问题是体内存在严重的慢性炎症现象和瓦博格(Warburg)效应,认为在存在免疫抑制细胞因子、免疫抑制T细胞、树突状细胞等的肿瘤微环境下,很难实现抗癌免疫细胞的有效激活。
发明详述
技术问题
本发明的目的是提供一种EB病毒(Epstein-Barr virus,EBV)阳性的癌症特异性肿瘤抗原表位,以及包含该表位的激活T细胞的组合物。
本发明的另一目的是提供一种负载有本发明的表位的抗原呈递细胞,该抗原呈递细胞能够激活T细胞用于癌症治疗。
本发明的另一个目的是提供一种生产用于癌症治疗的负载有表位的抗原呈递细胞的方法。
本发明的另一目的是提供一种T细胞,该T细胞被负载有本发明表位的抗原呈递细胞激活。
本发明的另一个目的是提供一种激活T细胞用于癌症治疗的方法。
本发明的另一个目的是提供一种使用负载有表位的抗原呈递细胞治疗癌症的方法。
本发明的另一目的是提供一种使用负载有表位的抗原呈递细胞激活的T细胞治疗癌症的方法。
然而,本发明要解决的技术问题不限于上述问题,并且从以下描述中本领域技术人员将清楚地理解其他未提到的问题。
技术问题的解决方案
根据本发明的一个实施方式,提供了一种癌症特异性肿瘤抗原表位。
在本发明中,“癌症特异性肿瘤抗原表位”来源于一种只存在于癌细胞中而不存在于正常细胞中的蛋白抗原。在本发明中,癌症特异性肿瘤抗原表位包括至少一个T细胞受体识别的表位;并且这种表位优选包括存在于EB病毒(EBV)阳性癌细胞中的表位,包括EBV病毒表位或癌细胞表位,并且可以更优选为EB病毒(EBV)阳性癌细胞抗原,即EB病毒潜伏膜蛋白2(LMP2a)或EB核抗原1(EBNA-1),或其表位。
在本发明中,“EB病毒潜伏膜蛋白2(LMP2a)”是在所有II型和III型疾病/恶性肿瘤中表达的几个EBV基因之一。LMP2a对应于一种跨膜蛋白,它作为B细胞受体信号传导的负调节因子,并通过隔离酪氨酸激酶促进细胞存活。HLA-A2限制性肽是抗原表位特异性的细胞毒性T淋巴细胞表位,可在60%-75%的个体中离体检测,是潜在疾病中最具免疫优势的LMP表位。CLGGLLTMV肽对应于NPC和HL治疗的潜在靶点,因为该表位在取自NPC和HL患者的活检中是保守的,并且与其他EBV潜在表位一样,在免疫学上很弱。
在本发明中,“EB核抗原1(EBNA-1)”对应于与EB病毒相关的多功能、二聚体病毒蛋白。这与仅在所有EBV相关恶性肿瘤中发现的EBV蛋白相对应。这在维持细胞被EBV感染时的改变状态方面起着重要的作用。另一方面,EBNA-1对应于一个甘氨酸-丙氨酸重复序列,其将蛋白分为氨基末端和羧基末端结构域。该序列用于稳定蛋白,防止蛋白酶体破裂,并损害抗原加工和MHC I类限制性抗原提呈。因此,EBNA-1抑制CD8限制性细胞毒性T细胞对病毒感染细胞的反应。EBNA-1在所有潜伏期程序中都由Qp启动子表达,与潜伏期程序I中唯一表达的病毒蛋白相对应。
在本发明中,所述“表位”是指在如正常、非癌细胞或生殖细胞等参考细胞中不存在的表位,而在癌细胞中发现的表位。例如,表位可以是但不限于10-mer至20-mer,优选为15-mer。
在本发明中,所述表位可以与HLA-A、HLA-B、HLA-C、HLA-E、HLA-F、HLA-G、β2-微球蛋白、HLA-DPA1、HLA-DPB1、HLA-DQA1、HLA-DQB1、HLA-DRA1、HLA-DRB1、HLA-DRB3、HLA-DRB4、HLA-DM、HLA-DOA和HLA-DOB位点中的至少一个显示结合亲和力,使得从人血液中提取的T细胞,优选记忆T细胞具有效力。在这些位点中,表位可以包括那些与韩国人表达最多的至少一种HLA类型具有高结合亲和力的位点,例如,HLA-A*2402、HLA-A*A0201、HLA-A*3303、HLA-A*1101、HLA-A*0206、HLA-A*3101、HLA-B*5101、HLA-B*4403、HLA-B*5401、HLA-B*5801和HLA-B*3501。
优选地,在本发明中,所述表位对HLA-A*2402具有高的结合亲和力,并且可以包括LMP2a抗原的表位,每个表位是由SEQ ID NO:1至3,SEQ ID NO:7至9,SEQ ID NO:11至15,SEQ ID NO:19至21,SEQ ID NO:23至39,SEQ ID NO:43至45,SEQ ID NO:47至51,SEQ IDNO:55至57,SEQ ID NO:59至63,SEQ ID NO:67至69,SEQ ID NO:71至75,SEQ ID NO:79至81,SEQ ID NO:83至111,SEQ ID NO:115至117,SEQ ID NO:119至122所示的肽;或者所述表位对HLA-A*3101具有高的结合亲和力,并且可以包括EBNA-1抗原的表位,每个表位是由SEQID NO:124至127,SEQ ID NO:129至149,SEQ ID NO:151至154,SEQ ID NO:156至158,SEQID NO:160至163,SEQ ID NO:165至167,SEQ ID NO:168至176,SEQ ID NO:178至181,SEQID NO:183至194,以及SEQ ID NO:196至199所示的肽。
这里,在本发明中,对于测量表位-HLA亲和力的方法,可以使用NetMHC 3.4(URL:www.cbs.dtu.dk/services/NETMHC-3.4/)来预测表位是否与特定的HLA等位基因结合。然而,本发明不限于此。
在本发明中,“HLA”或“人类白细胞抗原”是指编码负责调节免疫系统的细胞表面上的主要组织相容性复合物(MHC)蛋白的人类基因。“HLA-I”或“HLA-I类”是指人MHC I类基因,包括HLA-A、HLA-B、HLA-C、HLA-E、HLA-F、HLA-G和β2-微球蛋白位点。“HLA-II”或“HLA-II类”是指人MHC II类基因,包括HLA-DPA1、HLA-DPB1、HLA-DQA1、HLA-DQB1、HLA-DRA1、HLA-DRB1、HLA-DRB3、HLA-DRB4、HLA-DRB5、HLA-DM、HLA-DOA和HLA-DOB位点。
在本发明中,所述癌症可以是EB病毒(EBV)阳性癌,包括EBV阳性胃癌、EBV阳性宫颈癌、EBV阳性伯基特(Burkitt)淋巴瘤、EBV阳性T细胞淋巴瘤、EBV阳性乳腺癌、EBV阳性平滑肌肉瘤、EBV阳性平滑肌肿瘤、EBV阳性霍奇金(Hodgkin)淋巴瘤、EBV阳性鼻咽癌或EBV阳性移植后淋巴增生性疾病(PTLD),其中优选EBV阳性胃癌。
根据本发明的另一个实施方式,提供了一种核酸分子,其编码本发明中的癌症特异性肿瘤抗原表位,优选是EB病毒(Epstein-Barr virus,EBV)阳性癌细胞抗原的LMP2a或EBNA-1的表位。
本发明的核酸分子包括通过将本发明提供的多肽的氨基酸序列转换成多核苷酸序列而获得的任何核酸分子,这是本领域技术人员熟知的。因此,由于开放阅读框(ORF)可以制备各种多核苷酸序列,所有这些序列也包括在本发明的核酸分子中。
根据本发明的另一个实施方式,提供了一种插入本发明中提供的分离的核酸分子的表达载体。
在本发明中,“载体”是核酸分子,其能够运输与其连接的另一核酸。一种类型的载体是“质粒”,指环状双链DNA,额外的DNA片段可被连接其中。另一种类型的载体是噬菌体载体。再一种类型的载体是病毒载体,可以将额外的DNA片段连接到病毒基因组中。某些载体能够在引入它们的宿主细胞中进行自主复制(例如,具有细菌复制起点的细菌载体和游离型哺乳动物载体)。在引入宿主细胞时,可以将其他载体(例如,非游离型哺乳动物载体)整合到宿主细胞的基因组中,从而与宿主基因组一起复制。此外,某些载体能够引导与它们可操作地连接的基因的表达。这些载体在本文中称为“重组表达载体”或简称“表达载体”。通常,可用于重组DNA技术的表达载体通常是质粒的形式。在本说明书中,“质粒”和“载体”可以互换使用,因为质粒是载体中最常用的形式。
本发明中表达载体的具体实例可以选自但不限于下组:商业上广泛使用的pCDNA载体、F、R1、RP1、Col、pBR322、ToL、Ti载体;粘粒;噬菌体,如λ、λ型、M13、Mu、p1 P22、Qμμ、T-even、T2、T3、T7;植物病毒。本领域技术人员已知的任何表达载体,可作为表达载体用于本发明,并且根据靶宿主细胞的性质选择表达载体。将载体导入宿主细胞中可以通过磷酸钙转染、病毒感染、DEAE-葡聚糖介导的转染,脂质体转染或电穿孔来进行。然而,本发明不限于此,并且本领域技术人员可以采用和使用适合于使用的表达载体和宿主细胞的导入方法。载体可以优选至少含有一个选择标记。然而,本发明不限于此,并且根据是否生产产品,可以使用不包含选择标记的载体进行选择。根据目标宿主细胞来选择选择标记,其使用本领域技术人员已知的方法进行,因此本发明在其上没有限制。
为了便于纯化本发明的核酸分子,可以将标签序列插入并融合到表达载体上。标签包括但不限于六组氨酸标签、血凝素标签、MYC标签或flag标签,以及本领域技术人员已知的有助于纯化的任何标签均可用于本发明。
根据本发明的另一个实施方式,提供了一种用本发明提供的表达载体转染的宿主细胞。
在本发明中,“宿主细胞”包括单个细胞或细胞培养物,其可以是或已经是整合多肽插入物载体的受体。宿主细胞包括单个宿主细胞的子代,由于自然的、偶然的或有意的突变,子代不一定与原始亲本细胞完全相同(在形态或基因组DNA互补上)。宿主细胞包括用本文的多核苷酸在体内转染的细胞。
在本发明中,宿主细胞可包括哺乳动物、植物、昆虫、真菌或细胞来源的细胞,并且可以是例如细菌细胞,如大肠杆菌、链霉菌、鼠伤寒沙门氏菌;真菌细胞如酵母细胞和毕赤酵母;昆虫细胞如果蝇和烟草植物Sf9细胞;动物细胞如中国仓鼠卵巢(CHO)细胞、SP2/0(小鼠骨髓瘤)、人淋巴细胞、COS、NSO(小鼠骨髓瘤)、293T、Bowes黑色素瘤细胞、HT-1080、幼仓鼠肾(BHK)细胞、人胚胎肾(HEK)细胞,或PERC.6(人视网膜细胞);或植物细胞。然而,宿主细胞不限于此,任何本领域技术人员已知的细胞均可用作宿主细胞。
根据本发明的另一个实施方式,提供了一种用于激活T细胞的组合物,其包含本发明提供的癌症特异性肿瘤抗原表位、编码所述表位的核酸分子、插入所述核酸分子的表达载体或用所述表达载体转化的宿主细胞。
如本文所用,“T细胞的激活”是指具有识别至少一种肿瘤抗原肽的T细胞受体的单克隆(例如,编码相同TCR)或多克隆(例如,具有编码不同TCR的克隆)T细胞群。激活的T细胞可包括一种或多种T细胞亚型,包括但不限于,选自细胞毒性T细胞、辅助T细胞、自然杀伤T细胞、γδT细胞、调节性T细胞和记忆性T细胞的一种或多种,其中优选记忆性T细胞。
在本发明中,激活的T细胞可以治疗癌症或肿瘤疾病或防止癌症的复发、进展或转移,同时避免癌细胞的防御机制。
根据本发明的另一个实施方式,提供了一种抗原呈递细胞(APC),其负载有本发明中提供的癌症特异性肿瘤抗原表位。
在本发明中,所述抗原呈递细胞可以包括树突状细胞(DC)、B细胞和巨噬细胞中的至少一种,优选树突状细胞。
在本发明中,所述抗原呈递细胞可以从个体中分离。
在本发明中,所述“树突细胞”是指在淋巴组织或非淋巴组织中发现的形态相似的细胞类型的多样化群体的任何成员。这些细胞的特点是其独特的形态和表面I类和II类MHC分子的高表达水平,这些分子是向T细胞呈递抗原肽的蛋白。DC、其他APC和T细胞可以是分离的,或衍生(例如分化)于多种组织来源,并且方便地从外周血提取,例如来源于外周血的外周血单个核细胞(PBMC)。
在本发明中,抗原呈递细胞可以诱导癌症抗原特异性T细胞,优选记忆性T细胞的分化和增殖,从而治疗癌症或肿瘤疾病或防止癌症的复发、进展或转移,同时避免癌细胞的防御机制。
根据本发明的另一个实施方式,提供了一种融合蛋白,包含:本发明中提供的癌症特异性肿瘤抗原表位;以及树突状细胞特异性抗体或其片段。
本发明提供的融合蛋白使本发明提供的癌症特异性肿瘤抗原表位能够负载在树突状细胞上。
在本发明中,树突状细胞特异性抗体可以包括但不限于树突状细胞上的DCIR特异性抗体,MHC I类、MHC II类、CD1、CD2、CD3、CD4、CD8、CD11b、CD14、CD15、CD16、CD19、CD20、CD29、CD31、CD40、CD43、CD44、CD45、CD54、CD56、CD57、CD58、CD83、CD86、CMRF-44、CMRF-56、DCIR、DC-ASPGR、CLEC-6、CD40、BDCA-2、MARCO、DEC-205、CLEC-9A、33D1、甘露糖受体、朗格林(Langerin)、DECTIN-1、B7-1、B7-2、IFN-γ受体、IL-2受体、ICAM-1、FCγ受体、LOX-1或ASPGR。
本发明的融合蛋白中的癌特异性肿瘤抗原表位可以与树突状细胞特异性抗体或其片段偶联。在这里,术语“偶联物”是指任何由两个部分连接在一起形成的物质。根据本发明的代表性偶联物包括通过将抗原与抗体和TLR激动剂结合在一起而形成的那些偶联物。术语“偶联”是指形成偶联物的过程,通常表示物理耦合,例如共价键、共配位共价键或第二结合力,例如范德华结合力。将抗原连接到抗体的过程也可以通过非共价结合如dockerin-cohesin结合(如美国专利公开No.20100135994,Banchereau等人相关部分中所述,其通过引用并入本文)或通过形成肽或化学键的直接化学连接进行。
根据本发明的另一个实施方式,提供了一种用于产生抗原呈递细胞的方法,其中抗原呈递细胞负载有本发明提供的癌症特异性肿瘤抗原表位。
在本发明中,所述抗原呈递细胞可以包括树突状细胞、B细胞和巨噬细胞中的一种或多种,优选树突状细胞。
在本发明中,树突状细胞(例如未成熟的树突状细胞)可以从包括自体来源的各种来源获得,即来源于目标个体。树突状细胞可优选地从外周血来源的外周血单个核细胞(PBMC)获得,并且更优选地通过从个体来源的PBMC中分离单核细胞,并使单核细胞与多种细胞因子接触而获得。这里,诱导单核细胞分化为树突状细胞的细胞因子类型没有特别限制,并且可以包括,例如GM-CSF和IL-4中的一种或多种。
在本发明中,“目标个体”是指具有或处于发展为癌症的高风险中的个体。
在本发明中,一旦如上所述制备抗原呈递细胞,所述抗原呈递细胞可以负载本发明的癌症特异性肿瘤抗原表位。一般来说,未成熟树突状细胞通过吞噬或受体介导的内吞作用捕获抗原,并通过一系列的细胞内过程处理抗原,然后使抗原肽负载于MHC并呈递给T淋巴细胞。随着抗原的加工过程,树突状细胞逐渐成熟,其失去用于吞噬和内吞的受体,MHCⅠ、Ⅱ类、共刺激分子和粘附分子的表达增加,并表达新的趋化因子受体。这使得树突状细胞迁移到周围淋巴结中富含T淋巴细胞的区域,并将抗原呈递给T淋巴细胞,从而引起T淋巴细胞免疫反应。
在本发明的一个实施例中,为了使癌症特异性肿瘤抗原表位负载在抗原呈递细胞上,可以使抗原呈递细胞与本发明的癌症特异性肿瘤抗原表位接触,并且优选地,可以进行用本发明的癌症特异性肿瘤抗原表位脉冲抗原呈递细胞,例如未成熟树突状细胞,或PBMC中包含的或从PBMC衍生(例如分化)的抗原呈递细胞(例如树突状细胞)的步骤。如本领域所知,脉冲(pulsing)是指将细胞例如树突状细胞与含有本发明的癌症特异性肿瘤抗原表位肽的溶液混合,然后任选地从混合物中除去癌症特异性肿瘤抗原表位肽的过程。在本发明中,当未成熟树突状细胞与癌症特异性肿瘤抗原表位接触时,可以使用Toll样受体激动剂处理,以进一步诱导未成熟树突状细胞群的成熟。这里,示例性的TLR激动剂包括但不限于polyIC、MALP和R848。
在本发明的另一实施例中,为了将癌症特异性肿瘤抗原表位装载到抗原呈递细胞上,可以用插入有编码癌症特异性肿瘤抗原表位的核酸分子的表达载体,优选质粒,对抗原呈递细胞进行核转染。此处,核转染可以通过本领域中任何有用的方法进行,例如包括核转染系统或核转染系统。
在本发明的另一实施例中,为了将癌症特异性肿瘤抗原表位负载到抗原呈递细胞上,可以使用融合蛋白来进行负载,其包含本发明的癌症特异性肿瘤抗原表位;和树突状细胞特异性抗体或其片段。
根据本发明的另一个实施方式,提供了一种由本发明的抗原呈递细胞激活的T细胞。
在本发明中,所述T细胞可以从个体中分离。
在本发明中,T细胞是指具有识别至少一种肿瘤抗原肽的T细胞受体的单克隆(例如,编码相同TCR)或多克隆(例如,具有编码不同TCR的克隆)T细胞的群体,并且可以包括一种或多种的T细胞亚型,包括但不限于选自下组的一种或多种:细胞毒性T细胞、辅助T细胞、自然杀伤T细胞、γδT细胞、调节性T细胞和记忆T细胞,优选记忆T细胞。
在本发明中,“记忆T细胞”是以前遇到过特异性抗原并对其做出反应的T细胞,或从激活的T细胞中分化出来的T细胞。虽然肿瘤特异性记忆T细胞只占T细胞总量的一小部分,但它们在人的一生中对肿瘤细胞的监测起着重要的作用。在肿瘤特异性记忆T细胞遇到表达其特异性肿瘤抗原的肿瘤细胞时,记忆T细胞立即被激活并克隆扩增。活化扩增后的T细胞分化为效应T细胞,高效杀伤肿瘤细胞。记忆T细胞对于建立和维持T细胞的长期肿瘤抗原特异性应答极为重要。在本发明中,活化的T细胞,优选活化的记忆T细胞,特异性地识别癌细胞上的抗原,使得这样的T细胞可以治疗癌症或肿瘤疾病或防止癌症的复发、进展或转移,同时避免癌细胞的防御机制。
根据本发明的另一个实施方式,提供了一种使用本发明提供的抗原呈递细胞(APC)激活T细胞的方法。
在本发明中,为了激活T细胞,可以将T细胞与负载有本发明的癌症特异性肿瘤抗原表位的抗原呈递细胞共培养。
在本发明中,T细胞可以从各种来源获得,包括自体来源,即来源于目标个体,优选地可以从来源于外周血的外周血单个核细胞(PBMC)获得,并且更优选地可以从外周血单个核细胞的非粘附部分获得。在本发明的一个实施例中,PBMC的非粘附部分可以通过密度梯度离心外周血样而获得,或者可以通过在存在或不存在抗CD3抗体(如OKT3)的情况下用至少一种细胞因子(如IL-2)进行培养获得。
在本发明中,所述T细胞是指具有识别一种肿瘤抗原肽的T细胞受体的单克隆(例如,编码相同TCR)或多克隆(例如,具有编码不同TCR的克隆)T细胞的群体,并且可以包括一种或多种的T细胞亚型,包括但不限于选自下组的一种或多种:细胞毒性T细胞、辅助T细胞、自然杀伤T细胞、γδT细胞、调节T细胞和记忆T细胞,优选记忆T细胞。
此外,在本发明中,所述T细胞和抗原呈递细胞可以来自同一个体,例如患有癌症的个体,优选EBV阳性癌症(例如,低至中度癌症)。然而,本发明不限于此。
在本发明中,为了激活T细胞,可以将T细胞与本发明的抗原呈递细胞共培养1,2,3,4,6,8,10,12,14,16,18,20,22,24,26,28或30天的任何一个或多个时间段,并且优选1至21天,1至14天,2至10天,2至5天,2至5天,3天,5天,7天,10天,14天,16天,18天或21天。然而,本发明不限于此。
在本发明中,在T细胞与本发明的抗原呈递细胞共培养期间,可以添加一种或多种细胞因子来启动T细胞,从而促进T细胞的活化、成熟和/或增殖,并且T细胞随后分化为记忆T细胞。在此阶段可使用的示例性细胞因子包括但不限于白细胞介素-2(IL-2)、白细胞介素-4(IL-4)、白细胞介素-7(IL-7)、白细胞介素-15(IL-15)、白细胞介素-21(IL-21),或其组合等。
此外,在本发明中,在T细胞与本发明的抗原呈递细胞共培养期间,可以添加包含细胞因子和免疫球蛋白重链恒定区的融合蛋白来启动T细胞,从而促进T细胞的活化、成熟和/或增殖,并且T细胞随后分化为记忆性T细胞。此处,细胞因子可以包括但不限于干扰素-γ(IFN-γ)、白细胞介素-2(IL-2)、白细胞介素-4(IL-4)、白细胞介素-12(IL-12)、IL-18和肿瘤坏死因子(TNF),或粒细胞巨噬细胞集落刺激因子(GMCSF)。免疫球蛋白重链恒定区也可以是但不限于免疫球蛋白铰链区,以及任选地选自CH2结构域、CH3结构域和CH4结构域或其组合的免疫球蛋白重链恒定区。此外,免疫球蛋白重链恒定区可以来自属于本领域称为IgA(Igα)、IgD(Igδ)、IgE(Igε)、IgG(Igγ)和IgM(Igμ)的五种免疫球蛋白类别中的任何一个的免疫球蛋白,并且优选地可以是来自IgG类的免疫球蛋白重链恒定区。
此外,在本发明中,在T细胞与本发明的抗原呈递细胞共培养期间,包含与记忆T细胞中高表达的细胞表面蛋白结合的配体的融合蛋白,和免疫球蛋白重链恒定区,可以被添加以启动T细胞,从而促进T细胞的激活、成熟和/或增殖,随后T细胞分化为记忆T细胞。此处,在记忆T细胞中高表达的细胞表面蛋白可以是CD27、CXCR3或CD62L。能与CD27结合的配体可以是CD70;能够与CXCR3结合的配体可以是CXCR9或CXCR10;与CD62L结合的配体可以是GlyCAM-1、CD34、MadCAM-1或PSGL-1。然而,本发明不限于此。此外,免疫球蛋白重链恒定区可以来自属于本领域称为IgA(Igα)、IgD(Igδ)、IgE(Igε)、IgG(Igγ)和IgM(Igμ)的五种免疫球蛋白类别中的任何一种免疫球蛋白,并且优选地可以是来自IgG类的免疫球蛋白重链恒定区。
根据本发明的另一个实施方式,提供了一种免疫治疗剂,其包含负载有本发明提供的癌症特异性肿瘤抗原表位的抗原呈递细胞作为活性成分。根据本发明提供的免疫治疗剂可增加免疫应答或可选择性地增加治疗或预防某种疾病(例如癌症)所需的某些免疫应答。
根据本发明的另一个实施方式,提供了一种用于预防或治疗癌症的抗癌疫苗或药物组合物,其包括负载有本发明提供的癌症特异性肿瘤抗原表位的抗原呈递细胞和/或活化的T细胞作为活性成分。
如本文所用,术语“癌症”是指或表明一种以哺乳动物中的细胞生长不受典型方式调节为特征的生理状况。在本发明中要预防、改善或治疗的癌症可以是EB病毒(EBV)阳性癌,包括但不限于EBV阳性胃癌、EBV阳性宫颈癌、EBV阳性伯基特(Burkitt)淋巴瘤、EBV阳性T细胞淋巴瘤、EBV阳性乳腺癌、EBV阳性平滑肌肉瘤、EBV阳性平滑肌肿瘤、EBV阳性霍奇金(Hodgkin)淋巴瘤、EBV阳性鼻咽癌或EBV阳性移植后淋巴增生性疾病(PTLD),其中优选EBV阳性胃癌。
本发明提供的抗原呈递细胞能够诱导EBV阳性的癌抗原特异性T细胞,优选记忆T细胞的分化和增殖,并且由此激活的记忆T细胞能够治疗癌症或肿瘤疾病或防止癌症的复发、进展或转移,同时避免癌细胞的防御机制。
根据本发明的抗癌疫苗可以包括通过单次给药进行的免疫方法和通过连续给药进行的免疫方法。
在本发明中,“预防”可以包括但不限于使用本发明的药物组合物阻断癌症症状或抑制或延缓症状的任何行为。
此外,在本发明中,“治疗”可以包括但不限于使用本发明的药物组合物改善或有益地改变癌症症状的任何行为。
在本发明中,所述药物组合物的特征可以为胶囊、片剂、颗粒剂、注射剂、软膏、粉末或饮料的形式,并且所述药物组合物的特征可以是靶向人的。
在本发明中,所述药物组合物可以以口服制剂的形式配制,如粉末、颗粒剂、胶囊、片剂和水悬液,按照常规方法分别以外用制剂、栓剂和无菌注射溶液的形式制备并使用。然而,药物组合物不限于此。本发明的药物组合物可以进一步包含药学上可接受的载体。作为药学上可接受的载体,粘合剂、助流剂、崩解剂、赋形剂、增溶剂、分散剂、稳定剂、悬浮剂、色素、调味剂等可用于口服给药;缓冲液、防腐剂、镇痛剂、增溶剂、等渗剂、稳定剂等可混合使用以用于注射;以及碱、赋形剂、润滑剂、防腐剂等可用于局部给药。通过与如上所述的药学上可接受的载体混合,可以以各种方式制备本发明的药物组合物的制剂。例如,对于口服给药,药物组合物可以以片剂、锭剂、胶囊、酏剂、悬浮液、糖浆、晶片等形式配制。对于注射,药物组合物可以以单位剂量安瓿或多种剂型的形式配制。或者,可以将药物组合物配制成溶液、悬浮液、片剂、胶囊、缓释制剂等。
同时,作为适于制备制剂的载体、稀释剂或赋形剂的例子,乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯树胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡啶酮、水、羟苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁、矿物油等可以被使用。另外,还可以包括填料、抗凝血剂、润滑剂、润湿剂、香料、乳化剂、防腐剂等。
本发明的药物组合物的给药途径包括但不限于口服、静脉、肌肉内、动脉内、髓内、硬膜内、心内、经皮、皮下、腹腔内、鼻腔内、肠道、局部、舌下或直肠途径。口服或肠胃外给药是优选的。
如本文所用,术语“肠外”包括皮下、皮内、静脉内、肌肉内、关节内、腹内、胸骨内、硬膜内、皮下和颅内注射或输液技术。本发明的药物组合物也可以以栓剂的形式用于直肠给药。
本发明的药物组合物可以根据各种因素而变化,包括所使用的某种化合物的活性、患者年龄、体重、一般健康状况、性别、饮食、给药时间、给药途径、排泄速率、药物组合,以及待预防或治疗某种疾病的严重程度。药物组合物的剂量取决于患者的病症、体重、疾病严重程度、药物形式、给药途径和持续时间,并且可以由本领域技术人员适当地选择。药物组合物可以每天以0.0001至50mg/kg或0.001至50mg/kg施用。给药可以每天一次或每天几次。剂量不旨在任何情况下限制本发明的范围。本发明的药物组合物可以以药丸、糖衣片剂、胶囊、液体、凝胶、糖浆、浆料或悬浮液的形式配制。
根据本发明的另一实施方式,提供了一种用于预防或治疗癌症的方法,包括向目标个体施用负载有本发明提供的癌症特异性肿瘤抗原表位的抗原呈递细胞;和/或活化的T细胞的步骤。
在本发明中,所述癌症可以是EB病毒(EBV)阳性癌,包括但不限于EBV阳性胃癌、EBV阳性宫颈癌、EBV阳性伯基特(Burkitt)淋巴瘤、EBV阳性T细胞淋巴瘤、EBV阳性乳腺癌、EBV阳性平滑肌肉瘤、EBV阳性平滑肌肿瘤、EBV阳性霍奇金(Hodgkin)淋巴瘤、EBV阳性鼻咽癌或EBV阳性移植后淋巴增生性疾病(PTLD),其中优选EBV阳性胃癌。
可根据个体的大小和病症,并根据标准药学实践,确定负载有本发明提供的癌症特异性肿瘤抗原表位或活化的T细胞的抗原呈递细胞的给药剂量、时间表和途径。示例的给药途径包括静脉内、动脉内、腹腔内、肺内、血管内、肌肉内、气管内、皮下、眼内、鞘内或经皮途径。
给个体施用的细胞剂量可以根据,例如给药的特定类型的细胞、给药途径和所治疗癌症的特定类型和阶段而变化。该剂量应足以产生理想的反应,如针对癌症的治疗反应,但没有严重的毒性或不良事件。在一些实施方式中,活化的T细胞或抗原呈递细胞(例如树突状细胞)的剂量是治疗有效量。在一些实施方式中,与同一个体治疗前相应的肿瘤大小、癌细胞数量或肿瘤生长速度相比,或与未接受治疗的其他个体的相应活性相比,细胞(例如负载癌症特异性肿瘤抗原表位的树突状细胞或活化的T细胞)的数量足以减小肿瘤的大小,减少癌细胞数量或降低肿瘤生长速度至少约10%、20%、30%、40%、50%、60%、70%、80%、90%、95%或100%之一。影响的量级可以使用标准方法来测量,例如用纯化的酶进行的体外分析、基于细胞的分析、动物模型、或用人类进行的实验。
在本发明的一个实施方式中,负载有本发明的癌症特异性肿瘤抗原表位的抗原呈递细胞(例如树突状细胞)可以以1×105至5×105,5×105至1×106,1×106至2×106,2×106至3×106,3×106至4×106,4×106至5×106,5×106至6×106,6×106至7×106,7×106至8×106,8×106至1×108,1×106至3×106,3×106至5×106,5×106至7×106,2×106至4×106,1×106至5×106,或5×106至1×107细胞/个体之一的剂量施用。然而,本发明不限于此。
在本发明的另一个实施方式中,负载有本发明的癌症特异性肿瘤抗原表位的抗原呈递细胞(例如,树突状细胞)可以以1×104至5×104,5×104至1×105,1×105至2×105,2×105至4×105,4×105至6×105,6×105至8×105,8×105至1×106,1×106至2×106,2×106至1×107,1×104至1×105,1×105至1×106,1×106至1×107,1×104至1×106或1×105至1×107细胞/千克之一的剂量施用。然而,本发明不限于此。
此外,在本发明的一个实施方式中,本发明的活化T细胞可以以1×108至5×108,5×108至9×108,9×108至1×109,1×109至2×109,2×109至3×109,3×109至4×109,4×109至5×109,5×109至6×109,6×109至1×1010,1×109至3×109,3×109至5×109,5×109至7×109,7×109至1×1010,1×109至5×109,5×109至1×1010,3×109至7×109,1×1010至1.5×1010,1×1010至2×1010或1×109至1×1010细胞/个体之一的剂量施用。然而,本发明不限于此。
在本发明的另一个实施方式中,本发明的活化T细胞可以以1×107至1×108,1×108至2×108,2×108至4×108,4×108至6×108,6×108至8×108,8×108至1×109,1×109至2×109,2×109至4×109,4×109至1×1010,2×108至6×108,6×108至1×109,1×108至2×108,2×108至2×109,1×107至1×108,1×108至1×109,1×109至1×1010或1×107至1×109细胞/千克之一的剂量施用。然而,本发明不限于此。
在本发明中,稳定剂或赋形剂如人白蛋白可与负载有癌症特异性肿瘤抗原表位的抗原呈递细胞(如树突状细胞)和/或活化的T细胞共同施用。
在本发明中,负载有癌症特异性肿瘤抗原表位的抗原呈递细胞(例如树突状细胞)和/或活化的T细胞的剂量和给药时间表可以在治疗过程中基于给药医师的判断来调整。在一些实施方式中,活化的T细胞可以在负载肿瘤抗原肽的抗原呈递细胞施用后约1天、2天、3天、4天、5天、6天、7天、8天、9天、10天、11天、12天、13天、14天、15天、16天、17天、18天、19天、20天、21天或1个月的任何时间点给药,或者可以与抗原呈递细胞同时给药。然而,本发明不限于此。
在本发明中,负载有肿瘤特异性表位的抗原呈递细胞(例如树突状细胞)和/或活化的T细胞的给药可以单独进行,也可以与其他治疗,例如手术、放疗、基因治疗、免疫治疗、骨髓移植、干细胞移植、激素治疗、靶向治疗、冷冻治疗、超声治疗、光动力治疗、化疗等联合进行。此外,具有更大风险发展增殖性疾病的人可以接受治疗以抑制和/或延迟疾病发展。
发明的有益效果
本发明提供的负载有EB病毒(EBV)阳性癌特异性肿瘤抗原表位的抗原呈递细胞,即树突状细胞,能够快速有效地诱导癌抗原特异性T细胞,优选记忆T细胞的分化和增殖,由此激活的记忆T细胞能够治疗EB病毒(EBV)阳性癌性或肿瘤性疾病或防止癌症的复发、进展或转移,同时避免癌细胞的防御机制。
在常规的过继性T细胞治疗中,需要3到6个月的长时间产生大量的T细胞用于癌症患者的治疗,这给免疫细胞疗法中的细胞产生过程带来了很大的问题。然而,根据本发明,应用于患者治疗的109自体记忆T细胞可以在三周内生产出来,并实现成本降低并将外部污染物的感染风险因素最小化。因此,根据本发明,提供了一种可应用于晚期癌症患者的技术,因为这种技术使得快速治疗方法可用于大量实体癌患者。
附图简要说明
图1至4示出了根据本发明的一个实施方式,通过对每个LMP2A来源的表位进行ELISPOT,以检查由正常人来源的PBMC中的表位引起的T细胞活化程度而获得的结果。
图5至8示出了根据本发明的一个实施方式,通过对每个EBNA-1来源的表位进行ELISPOT,以检查由正常人来源的PBMC中的表位引起的T细胞活化程度而获得的结果。
具体实施方式
根据本发明的一个实施例,提供了一种EB病毒(EBV)阳性的癌症特异性肿瘤抗原表位,由SEQ ID NO:1至3,SEQ ID NO:7至9,SEQ ID NO:11至15,SEQ ID NO:19至21,SEQ IDNO:23至39,SEQ ID NO:43至45,SEQ ID NO:47至51,SEQ ID NO:55至57,SEQ ID NO:59至63,SEQ ID NO:67至69,SEQ ID NO:71至75,SEQ ID NO:79至81,SEQ ID NO:83至111,SEQID NO:115至117,SEQ ID NO:119至122,SEQ ID NO:124至127,SEQ ID NO:129至149,SEQID NO:151至154,SEQ ID NO:156至158,SEQ ID NO:160至163,SEQ ID NO:165至167,SEQID NO:168至176,SEQ ID NO:178至181,SEQ ID NO:183至194,以及SEQ ID NO:196至199中的任一所示。
根据本发明的另一个实施方式,提供了一种抗原呈递细胞(APC),其负载有本发明提供的癌症特异性肿瘤抗原表位。
根据本发明的又一个实施方式,提供了一种本发明提供的抗原呈递细胞激活的T细胞。
根据本发明的另一个实施方式,提供了一种用于预防或治疗癌症的抗癌疫苗或药物组合物,其包括负载有本发明提供的癌症特异性肿瘤抗原表位的抗原呈递细胞;和/或活化的T细胞作为活性成分。
根据本发明的又一个实施方式,提供了一种用于预防或治疗癌症的方法,包括给个体施用有效量的负载有本发明提供的癌症特异性肿瘤抗原表位的抗原呈递细胞;和/或活化的T细胞。
在下文中,将通过实施例更详细地描述本发明。这些实施例仅用于更详细地描述本发明,对于本领域技术人员显而易见的是,根据本发明的主旨,本发明的范围不受这些实施例的限制。
实施例
[实施例1]生产EBV阳性胃癌细胞抗原表位的方法
表位预测结果表明,该表位在LMP2a或EBNA-1的整个序列中含有15个氨基酸,如表1和表2所示;表1(LNP2a)和表2(EBNA-1)所示的序列表中的表位是根据与肽生产过程相关的常规方法生产的。
[表1]
[表2]
[实施例2]由负载有选定LMP2a表位的树突状细胞激活的T细胞的ELISPOT结果
从3例健康人(N5、N9和N15)血液中提取PBMC,经磁激活细胞分选分离为单核细胞和白细胞,将单核细胞在添加细胞因子GM-CSF和IL-4的培养液中培养4天来分化为树突状细胞。在单核细胞已分化为树突状细胞的培养物中,加入每组含有表3所示的10或11个表位肽以及poly(I:C),以便使各自的肽转移到树突状细胞。培养物成熟1天。另外,白细胞在添加抗CD3/CD28抗体和细胞因子IL-2的培养物中培养3天。
[表3]
然后,用磁激活细胞分选法从在添加有抗CD3/CD28抗体和细胞因子IL-2的培养物中培养的白细胞中分离出表达CD8的T细胞,并与成熟的树突状细胞以1:10(树突状细胞:表达CD8的T细胞)的比例共培养。在共培养过程中,将培养物与含有细胞因子IL-4和IL-7的细胞因子鸡尾酒混合并培养该混合物,细胞因子IL-4和IL-7的功能有助于T细胞的存活和免疫应答。18小时后,用ELISPOT检测激活的T细胞中IFN-γ的分泌水平,结果如图1至4所示。此处,使用由流感病毒表达蛋白之一的M1蛋白的第58至66位氨基酸序列组成的肽作为阳性对照肽。
如图1和图2所示,对于N5(N5-1和N5-2;用同一人的血液重复两次相同的实验),发现用表位组3、7、9、11、12、15、18或21转化的树突状细胞导致T细胞IFN-γ表达增加。
如图3所示,对于N9,用表位组1、2、3、7、8、10、15、16、19或20组转化的树突状细胞可导致T细胞IFN-γ表达增加。
另外,如图4所示,对于N15,发现用表位组1、2、3、5、6、7、8、9、11、15、21或22转化的树突状细胞可导致T细胞IFN-γ表达增加。
从这些结果中发现,在本发明中,细胞毒性T淋巴细胞(CTL)可以被负载有从上述表1和表2所示表位中选择的表位的树突状细胞激活,并且由此激活的T细胞具有抗原特异性,该抗原特异性能够识别作为新抗原的表位。
[实施例3]用负载有选定EBNA-1表位的树突状细胞激活的T细胞的ELISPOT结果
使用从三个健康人(N2、N15或N19)的血液中提取的PBMC,以与实施例2相同的方式检查T细胞激活程度,结果示于图5至8。此处,已分化为树突细胞的单核细胞用每组含有10或11个如表4所示的表位肽转化。
[表4]
如图5所示,对于N2,发现抗原表位组6'、7'、8'或15'转化的树突状细胞可激活细胞毒T淋巴细胞。
另外,如图6和图7所示,对于N15(N15-1和N15-2;用同一人的血液重复两次相同的实验),除某些组外,用所有表位组的每一个转化的树突状细胞均激活了细胞毒T淋巴细胞。
另外,如图8所示,对于N19,发现表位组3'、4'、5'、9'、12'或15'的树突状细胞可激活细胞毒T淋巴细胞。
从实施例2和3的结果可以看出,根据本发明的表位可以非常有效地激活细胞毒性T淋巴细胞。
尽管已经详细描述了本发明的特定部分,但对本领域技术人员来说,显然这种特定描述仅仅是优选实施例,并且本发明的范围不限于此。因此,本发明的实质范围将由所附权利要求及其等同物来限定。
工业实用性
本发明涉及癌症特异性肿瘤抗原表位、负载该表位的抗原呈递细胞,以及使用该抗原呈递细胞激活T细胞用于癌症治疗的方法。
<110> 古德T细胞有限公司
<120> 激活T细胞用于治疗癌症的方法
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1 5 10 15
<210> 43
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 43
Ser Ser Tyr Ala Ala Ala Gln Arg Lys Leu Leu Thr Pro Val Thr
1 5 10 15
<210> 44
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 44
Ala Ala Gln Arg Lys Leu Leu Thr Pro Val Thr Val Leu Thr Ala
1 5 10 15
<210> 45
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 45
Lys Leu Leu Thr Pro Val Thr Val Leu Thr Ala Val Val Thr Phe
1 5 10 15
<210> 46
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 46
Pro Val Thr Val Leu Thr Ala Val Val Thr Phe Phe Ala Ile Cys
1 5 10 15
<210> 47
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 47
Leu Thr Ala Val Val Thr Phe Phe Ala Ile Cys Leu Thr Trp Arg
1 5 10 15
<210> 48
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 48
Val Thr Phe Phe Ala Ile Cys Leu Thr Trp Arg Ile Glu Asp Pro
1 5 10 15
<210> 49
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 49
Ala Ile Cys Leu Thr Trp Arg Ile Glu Asp Pro Pro Phe Asn Ser
1 5 10 15
<210> 50
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 50
Thr Trp Arg Ile Glu Asp Pro Pro Phe Asn Ser Leu Leu Phe Ala
1 5 10 15
<210> 51
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 51
Glu Asp Pro Pro Phe Asn Ser Leu Leu Phe Ala Leu Leu Ala Ala
1 5 10 15
<210> 52
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 52
Phe Asn Ser Leu Leu Phe Ala Leu Leu Ala Ala Ala Gly Gly Leu
1 5 10 15
<210> 53
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 53
Leu Phe Ala Leu Leu Ala Ala Ala Gly Gly Leu Gln Gly Ile Tyr
1 5 10 15
<210> 54
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 54
Leu Ala Ala Ala Gly Gly Leu Gln Gly Ile Tyr Val Leu Val Met
1 5 10 15
<210> 55
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 55
Gly Gly Leu Gln Gly Ile Tyr Val Leu Val Met Leu Val Leu Leu
1 5 10 15
<210> 56
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 56
Gly Ile Tyr Val Leu Val Met Leu Val Leu Leu Ile Leu Ala Tyr
1 5 10 15
<210> 57
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 57
Leu Val Met Leu Val Leu Leu Ile Leu Ala Tyr Arg Arg Arg Trp
1 5 10 15
<210> 58
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 58
Val Leu Leu Ile Leu Ala Tyr Arg Arg Arg Trp Arg Arg Leu Thr
1 5 10 15
<210> 59
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 59
Leu Ala Tyr Arg Arg Arg Trp Arg Arg Leu Thr Val Cys Gly Gly
1 5 10 15
<210> 60
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 60
Arg Arg Trp Arg Arg Leu Thr Val Cys Gly Gly Ile Met Phe Leu
1 5 10 15
<210> 61
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 61
Arg Leu Thr Val Cys Gly Gly Ile Met Phe Leu Ala Cys Val Leu
1 5 10 15
<210> 62
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 62
Cys Gly Gly Ile Met Phe Leu Ala Cys Val Leu Val Leu Ile Val
1 5 10 15
<210> 63
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 63
Met Phe Leu Ala Cys Val Leu Val Leu Ile Val Asp Ala Val Leu
1 5 10 15
<210> 64
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 64
Cys Val Leu Val Leu Ile Val Asp Ala Val Leu Gln Leu Ser Pro
1 5 10 15
<210> 65
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 65
Leu Ile Val Asp Ala Val Leu Gln Leu Ser Pro Leu Leu Gly Ala
1 5 10 15
<210> 66
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 66
Ala Val Leu Gln Leu Ser Pro Leu Leu Gly Ala Val Thr Val Val
1 5 10 15
<210> 67
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 67
Leu Ser Pro Leu Leu Gly Ala Val Thr Val Val Ser Met Thr Leu
1 5 10 15
<210> 68
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 68
Leu Gly Ala Val Thr Val Val Ser Met Thr Leu Leu Leu Leu Ala
1 5 10 15
<210> 69
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 69
Thr Val Val Ser Met Thr Leu Leu Leu Leu Ala Phe Val Leu Trp
1 5 10 15
<210> 70
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 70
Met Thr Leu Leu Leu Leu Ala Phe Val Leu Trp Leu Ser Ser Pro
1 5 10 15
<210> 71
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 71
Leu Leu Ala Phe Val Leu Trp Leu Ser Ser Pro Gly Gly Leu Gly
1 5 10 15
<210> 72
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 72
Val Leu Trp Leu Ser Ser Pro Gly Gly Leu Gly Thr Leu Gly Ala
1 5 10 15
<210> 73
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 73
Ser Ser Pro Gly Gly Leu Gly Thr Leu Gly Ala Ala Leu Leu Thr
1 5 10 15
<210> 74
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 74
Gly Leu Gly Thr Leu Gly Ala Ala Leu Leu Thr Leu Ala Ala Ala
1 5 10 15
<210> 75
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 75
Leu Gly Ala Ala Leu Leu Thr Leu Ala Ala Ala Leu Ala Leu Leu
1 5 10 15
<210> 76
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 76
Leu Leu Thr Leu Ala Ala Ala Leu Ala Leu Leu Ala Ser Leu Ile
1 5 10 15
<210> 77
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 77
Ala Ala Ala Leu Ala Leu Leu Ala Ser Leu Ile Leu Gly Thr Leu
1 5 10 15
<210> 78
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 78
Ala Leu Leu Ala Ser Leu Ile Leu Gly Thr Leu Asn Leu Thr Thr
1 5 10 15
<210> 79
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 79
Ser Leu Ile Leu Gly Thr Leu Asn Leu Thr Thr Met Phe Leu Leu
1 5 10 15
<210> 80
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 80
Gly Thr Leu Asn Leu Thr Thr Met Phe Leu Leu Met Leu Leu Trp
1 5 10 15
<210> 81
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 81
Leu Thr Thr Met Phe Leu Leu Met Leu Leu Trp Thr Leu Val Val
1 5 10 15
<210> 82
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 82
Phe Leu Leu Met Leu Leu Trp Thr Leu Val Val Leu Leu Ile Cys
1 5 10 15
<210> 83
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 83
Leu Leu Trp Thr Leu Val Val Leu Leu Ile Cys Ser Ser Cys Ser
1 5 10 15
<210> 84
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 84
Leu Val Val Leu Leu Ile Cys Ser Ser Cys Ser Ser Cys Pro Leu
1 5 10 15
<210> 85
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 85
Leu Ile Cys Ser Ser Cys Ser Ser Cys Pro Leu Thr Lys Ile Leu
1 5 10 15
<210> 86
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 86
Ser Cys Ser Ser Cys Pro Leu Thr Lys Ile Leu Leu Ala Arg Leu
1 5 10 15
<210> 87
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 87
Cys Pro Leu Thr Lys Ile Leu Leu Ala Arg Leu Phe Leu Tyr Ala
1 5 10 15
<210> 88
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 88
Lys Ile Leu Leu Ala Arg Leu Phe Leu Tyr Ala Leu Ala Leu Leu
1 5 10 15
<210> 89
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 89
Ala Arg Leu Phe Leu Tyr Ala Leu Ala Leu Leu Leu Leu Ala Ser
1 5 10 15
<210> 90
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 90
Leu Tyr Ala Leu Ala Leu Leu Leu Leu Ala Ser Ala Leu Ile Ala
1 5 10 15
<210> 91
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 91
Ala Leu Leu Leu Leu Ala Ser Ala Leu Ile Ala Gly Gly Ser Ile
1 5 10 15
<210> 92
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 92
Leu Ala Ser Ala Leu Ile Ala Gly Gly Ser Ile Leu Gln Thr Asn
1 5 10 15
<210> 93
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 93
Leu Ile Ala Gly Gly Ser Ile Leu Gln Thr Asn Phe Lys Ser Leu
1 5 10 15
<210> 94
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 94
Gly Ser Ile Leu Gln Thr Asn Phe Lys Ser Leu Ser Ser Thr Glu
1 5 10 15
<210> 95
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 95
Gln Thr Asn Phe Lys Ser Leu Ser Ser Thr Glu Phe Ile Pro Asn
1 5 10 15
<210> 96
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 96
Lys Ser Leu Ser Ser Thr Glu Phe Ile Pro Asn Leu Phe Cys Met
1 5 10 15
<210> 97
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 97
Ser Thr Glu Phe Ile Pro Asn Leu Phe Cys Met Leu Leu Leu Ile
1 5 10 15
<210> 98
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 98
Ile Pro Asn Leu Phe Cys Met Leu Leu Leu Ile Val Ala Gly Ile
1 5 10 15
<210> 99
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 99
Phe Cys Met Leu Leu Leu Ile Val Ala Gly Ile Leu Phe Ile Leu
1 5 10 15
<210> 100
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 100
Leu Leu Ile Val Ala Gly Ile Leu Phe Ile Leu Ala Ile Leu Thr
1 5 10 15
<210> 101
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 101
Ala Gly Ile Leu Phe Ile Leu Ala Ile Leu Thr Glu Trp Gly Ser
1 5 10 15
<210> 102
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 102
Phe Ile Leu Ala Ile Leu Thr Glu Trp Gly Ser Gly Asn Arg Thr
1 5 10 15
<210> 103
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 103
Ile Leu Thr Glu Trp Gly Ser Gly Asn Arg Thr Tyr Gly Pro Val
1 5 10 15
<210> 104
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 104
Trp Gly Ser Gly Asn Arg Thr Tyr Gly Pro Val Phe Met Cys Leu
1 5 10 15
<210> 105
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 105
Asn Arg Thr Tyr Gly Pro Val Phe Met Cys Leu Gly Gly Leu Leu
1 5 10 15
<210> 106
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 106
Gly Pro Val Phe Met Cys Leu Gly Gly Leu Leu Thr Met Val Ala
1 5 10 15
<210> 107
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 107
Met Cys Leu Gly Gly Leu Leu Thr Met Val Ala Gly Ala Val Trp
1 5 10 15
<210> 108
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 108
Gly Leu Leu Thr Met Val Ala Gly Ala Val Trp Leu Thr Val Met
1 5 10 15
<210> 109
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 109
Met Val Ala Gly Ala Val Trp Leu Thr Val Met Thr Asn Thr Leu
1 5 10 15
<210> 110
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 110
Ala Val Trp Leu Thr Val Met Thr Asn Thr Leu Leu Ser Ala Trp
1 5 10 15
<210> 111
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 111
Thr Val Met Thr Asn Thr Leu Leu Ser Ala Trp Ile Leu Thr Ala
1 5 10 15
<210> 112
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 112
Asn Thr Leu Leu Ser Ala Trp Ile Leu Thr Ala Gly Phe Leu Ile
1 5 10 15
<210> 113
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 113
Ser Ala Trp Ile Leu Thr Ala Gly Phe Leu Ile Phe Leu Ile Gly
1 5 10 15
<210> 114
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 114
Leu Thr Ala Gly Phe Leu Ile Phe Leu Ile Gly Phe Ala Leu Phe
1 5 10 15
<210> 115
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 115
Phe Leu Ile Phe Leu Ile Gly Phe Ala Leu Phe Gly Val Ile Arg
1 5 10 15
<210> 116
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 116
Leu Ile Gly Phe Ala Leu Phe Gly Val Ile Arg Cys Cys Arg Tyr
1 5 10 15
<210> 117
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 117
Ala Leu Phe Gly Val Ile Arg Cys Cys Arg Tyr Cys Cys Tyr Tyr
1 5 10 15
<210> 118
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 118
Val Ile Arg Cys Cys Arg Tyr Cys Cys Tyr Tyr Cys Leu Thr Leu
1 5 10 15
<210> 119
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 119
Cys Arg Tyr Cys Cys Tyr Tyr Cys Leu Thr Leu Glu Ser Glu Glu
1 5 10 15
<210> 120
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 120
Cys Tyr Tyr Cys Leu Thr Leu Glu Ser Glu Glu Arg Pro Pro Thr
1 5 10 15
<210> 121
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 121
Leu Thr Leu Glu Ser Glu Glu Arg Pro Pro Thr Pro Tyr Arg Asn
1 5 10 15
<210> 122
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> LMP2a 表位
<400> 122
Leu Glu Ser Glu Glu Arg Pro Pro Thr Pro Tyr Arg Asn Thr Val
1 5 10 15
<210> 123
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 123
Gly Gly Ala Gly Ala Gly Gly Gly Gly Arg Gly Arg Gly Gly Ser
1 5 10 15
<210> 124
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 124
Ala Gly Gly Gly Gly Arg Gly Arg Gly Gly Ser Gly Gly Arg Gly
1 5 10 15
<210> 125
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 125
Gly Arg Gly Arg Gly Gly Ser Gly Gly Arg Gly Arg Gly Gly Ser
1 5 10 15
<210> 126
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 126
Gly Gly Ser Gly Gly Arg Gly Arg Gly Gly Ser Gly Gly Arg Gly
1 5 10 15
<210> 127
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 127
Gly Arg Gly Arg Gly Gly Ser Gly Gly Arg Gly Arg Gly Gly Ser
1 5 10 15
<210> 128
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 128
Gly Gly Ser Gly Gly Arg Gly Arg Gly Gly Ser Gly Gly Arg Arg
1 5 10 15
<210> 129
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 129
Gly Arg Gly Arg Gly Gly Ser Gly Gly Arg Arg Gly Arg Gly Arg
1 5 10 15
<210> 130
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 130
Gly Gly Ser Gly Gly Arg Arg Gly Arg Gly Arg Glu Arg Ala Arg
1 5 10 15
<210> 131
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 131
Gly Arg Arg Gly Arg Gly Arg Glu Arg Ala Arg Gly Gly Ser Arg
1 5 10 15
<210> 132
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 132
Arg Gly Arg Glu Arg Ala Arg Gly Gly Ser Arg Glu Arg Ala Arg
1 5 10 15
<210> 133
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 133
Arg Ala Arg Gly Gly Ser Arg Glu Arg Ala Arg Gly Arg Gly Arg
1 5 10 15
<210> 134
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 134
Gly Ser Arg Glu Arg Ala Arg Gly Arg Gly Arg Gly Arg Gly Glu
1 5 10 15
<210> 135
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 135
Arg Ala Arg Gly Arg Gly Arg Gly Arg Gly Glu Lys Arg Pro Arg
1 5 10 15
<210> 136
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 136
Arg Gly Arg Gly Arg Gly Glu Lys Arg Pro Arg Ser Pro Ser Ser
1 5 10 15
<210> 137
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 137
Arg Gly Glu Lys Arg Pro Arg Ser Pro Ser Ser Gln Ser Ser Ser
1 5 10 15
<210> 138
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 138
Arg Pro Arg Ser Pro Ser Ser Gln Ser Ser Ser Ser Gly Ser Pro
1 5 10 15
<210> 139
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 139
Pro Ser Ser Gln Ser Ser Ser Ser Gly Ser Pro Pro Arg Arg Pro
1 5 10 15
<210> 140
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 140
Ser Ser Ser Ser Gly Ser Pro Pro Arg Arg Pro Pro Pro Gly Arg
1 5 10 15
<210> 141
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 141
Gly Ser Pro Pro Arg Arg Pro Pro Pro Gly Arg Arg Pro Phe Phe
1 5 10 15
<210> 142
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 142
Arg Arg Pro Pro Pro Gly Arg Arg Pro Phe Phe His Pro Val Gly
1 5 10 15
<210> 143
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 143
Pro Gly Arg Arg Pro Phe Phe His Pro Val Gly Asp Ala Asp Tyr
1 5 10 15
<210> 144
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 144
Pro Phe Phe His Pro Val Gly Asp Ala Asp Tyr Phe Glu Tyr Leu
1 5 10 15
<210> 145
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 145
Pro Val Gly Asp Ala Asp Tyr Phe Glu Tyr Leu Gln Glu Gly Gly
1 5 10 15
<210> 146
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 146
Ala Asp Tyr Phe Glu Tyr Leu Gln Glu Gly Gly Pro Asp Gly Glu
1 5 10 15
<210> 147
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 147
Glu Tyr Leu Gln Glu Gly Gly Pro Asp Gly Glu Pro Asp Val Pro
1 5 10 15
<210> 148
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 148
Glu Gly Gly Pro Asp Gly Glu Pro Asp Val Pro Pro Gly Ala Ile
1 5 10 15
<210> 149
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 149
Asp Gly Glu Pro Asp Val Pro Pro Gly Ala Ile Glu Gln Gly Pro
1 5 10 15
<210> 150
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 150
Asp Val Pro Pro Gly Ala Ile Glu Gln Gly Pro Thr Asp Asp Pro
1 5 10 15
<210> 151
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 151
Gly Ala Ile Glu Gln Gly Pro Thr Asp Asp Pro Gly Glu Gly Pro
1 5 10 15
<210> 152
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 152
Gln Gly Pro Thr Asp Asp Pro Gly Glu Gly Pro Ser Thr Gly Pro
1 5 10 15
<210> 153
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 153
Asp Asp Pro Gly Glu Gly Pro Ser Thr Gly Pro Arg Gly Gln Gly
1 5 10 15
<210> 154
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 154
Glu Gly Pro Ser Thr Gly Pro Arg Gly Gln Gly Asp Gly Gly Arg
1 5 10 15
<210> 155
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 155
Thr Gly Pro Arg Gly Gln Gly Asp Gly Gly Arg Arg Lys Lys Gly
1 5 10 15
<210> 156
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 156
Gly Gln Gly Asp Gly Gly Arg Arg Lys Lys Gly Gly Trp Phe Gly
1 5 10 15
<210> 157
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 157
Gly Gly Arg Arg Lys Lys Gly Gly Trp Phe Gly Lys His Arg Gly
1 5 10 15
<210> 158
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 158
Lys Lys Gly Gly Trp Phe Gly Lys His Arg Gly Gln Gly Gly Ser
1 5 10 15
<210> 159
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 159
Trp Phe Gly Lys His Arg Gly Gln Gly Gly Ser Asn Pro Lys Phe
1 5 10 15
<210> 160
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 160
His Arg Gly Gln Gly Gly Ser Asn Pro Lys Phe Glu Asn Ile Ala
1 5 10 15
<210> 161
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 161
Gly Gly Ser Asn Pro Lys Phe Glu Asn Ile Ala Glu Gly Leu Arg
1 5 10 15
<210> 162
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 162
Pro Lys Phe Glu Asn Ile Ala Glu Gly Leu Arg Val Leu Leu Ala
1 5 10 15
<210> 163
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 163
Asn Ile Ala Glu Gly Leu Arg Val Leu Leu Ala Arg Ser His Val
1 5 10 15
<210> 164
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 164
Gly Leu Arg Val Leu Leu Ala Arg Ser His Val Glu Arg Thr Thr
1 5 10 15
<210> 165
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 165
Leu Leu Ala Arg Ser His Val Glu Arg Thr Thr Glu Glu Gly Asn
1 5 10 15
<210> 166
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 166
Ser His Val Glu Arg Thr Thr Glu Glu Gly Asn Trp Val Ala Gly
1 5 10 15
<210> 167
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 167
Arg Thr Thr Glu Glu Gly Asn Trp Val Ala Gly Val Phe Val Tyr
1 5 10 15
<210> 168
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 168
Glu Gly Asn Trp Val Ala Gly Val Phe Val Tyr Gly Gly Ser Lys
1 5 10 15
<210> 169
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 169
Val Ala Gly Val Phe Val Tyr Gly Gly Ser Lys Thr Ser Leu Tyr
1 5 10 15
<210> 170
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 170
Phe Val Tyr Gly Gly Ser Lys Thr Ser Leu Tyr Asn Leu Arg Arg
1 5 10 15
<210> 171
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 171
Gly Ser Lys Thr Ser Leu Tyr Asn Leu Arg Arg Gly Ile Ala Leu
1 5 10 15
<210> 172
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 172
Ser Leu Tyr Asn Leu Arg Arg Gly Ile Ala Leu Ala Val Pro Gln
1 5 10 15
<210> 173
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 173
Leu Arg Arg Gly Ile Ala Leu Ala Val Pro Gln Cys Arg Ile Thr
1 5 10 15
<210> 174
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 174
Ile Ala Leu Ala Val Pro Gln Cys Arg Ile Thr Pro Leu Ser Arg
1 5 10 15
<210> 175
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 175
Val Pro Gln Cys Arg Ile Thr Pro Leu Ser Arg Leu Pro Phe Gly
1 5 10 15
<210> 176
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 176
Arg Ile Thr Pro Leu Ser Arg Leu Pro Phe Gly Met Ala Pro Gly
1 5 10 15
<210> 177
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 177
Leu Ser Arg Leu Pro Phe Gly Met Ala Pro Gly Pro Gly Pro Gln
1 5 10 15
<210> 178
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 178
Pro Phe Gly Met Ala Pro Gly Pro Gly Pro Gln Pro Gly Pro Leu
1 5 10 15
<210> 179
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 179
Ala Pro Gly Pro Gly Pro Gln Pro Gly Pro Leu Arg Glu Ser Ile
1 5 10 15
<210> 180
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 180
Gly Pro Gln Pro Gly Pro Leu Arg Glu Ser Ile Val Cys Tyr Phe
1 5 10 15
<210> 181
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 181
Gly Pro Leu Arg Glu Ser Ile Val Cys Tyr Phe Met Val Phe Leu
1 5 10 15
<210> 182
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 182
Glu Ser Ile Val Cys Tyr Phe Met Val Phe Leu Gln Thr His Ile
1 5 10 15
<210> 183
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 183
Cys Tyr Phe Met Val Phe Leu Gln Thr His Ile Phe Ala Glu Val
1 5 10 15
<210> 184
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 184
Val Phe Leu Gln Thr His Ile Phe Ala Glu Val Leu Lys Asp Ala
1 5 10 15
<210> 185
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 185
Thr His Ile Phe Ala Glu Val Leu Lys Asp Ala Ile Lys Asp Leu
1 5 10 15
<210> 186
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 186
Ala Glu Val Leu Lys Asp Ala Ile Lys Asp Leu Val Met Thr Lys
1 5 10 15
<210> 187
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 187
Lys Asp Ala Ile Lys Asp Leu Val Met Thr Lys Pro Ala Pro Thr
1 5 10 15
<210> 188
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 188
Lys Asp Leu Val Met Thr Lys Pro Ala Pro Thr Cys Asn Ile Lys
1 5 10 15
<210> 189
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 189
Met Thr Lys Pro Ala Pro Thr Cys Asn Ile Lys Val Thr Val Cys
1 5 10 15
<210> 190
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 190
Ala Pro Thr Cys Asn Ile Lys Val Thr Val Cys Ser Phe Asp Asp
1 5 10 15
<210> 191
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 191
Asn Ile Lys Val Thr Val Cys Ser Phe Asp Asp Gly Val Asp Leu
1 5 10 15
<210> 192
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 192
Thr Val Cys Ser Phe Asp Asp Gly Val Asp Leu Pro Pro Trp Phe
1 5 10 15
<210> 193
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 193
Phe Asp Asp Gly Val Asp Leu Pro Pro Trp Phe Pro Pro Met Val
1 5 10 15
<210> 194
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 194
Val Asp Leu Pro Pro Trp Phe Pro Pro Met Val Glu Gly Ala Ala
1 5 10 15
<210> 195
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 195
Pro Trp Phe Pro Pro Met Val Glu Gly Ala Ala Ala Glu Gly Asp
1 5 10 15
<210> 196
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 196
Pro Met Val Glu Gly Ala Ala Ala Glu Gly Asp Asp Gly Asp Asp
1 5 10 15
<210> 197
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 197
Gly Ala Ala Ala Glu Gly Asp Asp Gly Asp Asp Gly Asp Glu Gly
1 5 10 15
<210> 198
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 198
Glu Gly Asp Asp Gly Asp Asp Gly Asp Glu Gly Gly Asp Gly Asp
1 5 10 15
<210> 199
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 199
Gly Asp Asp Gly Asp Glu Gly Gly Asp Gly Asp Glu Gly Glu Glu
1 5 10 15
<210> 200
<211> 15
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> EBNA-1 表位
<400> 200
Gly Asp Glu Gly Gly Asp Gly Asp Glu Gly Glu Glu Gly Gln Glu
1 5 10 15
Claims (36)
1.一种癌症特异性肿瘤抗原表位,由SEQ ID NO:1至3,SEQ ID NO:7至9,SEQ ID NO:11至15,SEQ ID NO:19至21,SEQ ID NO:23至39,SEQ ID NO:43至45,SEQ ID NO:47至51,SEQID NO:55至57,SEQ ID NO:59至63,SEQ ID NO:67至69,SEQ ID NO:71至75,SEQ ID NO:79至81,SEQ ID NO:83至111,SEQ ID NO:115至117,SEQ ID NO:119至122,SEQ ID NO:124至127,SEQ ID NO:129至149,SEQ ID NO:151至154,SEQ ID NO:156至158,SEQ ID NO:160至163,SEQ ID NO:165至167,SEQ ID NO:168至176,SEQ ID NO:178至181,SEQ ID NO:183至194,以及SEQ ID NO:196至199中的任一所示。
2.根据权利要求1所述的癌特异性肿瘤抗原表位,
其中所述癌症特异性肿瘤抗原表位与HLA-A、HLA-B、HLA-C、HLA-E、HLA-F、HLA-G、β2-微球蛋白、HLA-DPA1、HLA-DPB1、HLA-DQA1、HLA-DQB1、HLA-DRA1、HLA-DRB1、HLA-DRB3、HLA-DRB4、HLA-DRB5、HLA-DM、HLA-DOA和HLA-DOB位点中的至少一个显示出结合亲和力。
3.根据权利要求1所述的癌特异性肿瘤抗原表位,
其中所述癌症特异性肿瘤抗原表位与HLA-A*2402、HLA-A*A0201、HLA-A*3303、HLA-A*1101、HLA-A*0206、HLA-A*3101、HLA-B*5101、HLA-B*4403、HLA-B*5401、HLA-B*5801和HLA-B*3501中的至少一种表现出结合亲和力。
4.根据权利要求1所述的癌特异性肿瘤抗原表位,
其中所述癌症是EB病毒(EBV)阳性癌症。
5.根据权利要求4所述的癌特异性肿瘤抗原表位,
其中所述癌症是EBV阳性胃癌、EBV阳性宫颈癌、EBV阳性伯基特淋巴瘤、EBV阳性T细胞淋巴瘤、EBV阳性乳腺癌、EBV阳性平滑肌肉瘤、EBV阳性霍奇金淋巴瘤、EBV阳性鼻咽癌或EBV阳性移植后淋巴增生性疾病(PTLD)。
6.一种核酸分子,其编码根据权利要求1-5中任一项所述的癌症特异性肿瘤抗原表位。
7.一种表达载体,其中插入了根据权利要求6所述的核酸分子。
8.一种宿主细胞,其中转染有根据权利要求7所述的表达载体。
9.一种用于激活T细胞的组合物,包括:
一种癌症特异性肿瘤抗原表位,由SEQ ID NO:1至3,SEQ ID NO:7至9,SEQ ID NO:11至15,SEQ ID NO:19至21,SEQ ID NO:23至39,SEQ ID NO:43至45,SEQ ID NO:47至51,SEQ IDNO:55至57,SEQ ID NO:59至63,SEQ ID NO:67至69,SEQ ID NO:71至75,SEQ ID NO:79至81,SEQ ID NO:83至111,SEQ ID NO:115至117,SEQ ID NO:119至122,SEQ ID NO:124至127,SEQ ID NO:129至149,SEQ ID NO:151至154,SEQ ID NO:156至158,SEQ ID NO:160至163,SEQ ID NO:165至167,SEQ ID NO:168至176,SEQ ID NO:178至181,SEQ ID NO:183至194,以及SEQ ID NO:196至199中的任一所示。
10.根据权利要求9所述的组合物,
其中T细胞用于预防或治疗癌症。
11.根据权利要求9所述的组合物,
其中所述T细胞包括选自细胞毒性T细胞、辅助T细胞、自然杀伤T细胞、γδT细胞、调节性T细胞和记忆T细胞的一种或多种。
12.一种抗原呈递细胞,其负载由下列任一项所示的癌症特异性肿瘤抗原表位:
SEQ ID NO:1至3,SEQ ID NO:7至9,SEQ ID NO:11至15,SEQ ID NO:19至21,SEQ IDNO:23至39,SEQ ID NO:43至45,SEQ ID NO:47至51,SEQ ID NO:55至57,SEQ ID NO:59至63,SEQ ID NO:67至69,SEQ ID NO:71至75,SEQ ID NO:79至81,SEQ ID NO:83至111,SEQID NO:115至117,SEQ ID NO:119至122,SEQ ID NO:124至127,SEQ ID NO:129至149,SEQID NO:151至154,SEQ ID NO:156至158,SEQ ID NO:160至163,SEQ ID NO:165至167,SEQID NO:168至176,SEQ ID NO:178至181,SEQ ID NO:183至194,以及SEQ ID NO:196至199中的任一所示。
13.根据权利要求12所述的抗原呈递细胞,
其中所述抗原呈递细胞包括树突状细胞、B细胞和巨噬细胞中的一种或多种。
14.根据权利要求13所述的抗原呈递细胞,
其中所述抗原呈递细胞促进T细胞的增殖或分化。
15.一种融合蛋白,包括:
一种癌症特异性肿瘤抗原表位,由SEQ ID NO:1至3,SEQ ID NO:7至9,SEQ ID NO:11至15,SEQ ID NO:19至21,SEQ ID NO:23至39,SEQ ID NO:43至45,SEQ ID NO:47至51,SEQ IDNO:55至57,SEQ ID NO:59至63,SEQ ID NO:67至69,SEQ ID NO:71至75,SEQ ID NO:79至81,SEQ ID NO:83至111,SEQ ID NO:115至117,SEQ ID NO:119至122,SEQ ID NO:124至127,SEQ ID NO:129至149,SEQ ID NO:151至154,SEQ ID NO:156至158,SEQ ID NO:160至163,SEQ ID NO:165至167,SEQ ID NO:168至176,SEQ ID NO:178至181,SEQ ID NO:183至194,以及SEQ ID NO:196至199中的任一项所示;和
树突状细胞特异性抗体或其片段。
16.根据权利要求15所述的融合蛋白,
其中所述树突状细胞特异性抗体是针对树突状细胞上的DCIR、MHC I类、MHC II类、CD1、CD2、CD3、CD4、CD8、CD11b、CD14、CD15、CD16、CD19、CD20、CD29、CD31、CD40、CD43、CD44、CD45、CD54、CD56、CD57、CD58、CD83、CD86、CMRF-44、CMRF-56、DCIR、DC-ASPGR、CLEC-6、CD40、BDCA-2、MARCO、DEC-205、CLEC-9A、33D1、甘露糖受体、朗格林(Langerin)、DECTIN-1、B7-1、B7-2、IFN-γ受体、IL-2受体、ICAM-1、FCγ受体、LOX-1,或者ASPGR的特异性抗体。
17.一种产生抗原呈递细胞的方法,其中所述抗原呈递细胞负载由以下任一项所示的癌症特异性肿瘤抗原表位:
SEQ ID NO:1至3,SEQ ID NO:7至9,SEQ ID NO:11至15,SEQ ID NO:19至21,SEQ IDNO:23至39,SEQ ID NO:43至45,SEQ ID NO:47至51,SEQ ID NO:55至57,SEQ ID NO:59至63,SEQ ID NO:67至69,SEQ ID NO:71至75,SEQ ID NO:79至81,SEQ ID NO:83至111,SEQID NO:115至117,SEQ ID NO:119至122,SEQ ID NO:124至127,SEQ ID NO:129至149,SEQID NO:151至154,SEQ ID NO:156至158,SEQ ID NO:160至163,SEQ ID NO:165至167,SEQID NO:168至176,SEQ ID NO:178至181,SEQ ID NO:183至194,以及SEQ ID NO:196至199。
18.根据权利要求17所述的方法,
其中所述抗原呈递细胞包括树突状细胞、B细胞和巨噬细胞中的一种或多种。
19.根据权利要求17所述的方法,
其中所述抗原呈递细胞从来源于目标个体的外周血的外周血单个核细胞(PBMC)获得。
20.根据权利要求17所述的方法,
其中通过将抗原呈递细胞与癌特异性肿瘤抗原表位接触来进行负载。
21.根据权利要求17所述的方法,
其中所述负载通过用所述癌症特异性肿瘤抗原表位脉冲所述抗原呈递细胞来进行。
22.根据权利要求17所述的方法,
其中所述负载通过用插入编码癌特异性肿瘤抗原表位的核酸分子的表达载体核转染所述抗原呈递细胞来进行。
23.根据权利要求17所述的方法,
其中所述负载是使用包含所述癌症特异性肿瘤抗原表位的融合蛋白;以及树突状细胞特异性抗体或其片段来进行。
24.一种T细胞,由根据权利要求12-14中任一项所述的抗原呈递细胞激活。
25.一种使用权利要求12-14中任一项所述的抗原呈递细胞激活T细胞的方法。
26.根据权利要求25所述的方法,
其中所述方法通过将所述T细胞与所述抗原呈递细胞共培养来进行。
27.根据权利要求25所述的方法,
其中所述T细胞从来自目标个体的外周血单个核细胞(PBMC)获得。
28.根据权利要求25所述的方法,
其中所述T细胞包括选自细胞毒性T细胞、辅助T细胞、自然杀伤T细胞、γδT细胞、调节性T细胞和记忆T细胞的一种或多种。
29.根据权利要求26所述的方法,
其中,所述共培养是在加入白介素-2(IL-2)、白介素-4(IL-4)、白介素-7(IL-7)、白介素-15(IL-15)、白介素-21(IL-21)或其组合的情况下进行。
30.根据权利要求26所述的方法,
其中,所述共培养是在加入含有细胞因子和免疫球蛋白重链恒定区的融合蛋白的情况下进行。
31.根据权利要求30所述的方法,
其中所述细胞因子为干扰素-γ(IFN-γ)、白细胞介素-2(IL-2)、白细胞介素-4(IL-4)、白细胞介素-12(IL-12)、IL-18、肿瘤坏死因子(TNF)或粒细胞巨噬细胞集落刺激因子(GMCSF)。
32.根据权利要求26所述的方法,
其中所述共培养是在加入含有CD27、CXCR3或CD62L配体的融合蛋白;和免疫球蛋白重链恒定区的情况下进行。
33.一种用于预防或治疗癌症的药物组合物,包括作为活性成分的:
根据权利要求12-14中任一项所述的抗原呈递细胞。
34.根据权利要求33所述的药物组合物,
其中所述癌症是EB病毒(EBV)阳性癌症。
35.一种用于预防或治疗癌症的药物组合物,包括作为活性成分的:
根据权利要求24所述的激活的T细胞。
36.根据权利要求35所述的药物组合物,
其中所述癌症是EB病毒(EBV)阳性癌症。
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