CN104853764B - 用于预防和治疗癌症的msi-特异性移码肽(fsp) - Google Patents
用于预防和治疗癌症的msi-特异性移码肽(fsp) Download PDFInfo
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Abstract
描述了一种用于预防和治疗以微卫星不稳定性(MSI)为特征的癌症的疫苗,所述疫苗包括MSI‑特异性移码肽(FSP)或编码所述FSP的核酸,该移码肽产生针对肿瘤细胞的体液应答和细胞应答。本发明的疫苗特别用于预防/治疗结直肠癌、子宫内膜癌、胃癌或小肠癌。
Description
技术领域
本发明提供了一种用于预防和治疗以微卫星不稳定性(MSI)为特征的癌症的疫苗。该疫苗包含一种MSI-特异性移码肽(FSP)或编码所述FSP的核酸,所述FSP产生针对肿瘤细胞的体液应答或细胞应答。
背景技术
人类肿瘤通过两种主要的基因组不稳定性的路径形成:染色体不稳定性和由于DNA错配修复系统的缺陷导致的微卫星不稳定性(MSI)。15%的结直肠癌和各种显示有缺陷的DNA错配修复系统的肠外恶性肿瘤,包括子宫内膜癌、胃癌、小肠癌和其他器官的肿瘤都呈现MSI。MSI癌症可偶发地形成或出现在遗传性肿瘤综合征、遗传性非息肉病性结直肠癌(HNPCC)或Lynch综合征中。
MSI结直肠肿瘤的特征是高免疫原性,其源自当基因编码区的微卫星受到突变影响时,作为导致翻译阅读框改变的错配修复缺陷的直接结果,在MSI肿瘤的形成过程中产生了许多移码肽(FSP)(图1)。
大量可预见的MSI-特异性FSP抗原以及它们直接来自恶性转化过程的事实使FSP成为免疫治疗极具潜力的靶标。人们相信人类免疫系统是一种潜在的可以消除肿瘤细胞的资源,并且如果适当刺激免疫系统的组件来识别并清除癌细胞,则可以形成有效的治疗。因此,免疫疗法,其包括直接或间接地激活人体的免疫系统的组成物和方法以缩小或消除癌症,已经作为传统癌症治疗方法的辅助方法被研究多年。
人们普遍承认肿瘤的生长和转移主要取决于它们逃避宿主免疫系统的能力。大多数肿瘤表达在不同程度上能被宿主免疫系统识别的抗原,但在许多情况下,免疫应答是不充分的。肿瘤抗原的弱免疫原性或肿瘤细胞共刺激分子的不恰当表达或者表达缺失可导致不能够引发效应T-细胞的强烈活化。对于大多数的T-细胞,白细胞介素(IL)-2的生产和增殖需要一个T细胞抗原受体(TCR)同时参与的共同刺激信号,否则,T细胞会进入一个被称作克隆无能的功能无反应状态。
尽管研究这些治疗方法很长时间,但仍需要改进方案以增强针对肿瘤抗原的免疫应答。
然而,在本领域存在能够刺激免疫系统成为肿瘤免疫疗法的安全且有效的组合的需求。
发明内容
根据本发明,作为肿瘤免疫疗法的免疫系统的安全且有效的刺激物通过在权利要求书中限定的主题而实现。体外数据表明,FSP具有高免疫原性,在体外能诱发显著的FSP-特异性T细胞应答(Linnebacher等,2001,Ripberger等,2003,Schwitalle等,2004)。对采自MSI结肠癌患者的外周血的进一步研究证明FSP-特异性T细胞应答频率较高。尽管肿瘤和外周血中有大量的FSP-特异性T细胞,患者并没有任何自身免疫体征,这暗示FSP疫苗接种途径在自身免疫方面预期不会产生副作用。
对于携带易患遗传性非息肉性结直肠癌(HNPCC)的DNA错配修复基因的种系突变的个体的免疫分析,也被发现具有针对FSP的细胞免疫应答,即使未出现临床可检测到的肿瘤。这暗示FSP-特异性免疫应答对于HNPCC个体可具有保护作用,表明FSP疫苗接种也可作为非遗传性癌症的第一个特异性预防途径用于预防性设置(setting)中。
简要地说:
(a)移码肽(FSP)是MSI-特异性的且由MSI肿瘤发病机制直接导致;
(b)预计没有临床相关副作用;
(c)FSP的组合被预计靶向全部具有MSI的肿瘤;
(d)FSP疫苗接种已被设计成治疗15%的结肠癌和子宫内膜肿瘤、胃肿瘤、小肠肿瘤和其他器官肿瘤;
(e)分子肿瘤分析能够确定可受益于FSP疫苗接种(靶向治疗)的患者;以及
(f)FSP疫苗接种可被用作高危群体的预防性疫苗接种。
附图说明
图1为DNA错配修复缺陷导致的编码微卫星不稳定性的示意性说明(Kloor等,
2010)
当编码微卫星突变导致翻译阅读框改变时产生包括FSP序列的截短蛋白(红色)
(例如:TGFBR2蛋白)。
图2为针对新设计的在来自三个MSI结肠癌患者的外周血中的FSP的示例性T细胞 应答。
图3为针对从AIM2(-1)、HT001(-1)、TAF1B(-1)和TGFBR2(-1)产生的FSP的体液免 疫应答。
酶联免疫吸附试验实验(ELISA)揭示针对来自AIM2(-1)、HT001(-1)、TAF1B(-1)和TGFBR2(-1)的新肽(neopeptide)的FSP-特异性抗体应答。如先前所述通过预吸收各自的血清抗体证明了肽的特异性(Reuschenbach等,2008)。
图4为通过CD107a表面表达确定的细胞毒性应答。
(A)在用抗原刺激T细胞四个星期后,在不同健康个体中观察到显著的FSP-特异性应答。应答只发生在存在抗原提呈B细胞和FSP抗原的情况下。代表性应答如条形图所示。
(B)在不存在(左面板)或存在(右面板)FSP抗原HT001(-1)的情况下,对于接种作为抗原提呈细胞的B细胞的T细胞的CD107a测试的代表性FACS(荧光激活细胞分选仪)分析。
具体实施方式
因此,本发明提供了一种包含MSI肿瘤特异性移码肽(FSP)或编码所述FSP的核酸的疫苗,该移码肽例如源自TAF1B(登记号L39061)、HT001(登记号AF113539)、AIM2(登记号AF024714)、或TGFBR2(登记号NM_003242),其中FSP能诱发针对呈现MSI的癌症的免疫应答。
在优选的实施方式中,本发明的疫苗包含
(a)包含以下氨基酸序列的FSP或者由以下氨基酸序列构成的FSP:
NTQIKALNRGLKKKTILKKAGIGMCVKVSSIFFINKQP(TAFlB(-l));
EIFLPKGRSNSKKKGRRNRIPAVLRTEGEPLHTPSVGMRETTGLGC(HT001(-1));
HSTIKVIKAKKKHREVKRTNSSQLV(AIM2(-l));
或
ASPKCIMKEKKSLVRLSSCVPVALMSAMTTSSSQKNITPAILTCC(TGFBR2(-l));
(b)(b)的FSP的功能等同物;或
(c)(a)的FSP和/或(b)的FSP的组合。
这里使用的术语“功能等同物”涉及例如FSP的变体或片段,其仍能诱发对抗肿瘤的免疫应答,即仍可以作为有效疫苗。免疫应答被定义为满足下列标准中的至少一个标准的条件:1.诱导CD8-阳性T细胞,如通过细胞毒性试验或干扰素(IFN)-γ分泌或穿孔素的表达或颗粒酶B表达或可由CD8-阳性T细胞产生的其他细胞因子可检测到,其可通过酶联免疫斑点(ELISpot)或细胞内细胞因子染色或细胞因子酶联免疫吸附试验(ELISA)或其他等效方法测量作为上述背景。2.诱导CD4-阳性T细胞,其可通过由ELISpot或细胞内细胞因子染色或细胞因子ELISA或其他等效方法测量作为上述背景的细胞因子检测到。细胞因子可包括IFN-α、IFN-γ、白细胞介素(IL)-2、白细胞介素-4、白细胞介素-5、白细胞介素-6、白细胞介素-10、白细胞介素-12、白细胞介素-13、白介素-17、肿瘤坏死因子(TNF)-α、肿瘤坏死因子-β或其他可由CD4-阳性T细胞产生的细胞因子。3.诱导抗体,其可以通过蛋白质印迹、ELISA和其他等效或相关的方法检测。4.诱导不被如在1和2中所述的CD8-阳性T细胞或CD4-阳性T细胞介导的任何类型的细胞免疫应答。
变体的特征在于氨基酸缺失、替换、和/或添加。优选地,氨基酸差异是由于一个或多个保守氨基酸替换。术语“保守氨基酸替换”涉及脂肪族的或疏水性氨基酸丙氨酸(Ala)、缬氨酸(Val)、亮氨酸(Leu)和异亮氨酸(Ile)的替代;羟基残基丝氨酸(Ser)和苏氨酸(Thr)的替换;酸性残基天冬氨酸(Asp)和谷氨酸(Glu)的替换;酰胺残基天冬酰胺(Asn)和谷氨酰胺(Gln)的替换;碱性残基赖氨酸(Lys)、精氨酸(Arg)和组氨酸(His)的替换;芳香残基苯丙氨酸(Phe)、酪氨酸(Tyr)和色氨酸(Trp)的替换;和小型氨基酸丙氨酸(Ala)、丝氨酸(Ser)、苏氨酸(Thr)、甲硫氨酸(Met)、和甘氨酸(Gly)的替换。
为了生成对于FSP具有一定程度的同源性的多肽,例如可利用基因工程以在克隆的DNA序列的特定位置处引入氨基酸变化,进而识别肽功能的关键区域。例如,可以使用定点诱变或丙氨酸扫描诱变(在分子中的每个残基处引入单一丙氨酸突变)(Cunningham和Wells,1989年)。由此产生的突变分子可以使用实施例1的测试来测定免疫原性。
优选地,变体的特征在于不超过8个氨基酸(aa),更优选地不多于6个氨基酸,和甚至更优选地不多于4个氨基酸的替换、删除和/或添加。
在FSP片段中,特定的氨基酸序列的至少5个连续氨基酸、最好至少10个连续氨基酸、更优选至少连续15个氨基酸,甚至最好是至少20个连续氨基酸被剩留(left)。该片段仍能引发免疫应答。
在更优选的实施方式中,本发明的疫苗另外包括佐剂和/或免疫刺激的细胞因子和趋化因子。
合适的佐剂包括铝盐,如氢氧化铝凝胶(明矾)或磷酸铝,但也可是钙盐、铁盐或锌盐,或者可以是酰化酪氨酸或酰化糖、阳离子化或阴离子化衍生多糖或聚磷腈的不溶悬浮液。其他已知佐剂包括含胞嘧啶鸟嘌呤(CpG)的寡核苷酸。寡核苷酸的特征在于胞嘧啶鸟嘌呤二核苷酸是非甲基化的。这种寡核苷酸是众所周知的且例如在WO 96/02555中所示。
免疫刺激的细胞因子的使用已成为肿瘤免疫治疗中越来越有前景的方法。主要目标是激活肿瘤特异性T淋巴细胞,其能够使肿瘤细胞远离具有低肿瘤水平的患者,或防止患者疾病复发。在抗原位点局部提供高水平的免疫刺激细胞因子的策略已经证实了临床前疗效和临床疗效。优选的免疫刺激细胞因子包括IL-2、IL-4、IL-7、IL-12、干扰素、粒细胞-巨噬细胞集落刺激因子(GM-CSF)和TNF-α。
趋化因子是小型的(7-16kD)、分泌的和结构上相关的可溶性蛋白,其涉及白细胞和树突状细胞趋化性、多形核白细胞(PMN)脱颗粒和血管形成。趋化因子在宿主对损伤、过敏原、抗原或入侵微生物应答的初始阶段期间产生。趋化因子有选择性地吸引白细胞到炎症病灶,诱导细胞迁移和活化。趋化因子可增强先天的或特定的宿主抗肿瘤免疫性,因而也可用于与FSP结合。
本发明的疫苗还可包含编码用于DNA免疫的FSP的核酸,DNA免疫为用于有效地刺激对于蛋白抗原的体液免疫应答和细胞免疫应答的技术。遗传物质直接注入活的宿主中造成少量的宿主细胞产生注入基因产品。在宿主机体内这不适当的基因表达具有重要免疫的结果,导致宿主对基因传递的抗原的特定免疫激活。直接注射裸质粒DNA诱导对基因疫苗编码的抗原的强免疫应答。一旦注入了质粒DNA结构,则宿主细胞利用外来DNA,在细胞内表达病毒基因和产生FSP。这种形式的抗原提呈和处理诱导主要组织相容性复合体(MHC)以及第一类和第二类限制性细胞免疫应答和体液免疫应答。DNA疫苗由载体构成,通常包含两个单元:抗原表达单位和生产单元,抗原表达单元由启动子/增强子序列、随后是抗原(FSP)-编码且聚腺苷酸化序列组成,且生产单元由载体扩增和选择所必需的序列组成。具有疫苗插入物的载体的构建使用重组DNA技术来实现且本领域技术人员已知可用于该方法的载体。通过稳定DNA降解和提高DNA传递到抗原提呈细胞的效率可以提高DNA免疫效率。可以用DNA包被可生物降解的阳离子微粒(如利用十六烷基三甲基溴化铵配制的乙交酯与丙交酯共聚物)来说明。这种DNA包被的微粒在提高细胞毒性T淋巴细胞方面与重组痘苗病毒同样有效,尤其是当与明矾混合时。直径300纳米的粒子似乎最能有效被抗原提呈细胞摄取。
各种各样的表达载体,例如质粒载体或病毒载体,可以用来包含并表达编码本发明FSP的核酸序列。
优选的病毒载体是痘病毒、腺病毒、逆转录病毒、疱疹病毒或腺相关病毒(AAV)。特别优选的痘病毒是痘苗病毒、高度致弱的痘苗病毒株(NYVAC)、禽痘病毒、金丝雀痘病毒、ALVAC、ALVAC(2)、鸡痘病毒或TROVAC。
基于重组甲病毒的载体也被用于提高DNA疫苗接种效率。编码FSP的基因被插入到甲病毒的复制子中,代替结构基因,但完全保留非结构性复制基因。辛德毕斯(Sindbis)病毒和塞姆利基森林(Semliki Forest)病毒已用于构建重组甲病毒复制子。然而,不同于常规的DNA疫苗接种,甲病毒载体仅仅被暂时表达。由于该载体所表达的高水平蛋白,甲病毒复制子引起免疫应答,复制子诱导的细胞因子应答,或复制子诱导的细胞凋亡,其导致树突状细胞摄取抗原的增强。
在进一步优选的实施方式中,FSP包含一个标记序列,优选地在可用于纯化重组产生的FSP的C-末端。优选的标记序列是His标记。特别优选的His标记由6个His-残基组成。
本发明疫苗以适合个体免疫的量被施用,优选地,另外包含一个或多个常用助剂。采用的术语“适合个体免疫的量”包括个体能够被免疫所用的FSP的任何量。这个量取决于免疫的目的是预防还是治疗。另外,个体的年龄、性别和体重都决定该用量。因此,适合个体免疫的量指有效成分足以影响肿瘤的进程和严重程度的量,其引起这种病状的降低或缓解。“适合个体免疫的量”可以用本领域技术人员已知的方法来决定(如Fingl等,1975)。在此使用的术语“个体”包括任何类型的且能够患有癌的个体。这类个体的例子是人类或动物,或者其细胞。
通过注射而施用疫苗可在个体的不同位置通过肌注、皮下注射、皮内或任何其他应用形式而进行。执行一个或多个具有大约等量的“加强注射”(booster injection)也是有利的。
采用的术语“常用助剂”包括任何适用于对个人进行免疫的疫苗的助剂。这种助剂例如缓冲常见盐溶液、水、乳剂,例如油/水乳剂、润湿剂、无菌溶液等。
本发明的FSP、核酸序列或载体可以出现在这样的疫苗中或与载体相结合。个体内的载体没有免疫原性是有利的。这样的载体可以是个体的本身蛋白质或外源蛋白或其片段。载体,如血清白蛋白、纤维蛋白原、转铁蛋白或其片段都是优选的。
本发明的疫苗可以是治疗性的,即,化合物被施用以治疗现有的癌症或防止癌症的复发,或者预防性的,化合物被施用以防止或延缓癌症的发展。如果组合物用于治疗,则它们被施用至癌症患者,且被设计成诱发免疫应答,以通过阻止或减缓现有的癌症的生长来稳定肿瘤,防止肿瘤或转移瘤的扩散,减小肿瘤的尺寸,防止已治疗的癌症的复发,或消除早期治疗没有杀死的癌细胞。用作预防性治疗的疫苗被施用至没有患癌的个体,且被设计成诱发免疫应答以靶向潜在的癌细胞。
本发明还涉及如上述所述的FSP或功能等同物、核酸序列或载体用于生成预防癌症的疫苗的用途,如高危人群的预防性疫苗接种或癌症的治疗。例如,这些癌症可以是结直肠癌、优选地遗传性非息肉病性结直肠癌(HNPCC)、子宫内膜癌、胃癌或小肠癌。
通过本发明可对个体进行免疫,特别是人和动物。通过诱导抗体和刺激CD8+T细胞两者引起免疫反应。因此,可对癌症采取预防性和治疗性的措施。
下面的实施例更为详细地说明了本发明。
实施例1
来自MSI结肠癌患者和健康HNPCC突变携带者的外周血中的FSP-特异性T细胞的检测
(A)方法(酶联免疫斑点分析)
使用酶联免疫斑点分析,通过测定针对新设计的由3个包含cMS的候选基因得到的FSP的特异性分泌γ-干扰素(IFN-γ)Tc的数目,来定量FSP-特异性外周血T细胞(pTc)的频率。酶联免疫斑点分析采用96-孔硝酸纤维素板进行(Multiscreen;Millipore,贝德福德(Bedford),马萨诸塞州),该板包被小鼠抗人γ-干扰素单克隆抗体(mAb)(Mabtech,纳卡,瑞典)过夜并用包含血清的培养基封闭。六倍的pTc(0天、lxl05/孔)和作为抗原提呈细胞的自体CD-40激活的B细胞(4xl04/孔,单加TiBc或pBC)被铺在含有10%人AB型血清的200μl的IMDM培养基中。肽被添加到终浓度为10微克/毫升。作为阳性对照,用20nmol/L的佛波酯结合350nmol/L的离子霉素的混合物处理外周血T细胞。在37℃孵育24小时后,板被彻底冲洗、与生物素标记的兔抗人γ-干扰素单克隆抗体培养4个小时、再冲洗、和链霉亲和素-碱性磷酸酶培养2小时、再最后稀释。与NBT/BCIP(Sigma-Aldrich)培养1小时进行斑点检测,用水停止反应,干燥后,显微镜下斑点计数。Schwitalle等(2008)详细地描述了方法。
(B)结果
为了检查在MSI-H CRC(转移性结直肠癌)患者外周血中是否可检测到FSP-特异性T细胞应答,进行了酶联免疫斑点分析。显示I型和II型MHC高表达的自体pBc细胞、共刺激子(CD40、CD80和CD86)以及B-细胞-特异性抗原(CD19和CD23)被用作抗原提呈细胞。
针对来自AIM2(-1)、HTOOl(-l)、TAFlB(-l)、TGFBR2(-1)的新设计的FSP,观察到显著反应:
TAFlB(-l)NTQIKALNRGLKKKTILKKAGIGMCVKVSSIFFINKQKP
HT00l(-l)EIFLPKGRSNSKKKGRRNRIPAVLRTEGEPLHTPSVGMRETTGLGC
AIM2(-1)HSTIKVIKAKKKHREVKRTNSSQLV
TGFBR2(-1)ASPKCIMKEKKSLVRLSSCVPVALMSAMTTSSSQKNITPAILTCC
(带下划线是新肽序列)
从患者(n=8)身上得到的结果汇总于表1。代表性的ELISpot结果如图2所示。
表1
针对FSP的FSP-特异性T细胞应答
患者ID | 无肽 | TAF1B(-1) | HT001(-1) | AIM2(-1) | TGFBR2(-1) |
MSI01 | 4 | 8.17 | 5.83 | 3.5 | 6 |
MSI02 | 1.5 | 4.83 | 7.33 | 7.17 | 1.2 |
MSI03 | 11.83 | 28.17 | 31.83 | 23.33 | 10.16 |
MSI04 | 5.5 | 13 | 14.17 | 11.83 | 8.75 |
MSI05 | 3 | 7.75 | 16 | 10 | 2.8 |
MSI06 | 3.17 | 12 | 12.33 | 13.83 | 5.2 |
MSI07 | 6 | 17 | 16.83 | 14.5 | 9.33 |
MC01 | 1.17 | 3.5 | 3.5 | 3 | 8 |
MC02 | 1.67 | 2.83 | 5.83 | 4 | 3.33 |
MC03 | 0.83 | 1.17 | 1.17 | 2.17 | 4.4 |
MC04 | 15.17 | 18.83 | 18.67 | 15.17 | 20.75 |
MC05 | 0.33 | 3.17 | 2.17 | 1.33 | 5.67 |
MC06 | 30.5 | 37.83 | 37.8 | 34.83 | 39.5 |
对每个肽与被测试的个体给出来自平行分析的平均点数。MSI01-MSI07为MSI-HCRC患者,MC01-MC06为健康HNPCC种系突变携带者。
实施例2
FSP-特异性体液免疫应答在来自健康HNPCC突变携带者和具有MSI结肠癌患者的外周血中的检测
(A)方法(酶联免疫吸附实验)
对酶联免疫吸附试验(ELISA),在PBS中浓度为40微克/毫升的肽被涂覆到96孔聚苯乙烯微孔板"Maxisorp"'(Nunc,罗斯基勒,丹麦)上,在4℃过夜。涂覆后,用PBS(0.05%Tween)冲洗板4次且用0.5%在PBS中的酪蛋白封闭1小时。使用碱性磷酸酶-肽竞争法对结合到微孔板的肽和最佳饱和肽浓度进行评估。为了监控每个血清的个体背景反应,使用来自pl6INK4a蛋白的对照肽(pl6_76-105),在一大群个体中没有发现针对该对照肽的抗体反应性(Reuschenbach等,2008)。各个血清以1:100利用封闭缓冲液(PBS的0.5%酪蛋白)进行稀释,并两次测定用于针对全部FSP和对照肽的抗体的存在。作为板间方差的参考,在每块板上包括一个对照血清,且该对照组血清的肽特异性ODs被用于实现标准化。培养稀释的血清(50μl/孔)1小时,经过冲洗,板用HRP-标记的兔抗人IgG抗体(Jackson Immunoresearch、West Grove,宾夕法尼亚;1:1.0000,采用封闭缓冲液)培养1小时。经过冲洗、50μl/孔的TMB基质(Sigma,Deisenhofen,德国)被添加,且通过添加50μl/孔的1N H2SO4,30分钟后酶反应停止。测量在450nm处的吸收(参考波长595nm)。根据Reuschenbach等(2008)详细描述的方法,进行用于特异性对照的血清抗体的预吸收。
(B)结果
为了检查在MSI-H CRC患者、健康Lynch综合征突变携带者、健康对照的外周血中是否可检测到FSP-特异性抗体,采用了ELISA分析法。针对来自AIM2(-1)、HT00l(-l)、TAFlB(-l)和TGFBR2(-1)的新设计的FSP,观察到显著的反应性。ELISA结果如图3所示。
实施例3
FSP-特异性细胞毒性T细胞应答的检测
测定了当利用临床FSP抗原刺激时,CD107a在T效应细胞表面上的表达。CD107a检测方法用于证明从效应细胞中分泌含穿孔素/颗粒酶B的细胞毒性颗粒。如果在细胞毒性T细胞应答的环境下释放颗粒,则CD107a分子在细胞毒性颗粒表面上表达并且在细胞表面上可被检测。
为了确定FSP肽诱导细胞毒性细胞免疫应答的潜力,抽取健康供体的血,使用树突状细胞作为抗原提呈细胞,用FSP刺激T细胞。每周重复刺激且时间跨度为四周。四个星期后,采集T细胞,与靶细胞共同培养,FSP的CD107a试验被用于分析细胞毒性T细胞应答的肽-特异性诱导。
在抗原性的FSP存在下,对于与作为抗原提呈细胞的B细胞共培养的T细胞,观察到如通过CD107a表面表达所确定的细胞毒性应答(图4A)。在利用抗原刺激T细胞四周后,在不同的健康供体中观察到显著的应答。在条形图中示出代表性的应答。图4B显示在缺乏(左面板)FSP抗原HT001(-1)的情况下或者存在(右面板)FSP抗原HT001(-1)的情况下,对于与作为抗原提呈细胞的B细胞共培养的T细胞的CD107A测试的代表性FACS分析。
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Reuschenbach M,Waterboer T,Wallin KL,Einenkel J,Dillner J,HamsikovaE,Eschenbach D,Zimmer H,Heilig B,Kopitz J,Pawlita M,von Knebel Doeberitz M,Wentzensen N.Characterization of humoral immune responses against pl6,p53,HPV16E6and HPV16E7in patients with HPV-associated cancers.Int JCancer.2008Dec 1;123(11):2626-31。
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Claims (14)
1.一种由微卫星不稳定性MSI-特异性移码肽(FSP)的组合构成的疫苗,其中,所述移码肽能够诱发针对呈现MSI的肿瘤的免疫应答,且所述疫苗包含由以下氨基酸序列构成的移码肽的组合:
NTQIKALNRGLKKKTILKKAGIGMCVKVSSIFFINKQKP(SEQ ID No.:1);
EIFLPKGRSNSKKKGRRNRIPAVLRTEGEPLHTPSVGMRETTGLGC(SEQ ID No.:2);和
HSTIKVIKAKKKHREVKRTNSSQLV(SEQ ID No.:3)。
2.根据权利要求1所述的疫苗,其中,所述移码肽还包含标记序列。
3.一种包含编码权利要求1或2所述的移码肽的核酸序列的疫苗或包含含有所述核酸序列的载体的疫苗。
4.根据权利要求3所述的疫苗,其中,所述载体是质粒载体或病毒载体。
5.根据权利要求4所述的疫苗,其中,所述病毒载体是基于痘病毒、腺病毒、逆转录病毒、疱疹病毒、甲病毒的载体或腺相关病毒(AAV)。
6.根据权利要求5所述的疫苗,其中,所述痘病毒是痘苗病毒、NYVAC、禽痘病毒、金丝雀痘病毒、ALVAC、鸡痘病毒或TROVAC。
7.根据权利要求1至6中任一项所述的疫苗,还包含佐剂和/或免疫刺激细胞因子或趋化因子。
8.根据权利要求1或2所述的疫苗,其中,所述移码肽存在于水包油乳剂载体或油包水乳剂载体中。
9.根据权利要求1至6中任一项所述的疫苗,还包括一种或多种其他抗原。
10.根据权利要求1至6中任一项所述的疫苗,所述疫苗用于肿瘤的预防或治疗的方法。
11.如在权利要求1或3中所限定的MSI肿瘤特异性移码肽(FSP)、如在权利要求3中所限定的所述核酸、或者如在权利要求4至6中任一项中所限定的载体在制备预防或治疗癌症的疫苗中的用途。
12.根据权利要求11所述的用途,用于高危群体的预防性疫苗接种。
13.根据权利要求11或12所述的用途,其中,所述肿瘤是结直肠癌、子宫内膜癌、胃癌或小肠癌。
14.根据权利要求13所述的用途,其中,所述结直肠癌是遗传性非息肉病性结直肠癌(HNPCC)。
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