CN102014937A - 基于异基因癌细胞的免疫治疗 - Google Patents
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Abstract
通过向人类受治疗者频繁施用分泌修饰的热休克蛋白(例如，gp96)的异基因癌细胞、消除受治疗者中的B细胞、或两者，可改进基于细胞的免疫治疗(例如，免疫接种或疫苗接种)。抗原(例如，衍生于异基因癌细胞或同基因癌细胞的新抗原或肿瘤抗原的表位)可诱导受治疗者中的特异性免疫反应。例如，免疫原性复合物中与分泌的热休克蛋白结合的表位可从共表达分泌的gp96和抗原二者的异基因癌细胞、或从仅表达抗原的受治疗者的同基因癌细胞获得。
Description
相关申请的交叉引用
本申请要求2008年3月3日提交的申请第61/033,425号的权益，该申请以引用方式并入。
联邦政府赞助的研究或开发
美国政府在本发明中享有某些权利，如来自Department of Health andHuman Services(卫生与公众服务部)的NIH合同CA039201中所规定的。
发明背景
本发明涉及改进基于癌细胞的免疫治疗(例如，免疫接种或疫苗接种)，包括将分泌修饰的热休克蛋白的异基因癌细胞施用给人类受治疗者。基于癌细胞的免疫治疗是通过给受治疗者频繁施用异基因癌细胞、在第一次或至少一次异基因癌细胞的施用之前和/或期间消除受治疗者中的B细胞、或两者而改进的。
WO 99/42121公开了一种基于细胞的疫苗，其中由转染的表达构建体编码的修饰的热休克蛋白被分泌。所述疫苗对治疗或预防癌症或感染性疾病可是有效的。重组癌细胞的一次注射和间隔两周的重组癌细胞的两次注射被描述。自体的癌细胞是优选的。相反，本发明使用异基因癌细胞。
WO 2005/030136公开了通过施用被基因修饰以表达CD80和HLA的肺癌细胞而抑制肿瘤。该种癌细胞不分泌修饰的热休克蛋白。
通常通过肿瘤的外科切除、放射或药物杀死癌细胞、或其组合来治疗癌症。免疫系统能够抑制癌细胞的增殖和扩散。然而，癌细胞可以通过无免疫原性(例如非小细胞肺癌)来逃避免疫监视，无免疫原性阻断产生有效反应的免疫反应的启动，或通过有免疫原性但阻断免疫反应的效应期来逃避免疫监视(例如黑素瘤)。可选择地，启动的阻断可归因于肿瘤分泌免疫抑制介质或耐受趋化因子和/或调节性细胞的刺激、致耐受性抗原呈递细胞的刺激、或骨髓阻抑细胞(myelosuppressor cell)的刺激。通过施用异基因癌细胞的主动免疫治疗能够避开阻断，并启动先天性免疫反应和/或获得性免疫反应。肿瘤特异性的CD8+T-细胞反应的诱导及加强是特别期望的，如通过癌细胞的细胞溶解或由癌细胞刺激的干扰素γ的分泌所评价的。
Raez等(J.Clin.Oncol.22：2800-2807，2004)描述了在具有晚期转移疾病的患者中用于非小细胞肺癌的基于异基因癌细胞的疫苗的I期试验。腺癌细胞系AD100被转染以表达CD80和HLA-A1或HLA-A2。每两周一次用5×107个细胞皮内免疫患者。三次免疫接种代表一个疗程。除非患者对起始免疫接种没有反应，否则将施用多达三个疗程，共计九次免疫接种。使用这种基于细胞的疫苗获得的期望结果可能通过增加免疫接种的频率及在至少一次免疫接种之前和/或期间消除B细胞而改进。
因此，本发明的一个目的是提供改进的免疫治疗(例如，免疫接种或疫苗接种)，其包括给人类受治疗者施用分泌修饰的热休克蛋白的异基因癌细胞(通过频繁施用)、在起始或至少一次施用之前和/或期间消除B细胞、或两者。其他优势和改进将在下文描述或将是由本文的公开内容而明显的。
发明概述
本发明提供一种用于免疫接种和疫苗接种的基于异基因癌细胞的免疫治疗的改进。“治疗”可以是治疗性的、预防性的、或仅仅治标性的。
通过施用分泌修饰的热休克蛋白(例如，gp96)的异基因癌细胞治疗人类受治疗者。在本文，“异基因”意思是施用的细胞与治疗的受治疗者相差一个或多个主要组织相容性复合物(MHC)分子。热休克蛋白可通过去除含有内质网滞留信号的结构域而被修饰。任选地，所述结构域可用人或者小鼠免疫球蛋白IgG1或IgG2的一个或多个重链恒定区(例如，Fc结构域)替代。修饰的热休克蛋白由表达载体转染的或病毒载体感染的癌细胞中的核酸表达。载体可基于来自牛乳头状瘤病毒(BPV)的一个或多个调节信号(例如，转录起始和转录终止、剪接供体和剪接受体(slice donorand acceptor)、多腺苷酸化、复制起始)。载体优选地不含有BPV的E5、E6和E7基因。因此，所述癌细胞能够由于用于产生它们的技术被认为是“重组的”。
抗原(例如，衍生于异基因癌细胞或同基因癌细胞的新抗原或肿瘤抗原的表位)可在受治疗者中诱导先天性或获得性免疫反应。尤其，CD8+T-细胞反应的诱导和增强是期望的。CD8+细胞可特异性杀死癌细胞或分泌干扰素γ。
任选地，可通过表达不被受治疗者表达的至少一种MHC分子而使得癌细胞异基因，所述至少一种MHC分子来自由表达载体转染的或由病毒载体感染的癌细胞中的核酸。修饰的热休克蛋白和HLA分子可至少部分地由相同载体或者不同载体编码。
人类受治疗者可用异基因癌细胞免疫若干次。基于细胞的免疫原性组合物的两次相邻施用之间的间隔少于两周。另一个改进可以是基于细胞的免疫原性组合物的至少一次施用之前和/或期间受治疗者中的B细胞的消除。
本发明的进一步的目的和优势方面将从对具体的实施方案和权利要求书、及其概括的以下描述而对本领域技术人员是显然的。
发明具体实施方案的描述
将包含分泌修饰的热休克蛋白(例如，缺乏内质网天然滞留序列的热休克蛋白)至细胞中的异基因癌细胞的免疫原性组合物施用给受治疗者，所述修饰的热休克蛋白至少部分地由转染的表达载体或感染的病毒载体编码。作为新生的多肽链，修饰的热休克蛋白可具有它自己的或另一个蛋白的信号序列以靶向分泌途径。并且相反的N-端信号序列可以是包含一个或多个人免疫球蛋白重链(例如，IgG1或IgG2)恒定区的肽标签。任选地，癌细胞表达异基因的主要组织相容性复合物(MHC)分子(例如，至少部分地由相同的或不同的载体编码)。癌细胞可表达或可不表达CD80(例如，至少部分地由相同的或不同的载体编码)。修饰的热休克蛋白、HLA-A及CD80在各种癌细胞系中的表达的更多细节在以引用方式并入本文的WO99/42121和WO 2005/030136中提供。
受治疗者可按每剂1×107至10×107异基因癌细胞的范围施用。可将1至10×108的细胞总数施用给受治疗者。在任何两次相邻的施用之间，异基因癌细胞可每日至少两次、每日一次、每两天一次、每周两次、每周一次、每两周一次或每月一次施用。至少总计9、18或27剂的异基因癌细胞可被施用。剂量可按少于两周、少于一周或者更少、至少每周两次、至少每两天一次、至少每天一次、或者至少每天两次的间隔施用。治疗可持续至少六周、十周、15周、18周、22周或26周(例如，一至六个月)。这种治疗期间，细胞可按少于两周、一周或者更少、至少每周两次、至少每两天一次、至少每天一次、或者至少每天两次的间隔施用。细胞可被通过至少皮内、静脉内、腹膜内、或皮下途径注射。每剂量可被分成用于包含单次施用的分开注射的等份。治疗可通过频繁疫苗接种、B细胞的消除、或两者而被改进。
抗原(例如，衍生于异基因癌细胞的或同基因癌细胞的新抗原或肿瘤抗原的表位)可诱导受治疗者中的特异性免疫反应。例如，免疫原性复合物中与分泌的热休克蛋白结合的抗原可从共表达分泌的gp96和抗原二者的异基因癌细胞、或从仅表达抗原的受治疗者的同基因癌细胞获得。后者推测上将需要修饰的热休克蛋白被不同于合成gp96的癌细胞的癌细胞摄入，并且在合成抗原的癌细胞中形成复合物。免疫接种可不需要受治疗者具有功能性CD4+T细胞或淋巴结。因此，gp96所有修饰(包括ER滞留信号的去除)之后，修饰的gp96必须仍然在免疫原性复合物中结合表位。任选的修饰包括N端的添加或缺失、C端的添加、1至3个连续氨基酸的点突变、或1至10个氨基酸的内部添加或缺失。
受治疗者可以是人类受治疗者。癌细胞可从人类受治疗者获得。免疫原或疫苗可被施用于捐献癌细胞的相同受治疗者或不同受治疗者。异基因癌细胞可已经从与接受细胞的受治疗者相比具有不同移植抗原的受治疗者获得。任选地，主要组织相容性复合物分子(例如，一个或多个MHC I类分子比如HLA-A1、HLA-A2、HLA-A3、HLA-A27)可以通过表达载体转染或病毒载体感染在癌细胞中被表达。因为修饰或组织型可分别地通过同源重组被引入癌细胞的内源性基因中，所以载体的核酸需要至少部分地编码修饰的热休克蛋白或异基因MHC分子。
B细胞可通过本领域已知技术消除，比如活体外(ex vivo)血浆分离置换法(apheresis)或施用对B细胞受体特异性的抗体(例如，抗CD19、抗CD20、抗CD22、抗BLyS)、交联B细胞受体的二聚配体(例如，适体二聚体)，或可使用免疫抑制药物(例如，环磷酰胺或强的松龙)。但是与治疗淋巴瘤或自身免疫性疾病的利妥昔单抗的使用不同，根据本发明的与免疫治疗联合的B细胞的消除将空出免疫系统的其他部分以实现癌症的基于细胞的免疫治疗。例如，从100mg/m2至500mg/m2(或从200mg/m2至300mg/m2或从350mg/m2至400mg/m2)剂量的利妥昔单抗可按50mg/小时至400mg/小时的速率一次或多次(例如，每周一次持续两周至二个月)施用给患者。可用环磷酰胺和强的松龙补充利妥昔单抗。B细胞可被消除，之后紧接着免疫治疗(例如，免疫接种或疫苗接种)。免疫治疗期间可监测B细胞的水平，当高于正常(即，未消除的)水平的1％、5％或10％时重复消除。
经历异常增殖的受治疗者的癌细胞可以是赘生物或肿瘤(例如，癌瘤(carcinoma)、肉瘤、白血病、淋巴瘤)，尤其是肺癌。癌包括起源于胃肠器官系统(例如，食管、结肠、肠、回肠、直肠、肛门、肝、胰、胃)、泌尿器官系统(例如，膀胱、肾、前列腺)、肌肉骨骼器官系统、肺器官系统(例如，肺)、或生殖器官系统(例如，宫颈、卵巢、睾丸)的那些。例如，肺癌可以是非小细胞肺癌(例如，腺癌、鳞状细胞癌或大细胞癌)、小细胞肺癌、及类癌瘤。癌细胞可衍生自经历治疗的受治疗者或衍生自不同于所述受治疗的另一个体。对于前一种情形，异基因性可通过从转染的表达载体或感染的病毒载体表达不相关的主要组织相容性复合物I类分子而被赋予。只要癌细胞被改造为分泌修饰的热休克蛋白，癌细胞可以是无免疫原性的或具有低免疫原性。癌细胞可来自癌瘤。示例性的肺癌细胞是AD100腺癌，除衍生该细胞系的患者及共有该患者的MHC单元型(haplotype)的任何罕见个体外，AD100腺癌对于所有受治疗者均是异基因的。AD100腺癌的衍生在WO 2005/030136中描述。AD100不表达HLA-A1、HLA-A2、或CD80。胰腺癌可用来自ATCC CRL1420的分泌gp96-Ig的MIA PaCa-2治疗；卵巢癌可用来自ICLC HTL97004的分泌gp96-Ig的OVCAR-3治疗。
治疗效力可通过症状的减轻、疾病的延迟进展或疾病的消退、或存活的延长来评价。或者癌细胞CD8+T细胞细胞溶解或被它们刺激的干扰素γ的测定可在体外被测量。主动性免疫治疗的改进可结合手术、放射治疗、和/或化学治疗而被用于治疗癌症。加强可通过至少每月一次维持一至二年施用免疫原性复合物而发生。
免疫原性组合物包括异基因癌细胞和药学可接受的载体和/或媒介物(vehicle)。例如，载体可以是藻酸盐或PLGA珠或病毒颗粒，并且媒介物可以是注射用水或缓冲盐水溶液。配制组合物之前，载体或媒介物可被证实无病原体和致热原。细胞可被辐照并悬浮于含0.5％人血清白蛋白的缓冲盐水中。组合物优选地适合用于通过注射或储存(depot)用于全身或局部施用。优选地，施用前对组合物进行无细菌和病毒污染检测。为避免可能的污染源，在无血清、已知成分培养基中培养异基因癌细胞将是优选的。细胞可在补加20％二甲基亚砜作为冷藏保存剂的相同培养基中保存。
实施例
抗肿瘤疫苗接种当施用于首次接受试验的(naive)、无肿瘤小鼠时是非常有效的，导致随后攻击时阻止肿瘤生长。阻止一般是长效和肿瘤特异性的，显示获得性免疫反应的参与。当疫苗被用于已经建立肿瘤的治疗性治疗时，这种情况发生根本改变。能够有效地建立保护性免疫的相同剂量的疫苗一般不能提供治疗性益处。这种治疗性疫苗接种效力的缺乏的原因被认为源于肿瘤诱导的抑制性细胞的诱导、调节性细胞的生成、T细胞无反应或耐受性的诱导、或其组合。无论肿瘤诱导的免疫抑制的精确机制如何，用于癌症治疗的疫苗治疗的成功将依赖于克服或中和这些肿瘤诱导的抑制效应。
基于来自显示热休克蛋白gp96相关的肽被树突状细胞交叉提呈给CD8+细胞的Srivastava和Rammensee实验室的开创性工作，我们已经研制适合用于抗肿瘤治疗的疫苗接种系统。转染gp96-IgG1-Fc融合蛋白至肿瘤细胞中导致与陪伴的肿瘤肽形成复合物的gp96-Ig的分泌。分泌gp96-Ig的肿瘤的肠胃外施用触发强健的抗原特异性CD8+CTL扩增以及先天性免疫系统的激活。肿瘤分泌的gp96导致DC和NK细胞募集于gp96分泌位点并通过结合至CD91和TLR2及TLR4介导DC的激活。gp96及其陪伴的肽的胞吞摄入触发肽经由MHC I类的交叉提呈及不依赖CD4+细胞的强大的、同源CD8的激活。在这种模型系统中，通过使用获得性转移的TCR转基因的、gfp-标记的CD8+T细胞，可在疫苗接种的4至5天内精确地定量CD8+CTL的扩增。使用这套检测系统，我们现在显示在我们的模型系统中肿瘤诱导的免疫抑制是抗原非特异性的，并能够通过频繁的免疫接种或B细胞的缺失而被克服。
受治疗者、细胞系及抗体
C57BL/6J(B6)小鼠购自The Jackson Laboratory或Charles RiverLaboratories。具有B6背景的Ig-μ-链缺失小鼠(DCBM)购自The JacksonLaboratory。
gfp(绿色荧光蛋白)小鼠从其生产商获得。转基因C57BL/6J OT-I小鼠(获得自Dr.M.Bevan)表达对于H-2Kb-限制性鸡卵白蛋白-衍生肽257-264(SIINFEKL)特异性的TCR(Vα2Vβ5.1.2)。根据机构指导原则在Miami大学动物设施中将gfp小鼠与OT-I小鼠杂交产生gfp-OT-I小鼠。筛查后代小鼠的ova-TCR基因的表达并通过荧光筛查gfp的表达。所有小鼠在6-12周龄被使用。
用含gp96-Ig的载体pCMG-His转染EG7细胞系(获得自M.Bevan)。仅用载体转染对照细胞。Lewis肺癌(LLC)细胞获自美国典型培养物保藏中心(American Tissue Culture Collection)，并用在pAC-neo-ova中的卵白蛋白或用卵白蛋白载体和含gp96-Ig的pCMG-His二者转染。所有细胞在含10％胎牛血清(FCS)和庆大霉素(GIBCO)的IMDM培养基(GIBCO)中培养。为维持转染的细胞，用于筛选的抗生素(G418或L-组氨醇，Sigma，St.Louis，MO)被加入培养物。
以下抗体被用于染色：抗-CD16/32(2.4G2)、CyChrome-抗-CD3ε(145-2C11)、-抗-CD5(UCHT2)、-抗-CD8a(53-6.7)、PE-CD19(4G7)、PE或FITC-抗-NK1.1(PK136)、及PE或FITC-抗-CD11c(HL3)购自BDPharMingen。
ofgfp-OT-I细胞和CD19+B细胞的纯化和获得性转移
脾细胞和淋巴结(LN)细胞的单细胞悬液获自gfp-OT-I小鼠并将其混合。通过氯化铵溶解消除单细胞悬液中的红血细胞。根据制造商的说明使用抗-CD8α磁性微珠和MACS柱(Miltenyi Biotec)通过阳性柱选择分选Gfp-OT-I细胞。当用流式细胞计数分析测定时分离的OT-I细胞的纯度大于95％。通过流式细胞术定量Vα2和Vβ5.1.2在纯化的细胞中的表达。对于B细胞的纯化，用抗-CD19微珠(Miltenyi Biotec)纯化CD19+细胞。为了在BCDM小鼠中重建B细胞，在肿瘤细胞移植之前两天经尾静脉获得性转移107个纯化的细胞。
体内CD8+CTL扩增的分析
为测定CD8+CTL的扩增，用106gfp-OT-I获得性转移小鼠，两天后用1-4×106个未被辐照的EG7-gp96-Ig细胞的腹膜内(i.p.)注射免疫小鼠。继免疫之后，从腹膜腔、肠系膜、主动脉旁淋巴结(dLN)及外周血中按定时的间隔收获细胞。用氯化铵溶解从样品中去除红血细胞。一百万个细胞在4℃与在含0.5％BSA(PBA)的PBS中的抗-CD16/32单抗孵育10分钟以阻断FcR结合。之后细胞与指定抗体孵育30分钟。用CELL Quest软件(BD Bioscience)在FACScan(Becton Dickinson)上分析样品。由被靶向的细胞的百分数和每个组织中细胞的总数来计算每个组织指定的免疫细胞的总数。
肿瘤接种和治疗方案
将在200μl PBS中的未被辐照的EG7、LLC或LLC-ova细胞皮下(s.c.)注射入小鼠的肋腹。LLC-ova细胞接种后五天(第5天)，经尾静脉注射在0.3ml体积PBS中的106纯化的gfp-OT-I。两天后，按照在图中所示的时间表通过在0.5ml体积PBS中的106未被辐照的LLC-ova-gp96-Ig或106未被辐照的EG7-gp96-Ig细胞的i.p.注射免疫小鼠。用PBS、EG7或LLC-ova治疗对照小鼠。每周二次持续至少20天测量肋腹肿瘤的二维尺寸。
统计分析
用t检验评价显著性。认为p＜0.05的计算值显示统计学显著性。
建立的肿瘤不依赖TCR特异性而抑制gp96-介导的CD8-CTL扩增
转染热休克融合蛋白gp96-Ig至肿瘤细胞中导致gp96-Ig及gp96-陪伴的肽的分泌。gp96-Ig是通过用IgG1的Fc部分替代gp96的内质网滞留信号(KDEL)而产生的修饰蛋白。用分泌gp96-Ig的肿瘤细胞注射小鼠导致诱导肿瘤特异的免疫和对用相同的、但未转染的肿瘤的后续攻击的记忆及保护。由分泌的gp96-Ig产生的肿瘤免疫对gp96-陪伴肽(包括源于肿瘤内生抗原(诸如EL4特异性抗原)的肽)及对替代抗原(诸如转染入EL4(EG7)或LLC(LLC-ova)的卵白蛋白)是特异的。卵白蛋白替代抗原提供一种经由卵白蛋白特异的、OT-I TCR转基因的CD8+细胞的获得性转移在体内精确测定CD8+CTL扩增的方法。
已知建立的肿瘤对于CTL扩增是抑制性的。为测定在建立的肿瘤的存在和不存在时的CTL的反应，我们使用TCR转基因的OT-I系统，其中转基因的CD8+CTL响应于分泌gp96-Ig-ova的卵白蛋白-转染的同基因肿瘤或异基因肿瘤。作为可移植的肿瘤模型，我们使用了通过卵白蛋白转染源于EL4的被分类为免疫原性的和高致肿瘤性的EG7。另外，我们也使用了被认为具有较低免疫原性且高致肿瘤性的Lewis肺癌(LLC及LLC-ova)。两种细胞系的分裂速率非常迅速，在培养中具有8-12小时的倍增时间。
用一百万EG7-gp96-Ig-细胞单次i.p.免疫接种之后，24小时内每106细胞分泌60-80ng的gp96-Ig，OT-I由在CD8+门(gate)中的低免疫前水平(～0.2％)扩增至在无肿瘤小鼠中的高频率(15％-40％)。辐照的不分泌gp96-Ig的EG7的施用不能引起显著的OT-I扩增。但在肋腹中的远端位点出现的皮下建立的EG7肿瘤显著抑制gp96-疫苗诱导的在腹膜腔中及系统性地在脾和淋巴结中的OT-I的扩增。EG7肿瘤分泌卵白蛋白并表达Kb-ova。因此，通过肿瘤床或肿瘤引流淋巴结的再循环后，获得性转移的OT-I由于接收通过其Kb-ova-特异性TCR的信号而不接收共刺激信号2而变得无反应性是可能的。为评价这个假说，在远端位点皮下建立都不表达卵白蛋白的同基因肿瘤EL4和LLC。随后，静脉内(i.v.)获得性转移OT-I并用EG7-gp96-Ig i.p.免疫小鼠。建立的EL4和LLC通过分泌的gp96-ova在抑制OT-I扩增上与建立的EG7同样有效，表明所述抑制不依赖于肿瘤中合适的TCR抗原Kb-ova。虽然在腹膜腔中的和系统性的OT-I的扩增被在远端位点的LLC和EL4的出现抑制，但是当与无肿瘤小鼠相比时，EG7-gp96-Ig i.p.免疫接种后募集至腹膜腔的总细胞实际上增加。
也如其他人所报告的，数据显示建立的肿瘤能够诱导抗原非特异性的CTL扩增的抑制。这种抑制的诱导与增加的细胞募集至在腹膜腔中的疫苗位点相关。疫苗诱导的腹膜细胞从携带肿瘤小鼠至无肿瘤小鼠的转移抑制在受体小鼠中的OT-I的扩增，表明调节性或抑制性细胞的存在。因此，由于在携带肿瘤小鼠中不依赖抗原的细胞抑制反应，CD8+T细胞是无反应性的。
为克服抗原非特异性的免疫抑制，我们评价了通过疫苗接种对CD8+CTL的频繁地重复的抗原特异性刺激是否可抵消携带肿瘤小鼠中发现的抑制性活性。
建立的肿瘤的排斥需要频繁的gp96-Ig免疫接种
虽然许多疫苗接种策略(包括分泌的gp96-Ig)能够在小鼠中建立对抗肿瘤和肿瘤抗原的保护性免疫，但是通过治疗性的疫苗接种排斥已经建立的肿瘤是更困难的。考虑到抗原非特异的CD8扩增的抑制的观察，我们分析了不同的疫苗接种时间表如何影响肿瘤排斥和/或肿瘤生长。
我们首先通过在与肿瘤移植同一天开始疫苗接种以分析治疗性疫苗接种的效应。将一百万个EG7肿瘤细胞皮下移植于同基因小鼠的肋腹中。在同一天(第0天)，一百万个分泌gp96-Ig的EG7疫苗细胞(EG7-gp96-Ig)，以60-80ng/106细胞×24小时的速率分泌gp96-Ig)作为疫苗i.p.施用，并在第3、7、10和14天重复疫苗接种。与未接受治疗的小鼠相比，肿瘤生长被在与肿瘤移植的同一天开始的四次EG7-gp96-Ig疫苗接种降低。治疗效应是gp96依赖和抗原依赖的。不分泌gp96-Ig的辐照的EG7或不表达EG7-抗原但以与EG7-gp96-Ig相同的速率分泌gp96-Ig的LLC-gp96-Ig，当按与EG7-gp96-Ig相同的剂量和时间表作为疫苗i.p.施用时不能延缓肿瘤生长。当在EG7接种之后两天或更迟开始用EG7-gp96-Ig疫苗接种时，使用相同疫苗接种时间表的治疗效应实质上被降低。这些数据说明即使在两天后建立的肿瘤也比新移植的肿瘤更难以被疫苗接种控制。
我们接下来评价建立的肿瘤是否可以被更频繁的疫苗接种时间表所控制。将一百万个EG7肿瘤细胞皮下移植于肋腹中并允许其建立三到七天，允许至少七次或更多次肿瘤细胞倍增。在这期间，出现肉眼可检测的肿瘤结节的血管形成。之后每天一次用一百万个EG7-gp96-Ig细胞i.p.接种小鼠，或在特异性对照中用相同的时间表和剂量的LLC-gp96-Ig细胞、或辐照的EG7细胞i.p.接种小鼠，或保持小鼠未接种。用EG7-gp96-Ig每天一次的疫苗接种有效地控制了已经建立三天的EG7的生长，而用辐照的EG7或用LLC-gp96-Ig的每天一次的疫苗接种对建立的EG7的生长无效应。在进一步的研究中，在用EG7-gp96-Ig开始疫苗接种之前，我们允许移植的EG7肿瘤建立5和7天。需要每天两次的疫苗接种以在肿瘤建立的这个较晚阶段延缓肿瘤生长。数据显示频繁的免疫接种能够在小鼠中抑制肿瘤生长达24天的时期。将需要进一步的研究以确定持续的长期疫苗接种时间表是否能够彻底根除肿瘤。
为证实用免疫原性EG7淋巴瘤获得的数据，用较低免疫原性、建立的LLC重复实验。开始于肿瘤移植后第三天的用LLC-gp96-Ig的重复的i.p.免疫接种(第3天、7天、10天、14天)导致LLC的肿瘤进展的延缓。LLC的每天一次的免疫接种在肿瘤延缓中并未更有效。由于EG7-gp96-Ig疫苗接种不能够控制LLC肿瘤生长，所以免疫接种效应是肿瘤特异性的。肿瘤生长的控制也不能通过辐照的LLC实现，但肿瘤生长的控制依赖于gp96-Ig的分泌。
这些数据启示通过分泌的gp96-Ig和它的陪伴肽的频繁的DC激活和NK激活与抗原交叉呈递相结合能够克服建立的肿瘤诱导的、抗原非特异性免疫抑制。
gp96介导的DC募集和NK募集及CD8 CTL扩增在B细胞缺陷小鼠中被增强
若干团体已经报导当与野生型小鼠相比时Th1抗肿瘤反应在B细胞缺陷小鼠(BCDM)中被增强。因此我们研究B细胞在gp96介导的CTL扩增和抗肿瘤免疫中的作用。腹膜腔中被CD5-CD19+B细胞和CD5+CD19+B1-B细胞填充，CD5+CD19+B1-B细胞产生IgM抗体且在激活后不经历同种型转换。用EG7-gp96-Igi.p.免疫接种后，CD5-CD19+群到免疫接种后第4天增加约五倍，而CD5+B1B细胞仅适度增加。gp96介导的OT-I扩增在免疫接种后第4天和第5天是最大的。这在疫苗接种位点腹膜腔中DC和NK细胞的募集和激活之后。在B细胞缺陷小鼠中，DC细胞并且尤其NK细胞的募集在三次独立试验中增加并且募集的NK细胞在腹膜腔中保留较长久。差异未达到显著性但是可重复的。野生型B细胞至BCDM的获得性转移消除了DC细胞和NK细胞的募集的增加。该发现启示B细胞影响gp96诱导的先天性免疫细胞的募集并启示B细胞也可参与调节或抑制CD8+CTL的扩增。
因此我们评价了gfp-标记的OT-I的扩增在BCDM中是否增加。到第4天，BCDM中gp96免疫接种之后的OT-I扩增是在野生型小鼠中所见的约二倍强。重要的是，在腹膜腔中和在引流淋巴结中OT-I在免疫接种后第7天和第12天维持在显著更高的频率。先于免疫接种的野生型B细胞至BCDM的获得性转移降低OT-I的扩增至在野生型小鼠中所见的那些水平或以下。由于IL-10缺陷小鼠展示类似于野生型小鼠的OT-I扩增而非在BCDM中所见的增强的扩增，因此B细胞存在对OT-I扩增的抑制不是由IL-10的产生介导。
gp96介导的对建立的肿瘤的排斥在B细胞不存在时被加强
如上述所示，在野生型小鼠中建立的EG7的生长控制最低限度需要每天一次的gp96免疫接种。类似地，LLC的进展能够被频繁的免疫接种延缓。在BCDM中EG7细胞和EL4细胞被排斥并且不能建立肿瘤；但是LLC和LLC-ova能够在BCDM中建立，虽然它们以比在野生型小鼠中更缓慢的速率生长。在BCDM中和在野生型小鼠中LLC-ova在肋腹皮下地建立7天。i.v.获得性转移OT-I并且两天后以单次剂量i.p.施用LLC-ova-gp96-Ig并监测肿瘤生长。在BCDM中单次的免疫接种导致在三只小鼠中建立的七天LLC-ova肿瘤的彻底的排斥且在两只小鼠中导致显著的肿瘤减小。在治疗不存在时LLC-ova在BCDM中继续逐渐生长，虽然是以比在野生型小鼠中更低的速率。BCDM的B细胞重建产生类似于在野生型小鼠中所见的疫苗接种效应，即进展延缓。
单次免疫接种对BCDM中建立的LLC的最适的肿瘤控制被足够高的数量的肿瘤特异的CTL前体(OT-I)和被抗原特异的免疫接种(LLC-ova-gp96-Ig)二者支持。在BCDM中一百万个获得性转移的OT-I的存在而无gp96免疫接种在大多数小鼠中不导致肿瘤排斥。同样地仅gp96-免疫接种而无OT-I转移比组合有效性低。
在非小细胞肺癌(NSCLC)中的异基因癌疫苗的临床试验
用gp96-Ig和HLA-A1转染异基因肺癌细胞系AD100。一百万细胞中至少70％的细胞每24小时表达多于60ng gp96-Ig。重组癌细胞被辐照并且然后被皮内注射于患有晚期、复发或转移的NSCLC(IIIB/IV期)的人类受治疗者。不需要HLA匹配。如果未产生关于毒性的顾虑，将在17周期间每周一次或每两周一次用5×107个异基因癌细胞接种患者。可选择地，可通过以下递送总计4.5×108个异基因癌细胞：(a)在18周期间的九次注射，(b)在18周期间的18次注射，或(c)在18周期间的36次注射。
讨论
非常期望建立的肿瘤抑制抗肿瘤免疫。在建立的肿瘤存在时肿瘤特异性T细胞变得无反应性。对本研究中使用的B细胞淋巴瘤的无反应性是抗原特异的、MHC限制的且依赖于MHC匹配的骨髓来源的抗原呈递细胞的存在。在其他研究中抗原非特异的骨髓抑制性细胞和抗原非特异的T调节性细胞已经被牵涉在抗肿瘤免疫的抑制中。我们的研究显示体内CTL反应的抑制能够通过抗原非依赖途径由建立的肿瘤获得。响应于gp96-ova疫苗接种的OT-I扩增不依赖于肿瘤的卵白蛋白表达被建立的肿瘤抑制。这种类型的抑制可由T调节性细胞或通过其他抑制性细胞(诸如骨髓抑制性细胞或M2巨噬细胞)实现。根据这个假说，通过在携带肿瘤小鼠中由gp96-疫苗接种引发的腹膜细胞的转移，抑制性活性可转移至无肿瘤小鼠。
虽然针对gp96-ova免疫接种的OT-I反应在建立的肿瘤存在时被强烈抑制，但是它未被完全阻断，启示建立的肿瘤的免疫抑制和由分泌的gp96-ova刺激的激活的DC经由抗原交叉呈递对CD8-CTL的激活之间存在平衡。我们先前已经显示在肿瘤首次接受试验的小鼠中gp96-ova导致NK和DC的募集和激活及随后的OT-I扩增。建立的肿瘤，虽然通过LLC-gp96-Ig疫苗接种实际上增强细胞募集入腹膜腔，但抑制OT-I扩增并启示在建立的肿瘤存在时，许多募集的细胞可能是抑制性细胞。这个假说预测，用gp96-ova频繁的免疫接种可经由通过重复的gp96介导的DC的刺激和NK的刺激、增加的抗原交叉呈递及CTL启动来使平衡由抑制转向增加的免疫激活以克服抑制活性。频繁的免疫接种确实对肿瘤进展的延缓具有显著效应。在建立的EG7情况中，每天一次或每天两次的疫苗接种在停止肿瘤进展中更有效。对于LLC，每两天一次或每三天一次的免疫接种是足够的且每天一次的免疫接种并不是更有效的。这些肿瘤特异性差异可能与在外周肿瘤存在时产生抑制性细胞的速率相关。可选择地，这些肿瘤特异的差异可取决于肿瘤介导抑制性细胞的诱导的机制或已经诱导出的抑制性细胞的性质。这些疑问正在研究中。
通过研究OT-I对用肿瘤分泌的gp96-ova i.p.免疫接种的反应，我们注意到大量的B细胞被募集入腹膜腔。已经报导B细胞对于抗肿瘤免疫是抑制的，提示问题在于B细胞在gp96介导的OT-I扩增中的作用。使用B细胞缺陷小鼠，立即变得清楚的是，B细胞抑制gp96-ova免疫接种后的NK和DC的募集以及OT-I扩增二者。B细胞重建的BCDM对gp96-ova介导的OT-I扩增的反应类似野生型小鼠，排除B细胞缺陷已经以与B细胞的不存在无关的方式改变BCDM对gp96-ova免疫接种的反应性的可能性。即使在仅一次的gp96-ova免疫接种后，B细胞缺陷导致增强的OT-I扩增并导致七天建立的LLC-ova肿瘤的强烈增强的肿瘤排斥。数据显示肿瘤介导的抑制性细胞的诱导在B细胞不存在下大大减少或B细胞自身充当抑制性细胞。B细胞是否参与抑制性细胞的诱导或B细胞自身是否对CTL反应是免疫抑制性的需要进一步研究；但是IL-10看来似乎不参与B细胞介导的肿瘤免疫的抑制。在进行中的研究中，我们已经发现OX40-L缺陷的B细胞显示抑制抗肿瘤免疫反应的能力下降。仍需确定B细胞上表达的OX40-L如何介导gp96的抗肿瘤免疫的抑制和CTL扩增。
我们的研究提供能够研究和进一步确定抗原非依赖性的免疫抑制的模型。尤其B细胞在这个过程中的作用将是极受关注的。另外，我们的研究指出能够使抗肿瘤疫苗更有效的方法。用抗体和后续的频繁疫苗接种例如用肿瘤分泌的gp96-疫苗进行的B细胞的消除，可导致比用常规疫苗接种方法所见更有效的肿瘤生长的控制。
本文引用的专利、专利申请、书籍、及其它出版物通过引用方式以它们的整体并入。尤其，本文描述的改进可应用于施用以引用方式并入的美国专利申请第11/878,460号的癌细胞疫苗。
在陈述数值范围中，应理解也描述该范围内的所有值(例如，一至十也包括一和十之间的每个整数以及所有的中间范围比如二至十、一至五和三至八)。术语“约”可指与测量相关的统计学不确定性或数量的变化性，本领域技术人员将理解其不影响本发明的操作或其专利性。
在权利要求的含义及它们的法律等效物的范围内的所有修改和替代均包含于权利要求的范围内。叙述“包含”的权利要求允许其他要素包括在权利要求的范围内；本发明也通过叙述过渡词“主要由......组成”(即，如果其他要素不实质上影响本发明的操作，允许它们包括在权利要求的范围内)”或“由......组成”(即，仅允许权利要求中列举的要素而不允许通常与本发明相关的杂质或无关紧要的活性)替代叙述“包含”术语的这种权利要求而被描述。
应理解，如果权利要求中没有明确地叙述，在本说明书中描述的要素不应被解释为对要求保护的发明的限制。因此，授权的权利要求而不是对权利要求作出解释的来自说明书的限制是用于确定法律保护的范围的基础。截然相反，现有技术被明确地从本发明排除至预料到要求保护的发明或破坏新颖性的具体实施方案的程度。
此外，预期权利要求的限定之间无特定关系，除非权利要求中明确地叙述这种关系(例如，产品权利要求中组分的排列或方法权利要求中步骤的顺序不是对权利要求的限制，除非明确陈述是限制)。本文公开的单独要素的所有可能的组合及排列被认为是本发明的方面。类似地，对本发明描述的概括被认为是本发明的部分。
由上所述，可以其他特定形式实施本发明而不背离本发明的精神或本质特征，这将对本领域技术人员是显然的。因为提供给本发明的法律保护范围将由所附的权利要求书而非本说明书标明，所以所描述的实施方案应该仅被当作说明性的、而非限定性的。
Claims (14)
1.一种免疫人类受治疗者的方法，所述方法包括：
(a)施用给人类受治疗者分泌修饰的gp96热休克蛋白的异基因癌细胞的免疫原性组合物，其中所述修饰至少去除天然gp96中含有内质网(ER)滞留信号的结构域，以及之后
(b)施用给人类受治疗者分泌修饰的gp96热休克蛋白的异基因癌细胞的另一种免疫原性组合物，其中所述修饰至少去除天然gp96中含有内质网滞留信号的结构域；
其中施用所述免疫原性组合物和所述另一种免疫原性组合物之间间隔少于二周。
2.根据权利要求1所述的方法，其中施用所述免疫原性组合物和所述另一种免疫原性组合物之间间隔一周或更少。
3.根据权利要求1所述的方法，其中至少每周将至少九种免疫原性组合物施用给人类受治疗者，所述至少九种免疫原性组合物的每一种包括分泌所述修饰的gp96热休克蛋白的异基因癌细胞。
4.根据权利要求1至3中任一项所述的方法，其中所述天然gp96通过至少用IgG1或IgG2的一个或多个重链恒定区替代含有ER滞留信号的结构域而被修饰。
5.根据权利要求1至3中任一项所述的方法，其中所述天然gp96通过至少用IgG1或IgG2的Fc结构域替代含有ER滞留信号的结构域而被修饰。
6.根据权利要求1至5中任一项所述的方法，其中所述癌细胞表达HLA-A1或HLA-A2。
7.根据权利要求1至6中任一项所述的方法，其中至少所述修饰的gp96热休克蛋白由包括来自牛乳头状瘤病毒的一个或多个调节信号的载体编码。
8.根据权利要求1至7中任一项所述的方法，其中所述癌细胞来自癌瘤。
9.根据权利要求1至7中任一项所述的方法，其中所述癌细胞来自肺癌。
10.根据权利要求1至3中任一项所述的方法，其中AD100用编码至少用IgG1或IgG2的Fc结构域替代含有ER滞留信号的结构域而被修饰的天然gp96(gp96-Ig)和HLA-A1或HLA-A2并包括来自牛乳头状瘤病毒的一个或多个调节信号的一个或两个表达载体转染。
11.根据权利要求1至10中任一项所述的方法，还包括：在所述免疫原性组合物的初始施用之前和/或期间消除受治疗者的B细胞。
12.根据权利要求1至10中任何一项所述的方法，还包括：在所述免疫原性组合物的至少一次施用之前和/或期间消除受治疗者的B细胞。
13.一种改进的使用分泌修饰的gp96热休克蛋白的异基因癌细胞免疫接种或疫苗接种人类受治疗者的方法，其中天然gp96的所述修饰至少去除含有内质网(ER)滞留信号的结构域；所述改进包括：频繁地施用异基因癌细胞，其中异基因癌细胞以少于两周的间隔被施用给受治疗者；在所述异基因癌细胞的至少一次施用之前和/或期间消除受治疗者中的B细胞；或既频繁地施用所述异基因癌细胞又消除受治疗者中的B细胞。
14.免疫原性组合物用于人类受治疗者的免疫治疗的用途，所述免疫原性组合物包含分泌修饰的gp96热休克蛋白的异基因癌细胞，其中天然gp96的所述修饰至少去除含有内质网(ER)滞留信号的结构域，其中至少两种免疫原性组合物以少于两周的间隔被施用给受治疗者、在所述免疫原性组合物的至少一次施用之前和/或期间消除受治疗者中的B细胞、或两者。
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| EP2257301A4 (en) | 2013-01-16 |
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| ES2460899T3 (es) | 2014-05-14 |
| AU2009223838A1 (en) | 2009-09-17 |
| AU2009223838B2 (en) | 2012-07-26 |
| EP2257301A2 (en) | 2010-12-08 |
| IL207958A0 (en) | 2010-12-30 |
| CA2717854A1 (en) | 2009-09-17 |
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