CN111671908A - 用于癌症治疗的检查点抑制剂和分枝杆菌全细胞 - Google Patents
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Abstract
一种免疫调节剂,用于治疗、减轻、抑制或控制肿瘤疾病,所述肿瘤疾病的患者将接受检查点抑制治疗和与之同时、分别或依次给予的该免疫调节剂。该免疫调节剂宜包含分枝杆菌全细胞,例如牝牛分枝杆菌或奥布分枝杆菌全细胞。
Description
发明领域
本发明涉及癌症治疗领域。尤其,本发明涉及一种预防、治疗或抑制肿瘤和/或转移的方法。
发明背景
癌晚期人患者中,抗肿瘤免疫常因促炎、抗炎、免疫刺激、免疫抑制多种信号之间密切调控的相互作用而失效。例如,抗炎信号缺失导致慢性炎症和持续的增殖信号转导。有意思的是,肿瘤部位既有促进肿瘤细胞增殖的细胞因子又有抑制肿瘤细胞增殖的细胞因子产生。正是这多种过程之间的失衡导致了肿瘤诱发。
目前,研发有效抗癌免疫疗法的主要障碍之一是无法破除癌症部位的免疫抑制并恢复正常的免疫反应网络。免疫疗法的生理学手段是恢复正常的免疫反应性从而,作为举例,内源性肿瘤抗原被识别并针对肿瘤细胞产生有效的溶胞反应。虽然曾一度不清楚是否存在肿瘤免疫监控,目前认为免疫系统持续监测并清除新转化细胞。于是,癌细胞会改变其表型来应对免疫压力,从而逃避攻击(免疫编辑)并上调抑制性信号的表达。原发肿瘤和转移通过免疫编辑及其他破坏性程序维持其自身生存。
抗瘤免疫破坏的主要机制之一是‘T细胞耗竭’,其缘于长期接触抗原,其特征在于抑制性受体上调。这些抑制性受体起着避免非控免疫反应的检查点的作用。
PD-1和协同抑制受体,例如细胞毒T淋巴细胞抗原4(CTLA-4),B淋巴细胞和T淋巴细胞衰减蛋白(BTLA,CD272),T细胞免疫球蛋白粘蛋白结构域-3(Tim-3),淋巴细胞激活基因-3(Lag-3,CD223)等等,常被称作检查点调控者。它们就像分子“收费站”,让胞外信息得以指示细胞周期进程及其他胞内信号转导过程是否应该进行。
TCR的特异性抗原识别之外,T细胞激活还受控于协同刺激受体所发出正信号与负信号之间的平衡。这些表面蛋白通常是TNF受体或B7超家族的成员。针对激活性协同刺激分子的激动性抗体和针对负协同刺激的阻抑性抗体会增强T细胞刺激,从而诱发肿瘤消解。
细胞程序性死亡蛋白1(PD-1或CD279),是一种55-kD的1型跨膜蛋白,是T细胞协同刺激受体CD28家族中的一员,该家族成员包括免疫球蛋白超家族成员CD28、CTLA-4、诱导性协同刺激因子(ICOS)和BTLA。PD-1在活化的T细胞和B细胞上高表达。各亚组记忆T细胞上也可检到不同水平的PD-1表达。已鉴定了两个PD-1的特异性配体:程序性死亡配体1(PD-L1,亦称B7-H1或CD274)和PD-L2(亦称B7-DC或CD273)。已知PD-L1和PD-L2结合PD-1后下调T细胞激活,在小鼠和人系统中皆然(Okazaki等,Int Immunol.,2007;19:813-824)。PD-1与抗原呈递细胞(APC)和树突细胞(DC)表达的其配体PD-L1和PD-L2之间相互作用,传递各种负调节刺激,从而下调活化T细胞免疫反应。阻断PD-1能抑制这一负信号从而增强T细胞反应。
大量研究提示:癌症微环境操控着PD-L1-/PD-1信号转导路径;PD-L1表达的诱导与抗癌免疫反应的抑制相关,并由此容许癌症发展和转移。PD-L1/PD-1信号转导路径是癌免疫逃逸的主要机制之一,理由有多项。首先且最重要的是,该路径参与外周活化T效应细胞免疫反应的负调节。其次,癌症微环境中PD-L1上调,肿瘤浸润性活化T细胞上PD-1也上调,因此可能加强了抑制作用的恶性循环。其三,该路径通过双向信号转导同时参与先天免疫和获得性免疫,错综复杂。这些因素使得PD-1/PD-L1复合物成为一个中心点,癌症通过该中心点操控免疫反应并促其发展。
第一个进入临床试验的免疫检查点抑制剂是易普利姆玛(ipilimumab)(Yervoy,百时美施贵宝药厂(Bristol-Myers Squibb)),一种CTLA-4单抗(mAb)。CTLA-4属于免疫球蛋白受体超家族,该家族还包括PD-1、BTLA、TIM-3和T细胞活化的免疫球蛋白抑制V型结构域(VISTA)。抗CTLA-4单抗是高效检查点抑制剂,既能去除原初细胞的又能从接触过抗原的细胞的“故障”。治疗增强CD8+ T细胞的抗瘤功能,提高CD8+ T细胞与Foxp3+调节性T细胞之比,抑制调节性T细胞的抑制功能。抗CTLA-4单抗疗法的主要缺点是免疫系统丧失自我抑制能力而过度活跃时目标打击效应所致的自身免疫毒性。据报道,接受易普利姆玛治疗的患者中发生严重的、3-4级不良反应/自身免疫型副作用的达25%,包括皮炎、肠结肠炎、肝炎、内分泌病(包括下垂体炎、甲状腺炎和肾上腺炎)、关节炎、葡萄膜炎、肾炎和无菌性脑膜炎。相比抗CTLA-4,抗PD-1疗法显得耐受性好、自身免疫型副作用诱发率低。
TIM-3被鉴定为另一种在耗竭CD8+ T细胞上表达的重要抑制性受体。小鼠癌症模型中,大多数肿瘤浸润性功能异常CD8+T细胞实际上同时表达PD-1和Τ′IΜ-3。
LAG-3是新近发现的另一抑制性受体,它限制效应T细胞功能并放大调节性T细胞的抑制活性。最近发现,小鼠肿瘤浸润性T细胞广泛共表达PD-1和LAG-3,并且,PD-1和LAG-3的联合抑制在小鼠癌症模型中激发强协同抗瘤免疫反应。
PD-1路径的阻抑可与疫苗或其他免疫调节性抗体联合用于改善治疗效果(Hirano,F.等,Cancer Res.,65(3):1089-1096(2005);Li,B.等,Clin.Cancer Res,15:1507-1509(2009);Curran,M.A.等,Proc.Natl.Acad.Set,107(9):4275-4280(2010))。
目前,针对PD-1及其配体PD-L1的拮抗剂单抗用于癌症治疗的研发各自处于不同阶段,近期的人体试验显示在患有晚期、难治性疾病的癌症患者中结果喜人。
第一个进入I期临床试验的B7-H1/PD-1路径阻抑剂是纳武单抗(Nivolumab)(MDX-1 106/BMS-936558/ONO-4538),百时美施贵宝(Bristol-Myers Squibb)研发的全人lgG4型抗PD-1单抗。另一正处于临床评价期的PD-1单抗是CT-011,治疗技术有限公司(CureTechLtd)研发的PD-1特异性人源化lgG1单抗。其他还包括Lambrolizumab(MK-3475-Merck),一种人源化单克隆lgG4型PD-1抗体;BMS-936559,全人lgG4型PD-L1抗体和罗氏(Roche's)的MPDL3280A,靶向PD-L1路径的人单克隆抗体。
于是,本发明的目标是治疗癌症的联合疗法,包括免疫调节剂和检查点抑制剂阻抑,能够激发强而持久的免疫反应。
发明概要
本发明提供一种通过给予检查点抑制剂与全细胞分枝杆菌(Mycobacterium)协同作用来治疗和/或预防癌症和/或转移的方法。
本发明内容之一,用于治疗、减轻、抑制或控制患者的肿瘤疾病的免疫调节剂,其中,肿瘤患者将接受检查点抑制治疗和与之同时、分别或依次给予的免疫调节剂。
本发明内容之二,治疗、减轻、抑制或控制对象中肿瘤形成、肿瘤或癌症的方法,所述方法包括同时、分别或依次给予对象(i)检查点抑制剂和(ii)免疫调节剂,该方法疗效高于单独给予所述检查点抑制剂或免疫调节剂。
本发明内容之三,治疗、减轻、抑制或控制对象中肿瘤形成、肿瘤或癌症的方法,该方法包括同时、分别或依次给予对象(i)亚治疗量和/或亚疗程的检查点抑制剂和(ii)免疫调节剂,该方法疗效高于单独给予所述检查点抑制剂或免疫调节剂。
所以,本发明提供一种检查点抑制剂疗法结合给予免疫调节剂的特定免疫疗法的联合疗法。本发明的发明人发现:这两种疗法联合具有协同作用,超过各自单用效果的叠加。
附图说明
本发明的说明将结合以下附图,其中:
图1:胰腺癌异种移植模型(皮下注射KPC细胞)中,热灭活奥布分枝杆菌(NCTC13365)制剂联合或不联合检查点抑制剂(抗PD-L1单抗)的效果。
详细说明
本发明提供一种治疗、减轻、抑制或控制对象中肿瘤形成、肿瘤或癌症的方法,包括给予免疫调节剂和检查点抑制剂。该方法是基于以下发现:免疫调节剂(全细胞热灭活分枝杆菌)联合抗PD-L1抗体(检查点抑制剂)产生协同性抗瘤活性和/或优于单用免疫调节剂或抗PD-L1抗体的抗瘤活性。
为便于理解本发明,首先给出某些术语的定义。其他定义可见于详细说明各处。
“检查点抑制剂”是这样一种物质:它作用于类属TNF受体或B7超家族成员的表面蛋白,包括结合负协同刺激分子(选自CTLA-4、PD-1、TIM-3、BTLA、VISTA、LAG-3)和/或它们各自的配体(包括PD-L1)的物质。(Mellman等,同上)。
免疫调节剂,按照本发明中定义,是这样一种组分:它刺激先天免疫和1型免疫,包括Th1和巨噬细胞激活及细胞毒细胞活性,并通过免疫调节机制独立下调过度的抗Th2反应。
“肿瘤”、“癌症”和“肿瘤形成”同义,指这样的细胞或细胞群:其生长、增殖或生存超出了相应正常细胞的生长、增殖或生存,例如,细胞增殖紊乱或分化紊乱。典型地,此类生长是失控的。“恶性”指侵润邻近组织。“转移”指肿瘤、癌症或肿瘤扩展或扩散到患者非原发肿瘤或癌症所在的其他部位、位置或区域。
“程序性死亡1”、“细胞程序性死亡1”、“蛋白PD-1”、“PD-1”和“PD1”同义,包括人PD-1的变体、异构体、异种同源蛋白以及与PD-1至少有一个共同表位的类似物。PD-1全序列可见GenBank登录号U64863。
“细胞毒T淋巴细胞-相关抗原-4”、“CTLA-4”、“CTLA4”和“CTLA-4抗原”(见,例如,Murata,Am.J.Pathol.(1999)155:453-460)同义,包括人CTLA-4的变体、异构体、异种同源蛋白以及与CTLA-4至少有一个共同表位的类似物。(见,例如Balzano(1992)Int.J.CancerSuppl.7:28-32)。全长CTLA-4核酸序列可见GenBank登录号L15006。
“亚治疗量”在此表示治疗用化合物(如抗体)的剂量低于其单独用于治疗癌症时的常用或典型剂量或疗程较短。例如,CTLA-4抗体的一个亚治疗量是抗体一次给药低于3mg/kg(此为抗CTLA-4抗体的已知剂量)。
“治疗有效量”即与免疫调节剂联用时优选能产生以下效果的检查点抑制剂的量:症状的严重程度减轻,无症状期延长或频率增加,或避免了疾病致伤或致残。“有效量”或“药学有效量”指提供所需生物学效果或治疗效果的量。所述效果可以是一项或多项疾病表征、症状或病因的减少、改善、缓和、减轻、推迟和/或缓解,或生物系统其他各种如人所愿的变化。就癌症而言,有效量可包含足以引起以下效果的量:肿瘤收缩和/或肿瘤生长减慢(如抑制肿瘤生长)或避免或推迟了其他人所不欲的细胞增殖。某些实施方式中,有效量是足以令癌症或肿瘤进展延迟、生存期延长或病情稳定的量。
某些实施方式中,治疗有效量是足以避免或推迟复发的量。治疗有效量可一次或分多次给予。药物或联合疗法的治疗有效量会获得以下一项或多项效果:(i)癌细胞数量减少;(ii)肿瘤尺寸缩减;(iii)癌细胞向周围器官的浸润被抑制、阻滞或减缓到一定程度,最好是停止;(iv)抑制(即减缓到一定程度,最好是停止)肿瘤转移;(v)抑制肿瘤生长;(vi)避免或推迟肿瘤的发生和/或复发;和/或(vii)一项或多项癌症相关症状缓解到一定程度。
例如,就肿瘤治疗而言,“治疗有效剂量”可使得肿瘤相比基线测量值收缩至少约5%,如至少约10%、或约20%、或约60%或更多。所述基线测量值可采自无治疗患者。
治疗用化合物的治疗有效量可减小肿瘤尺寸,或者缓解症状。本领域技术人员懂得如何根据多种因素—如患者身量、症状严重程度、选定配方或给药途径—来确定这样的量。
“免疫反应”指例如淋巴细胞、抗原呈递细胞、吞噬细胞、粒细胞和这些细胞或肝脏所产生的可溶性大分子(包括抗体、细胞因子和补体)所起的导致以下结果的反应:癌细胞破坏、摧毁、或从人体清除。
“抗体”在此包括全抗体及其各种抗原结合片段(即“抗原结合部分”)或单链。
抗体的“抗原结合部分”(或简称“抗体部分”)在此指一种或多种保留了特异性结合受体和其配体(如PD-1)的能力的抗体片段,包括:(i)Fab片段;(ii)F(ab')2片段;(iii)VH和CHI结构域构成的Fd片段;(iv)Fv片段,(v)VH结构域构成的dAb片段(Ward等,Nature,341:544-546(1989));和(vi)分离的互补性决定区(CDR)。单链抗体也涵盖于抗体的“抗原结合部分”。这些抗体片段可用本领域技术人员所知的常规方法获得,这些片段经筛选其应用与完整抗体相同。
“单克隆抗体”或“单克隆抗体组合物”在此指单一分子组成的抗体分子所构成的制备物。单克隆抗体组合物表现出对特定表位单一的结合特异性和亲和力。
“人抗体”在此包括可变区中框架区和CDR区都来自人免疫球蛋白序列的抗体。
“人源化抗体”指其他哺乳动物物种系例如小鼠的CDR序列植入人框架区序列所得的抗体。人框架区序列内还可作其他框架区修饰和改变。
抗体之外还有其他生物分子可作为检查点抑制剂,包括具有定靶结合亲合力的肽。
“处理(treatment)”或“治疗”指为以下目的给予活性物质:治疗、治愈、缓解、减轻、改变、修复、缓和、改善或影响某种状态(如疾病)、该状态的症状,或避免或推迟某疾病症状、并发症、生化表征的发生或出现,或阻止或抑制疾病、状态或紊乱的进一步发展,以统计学显著的程度。
“对象”在此包括人和非人动物。优选对象包括需要增强免疫反应的人患者。此处所述方法特别适合其疾病能通过增强T细胞介导的免疫反应来治疗的人患者。实施方式之一中,所述方法特别适合体内癌细胞处理。
“并行施用(给药)”或“并行(地)”或“同时”在此表示同日施用或给药。“依次施用(给药)”或“依次”或“分别”表示给药或施用不在同一天。
“同时”施用或给药在此包括:2小时或更短时间内、或1小时或更短时间内施用免疫调节剂和包含检查点抑制剂的物质或程序、更好的是同时施用。
“分别”施用或给药在此包括:免疫调节剂的施用与包含检查点抑制剂的物质或程序的施用间隔大于约12小时、或约8小时、或约6小时、或约4小时、或约2小时。
“依次”施用或给药在此包括:多份和/或多剂次和/或非同一场合地各自给予免疫调节剂和化疗药。给予患者免疫调节剂可在给予检查点抑制剂之前和/或之后。或者,在检查点抑制剂治疗之后继续对患者施用免疫调节剂。
或选性表示(如“或”)应理解为选项之一、其二或选项间的任意组合。当提到或列举某些事项时的“一”、“一个”、“一种”等不定冠词以及单数形式涵盖单数和复数含义。
“约”在此表示就某特定数值而言本领域技术人员可以确定的可接受的误差范围,这部分地取决于该值的测量和确定方式,即,检测系统的限度。例如,“约”可以表示本领域常规实践中的1个单位或大于1个单位的标准偏差。或者,“约”表示的范围可达20%。当说明书和权利要求中给出特定数值,除非另作说明,应推定其涵盖围绕该特定数值可接受误差范围内“约”的意思。
本发明内容之一中,所述免疫调节剂包含热灭活的分枝杆菌,优选全细胞分枝杆菌。本发明可用的分枝杆菌种类有例如:牝牛分枝杆菌(M.vaccae)、抗热分枝杆菌(M.thermoresistibile)、微黄分枝杆菌(M.flavescens)、杜氏分支杆菌(M.duvalii)、草分枝杆菌(M.phlei)、奥布分枝杆菌(M.obuense)、副偶发分枝杆菌(M.parafortuitum)、泥炭藓分枝杆菌(M.sphagni)、爱知分枝杆菌(M.aichiense)、罗氏分枝杆菌(M.rhodesiae)、新金色分枝杆菌(M.neoaurum)、楚布分枝杆菌(M.chubuense)、托凯分支杆菌(M.tokaiense)、科莫斯分枝杆菌(M.komossense)、金色分枝杆菌(M.aurum)、w分枝杆菌(M.w)、结核分枝杆菌(M.tuberculosis)、田鼠分枝杆菌(M.microti)、非洲分枝杆菌(M.africanum)、堪萨斯分枝杆菌(M.kansasii)、海洋分枝杆菌(M.marinum)、猿分枝杆菌(M.simiae)、胃分枝杆菌(M.gastri)、无色分枝杆菌(M.nonchromogenicum)、土分枝杆菌(M.terrae)、次要分枝杆菌(M.triviale)、戈登分枝杆菌(M.gordonae)、瘰疠分枝杆菌(M.scrofulaceum)、石蜡分枝杆菌(M.paraffinicum)、胞内分枝杆菌(M.intracellulare)、鸟分枝杆菌(M.avium)、蟾分枝杆菌(M.xenopi)、溃疡分枝杆菌(M.ulcerans)、迪尔诺弗分枝杆菌(M.diernhoferi)、耻垢分支杆菌(M.smegmatis)、蛇分枝杆菌(M.thamnopheos)、微黄分枝杆菌(M.flavescens)、偶发分枝杆菌(M.fortuitum)、外来分枝杆菌(M.peregrinum)、龟分枝杆菌(M.chelonei)、副结核分枝杆菌(M.paratuberculosis)、麻风分枝杆菌(M.leprae)、鼠麻风分枝杆菌(M.lepraemurium),及其各种组合。
较好的是,热灭活的分枝杆菌无病原性。非病原性热灭活分枝杆菌优选牝牛分枝杆菌、奥布分枝杆菌、副偶发分枝杆菌、金色分枝杆菌、潘氏印度分枝杆菌(M.indicuspranii)、草分枝杆菌以及它们的各种组合。更好的是,非病原性热灭活分枝杆菌是粗糙型变体。给予患者的分枝杆菌的量足以激发患者体内保护性免疫反应,从而使患者免疫系统能够产生有效的抗癌症或抗肿瘤免疫反应。本发明某些实施方式中有一容纳机构(containment means),其中包含用于本发明有效量的热灭活分枝杆菌,一般可以是103至1011个微生物,优选104至1010,更优选106至1010,更优选106至109个微生物。用于本发明的热灭活分枝杆菌有效量可以是103至1011个微生物,优选104至1010,更优选106至1010,更优选106至109个微生物。用于本发明的热灭活分枝杆菌最佳量是107至109个细胞或微生物。典型地,本发明组合物的人用或动物用给药量可以是108至109个细胞。或者,剂量为0.01mg至1mg或0.1mg至1mg悬浮剂或干制剂形式的微生物。
特别优选牝牛分枝杆菌和奥布分枝杆菌。
牝牛分枝杆菌和奥布分枝杆菌在宿主中诱导复杂的免疫反应。用此类制剂处理将激发先天免疫和1型免疫,包括Th1和巨噬细胞激活和细胞毒细胞活性。它们还独立地通过免疫调节机制下调过度Th2反应。这恢复了免疫系统的健康平衡。
本发明可用来治疗肿瘤疾病,例如实体或非实体癌症。“处理”或“治疗”在此包括预防、减少/轻、控制和/或抑制肿瘤疾病。此类疾病包括:肉瘤、癌、腺癌、黑素瘤、骨髓瘤、胚细胞瘤、神经胶质瘤、淋巴瘤或白血病。癌症的例子包括(例如):癌瘤、肉瘤、腺癌、黑素瘤、神经系统癌症(胚细胞瘤、神经胶质瘤)、间皮瘤和网状内皮系统、淋巴系统或造血系统瘤肿瘤性疾病(如骨髓瘤、淋巴瘤或白血病)。尤其,肿瘤体(neoplasm)、肿瘤或癌症包括:肺腺癌、肺癌、弥漫型胃癌或间质性胃癌、结肠腺癌、前列腺腺癌、食管癌、乳腺癌、胰腺腺癌、卵巢腺癌、肾上腺腺癌、子宫内膜腺癌或子宫腺癌。
肿瘤形成、肿瘤和癌症包括它们的良性、恶性、转移和非转移型,以及各阶段(I、II、III、IV或V)或各等级(G1、G2、G3等),或者,发展中、恶化中、已稳定或缓解(remission)状态的肿瘤形成、肿瘤、癌症或转移。可用本发明治疗的癌症包括但不限于:膀胱、血液、骨、骨髓、脑、乳房、结肠、食道、胃肠、胶、头、肾、肝、肺、鼻咽、颈、卵巢、前列腺、皮肤、胃、睾丸、舌或子宫的细胞或肿瘤体。此外,还可以是以下组织学分型的癌症,包括但不限于:肿瘤体,恶性;癌;癌,未分化的;巨细胞和梭形细胞癌;小细胞癌;乳头状癌;鳞状细胞癌;淋巴上皮癌;基底细胞癌;毛基质癌(pilomatrix carcinoma);移行细胞癌;乳头状移行细胞癌;腺癌;胃泌素瘤,恶性;胆管癌;肝细胞癌;合并肝细胞癌和胆管癌;小梁腺癌;腺样囊性癌;腺瘤性息肉的腺癌;腺癌,家族性结肠息肉病;实体癌;类癌肿瘤,恶性;细支气管肺泡癌;乳头状腺癌;嫌色细胞癌;嗜酸细胞癌;嗜酸性腺癌;嗜碱粒细胞癌;透明细胞腺癌;颗粒细胞癌;滤泡状腺癌;乳头和滤泡状腺癌;无包膜形成的硬化性癌;肾上腺皮质癌;子宫内膜样癌;皮肤附属器癌;大汗腺腺癌;皮脂腺腺癌;耵聍腺癌(ceruminous adenocarcinoma);粘液表皮样癌;囊腺癌;乳头状囊腺癌;乳头状浆液性囊腺癌;粘液性囊腺癌;粘液腺癌;印戒细胞癌;浸润性导管癌;髓样癌;小叶癌;炎性癌;佩吉特病(Paget's disease),乳腺;腺泡细胞癌;腺鳞癌;腺癌伴鳞状上皮化生;胸腺瘤,恶性;卵巢间质肿瘤,恶性;卵泡膜细胞瘤,恶性;颗粒细胞肿瘤,恶性;男性母细胞瘤(androblastoma),恶性;支持细胞癌(Sertoli cellcarcinoma);间质细胞肿瘤(Leydig cell tumour),恶性;脂质细胞肿瘤,恶性;副神经节瘤,恶性;乳房外副神经节瘤,恶性;嗜铬细胞瘤;血管球肉瘤;恶性黑色素瘤;非黑色素性黑色素瘤;浅表扩散性黑色素瘤;巨大色素痣内恶性黑素瘤;上皮样细胞黑色素瘤;蓝痣,恶性;肉瘤;纤维肉瘤;纤维组织细胞瘤,恶性;粘液肉瘤;脂肪肉瘤;平滑肌肉瘤;横纹肌肉瘤;胚胎性横纹肌肉瘤;肺泡横纹肌肉瘤;间质肉瘤;混合瘤;苗勒氏混合瘤(Mullerian mixedtumor);肾母细胞瘤;肝母细胞瘤;癌肉瘤;间叶瘤,恶性;布伦纳瘤(Brenner tumor),恶性;叶状瘤,恶性;滑膜肉瘤;间皮瘤,恶性;无性细胞瘤;胚胎癌;畸胎瘤,恶性;卵巢甲状腺肿样瘤,恶性;绒膜癌;中肾瘤,恶性;血管肉瘤;血管内皮细胞瘤,恶性;卡波济氏肉瘤(Kaposi'ssarcoma);血管外皮细胞瘤,恶性;淋巴管肉瘤;骨肉瘤;近皮层骨肉瘤;软骨肉瘤;软骨母细胞瘤,恶性;间质软骨肉瘤;骨头巨细胞肿瘤;尤文氏肉瘤(Ewing's sarcoma);牙源性肿瘤,恶性;成釉细胞牙肉瘤;成釉细胞瘤,恶性;成釉细胞纤维肉瘤;松果体瘤,恶性;脊索瘤;神经胶质瘤,恶性;室管膜瘤;星形细胞瘤;原浆星形细胞瘤;纤维星形细胞瘤;星形母细胞瘤;胶质母细胞瘤;少突胶质细胞瘤;少突神经胶质母细胞瘤;原始神经外胚层肿瘤;小脑肉瘤;神经节母细胞瘤;神经母细胞瘤;视网膜母细胞瘤;嗅神经源性肿瘤;脑脊膜瘤,恶性;神经纤维肉瘤;神经鞘瘤,恶性;颗粒细胞肿瘤,恶性;恶性淋巴瘤;霍奇金病(Hodgkin'sdisease);霍奇金氏(Hodgkin's);类肉芽肿;恶性小淋巴细胞淋巴瘤;恶性弥散性大淋巴细胞淋巴瘤;滤泡性恶性淋巴瘤;蕈样真菌病;其他指定非霍奇金淋巴瘤;恶性组织细胞增生症;多发性骨髓瘤;肥大细胞肉瘤;免疫增殖性小肠病;白血病;淋巴样白血病;浆细胞白血病;红白血病;淋巴肉瘤细胞白血病;髓性白血病;嗜碱性白血病;嗜酸性粒细胞白血病;单核细胞白血病;肥大细胞白血病;巨核细胞白血病;髓样肉瘤和毛细胞白血病。较好的,肿瘤疾病是以下癌症相关肿瘤:前列腺癌、肝癌、肾癌、肺癌、乳癌、结直肠癌、胰腺癌、脑癌、肝细胞癌、淋巴瘤、白血病、胃癌、子宫颈癌、卵巢癌、甲状腺癌、黑色素瘤、头颈部癌、皮肤癌和软组织肉瘤和/或其他形式癌症。肿瘤可以是转移性或恶性肿瘤。
更好的是,待治疗的肿瘤疾病是胰腺癌、乳癌、肺癌、前列腺癌和皮肤癌症,最好是胰腺癌。
本发明实施方式之一中,检查点抑制剂治疗在与免疫调节剂(最好是全细胞热灭活分枝杆菌)的联合疗法中用于降低或抑制原发肿瘤或癌症向其他部位转移、或在离开原发肿瘤或癌症的其他部位形成或建立起转移性肿瘤或癌症,由此抑制或降低肿瘤或癌症复发或肿瘤或癌症恶化。
本发明另一实施方式中,提供的是一种治疗癌症的联合疗法,包括检查点抑制剂阻抑和免疫调节剂,能够激发强而持久的免疫反应,增强的治疗效果和更为可控的毒性。
本发明另一实施方式中,提供的是一种治疗癌症的联合疗法,包括检查点抑制剂阻抑和免疫调节剂,所述免疫调节剂(i)激发先天免疫和1型免疫,包括Th1和巨噬细胞激活和细胞毒细胞活性,并且(ii)通过免疫调节机制独立下调过度的抗Th2反应;所述免疫调节剂可以是全细胞分枝杆菌,可选牝牛分枝杆菌或奥布分枝杆菌。
本发明实施方式之一中,提供的是一种治疗癌症和/或避免转移确立的方法,该方法采用检查点抑制剂与全细胞分枝杆菌发生协同作用。
其他实施方式中,本发明方法包括以下一项或多项:1)降低或抑制可能或的确发生转移的肿瘤或癌细胞的生长、增殖、可动性(mobility)或侵润性,2)减少或抑制原发肿瘤或癌症向一个或多个其他部位、位置或区域转移的形成或确立,3)降低或抑制原发肿瘤或癌症之外一个或多个其他部位、位置或区域已形成或已确立的转移肿瘤或癌症的生长或增殖,4)减少或抑制转移形成或确立后的进一步转移,5)延长总体生存期,6)延长无恶化生存期,或7)稳定病情。
本发明实施方式之一中,给予检查点抑制剂治疗在与免疫调节剂(最好是全细胞热灭活分枝杆菌)的联合疗法中令对象的病情产生可测或可量的改善,例如减轻或缓解一项或多项与存在细胞增殖或细胞增生性病症、肿瘤形成、肿瘤或癌症或转移相关的不良(身体)症状或结果,即有疗效或良效。
疗效或良效是各种客观或主观、瞬时、短期或长期的状态或病情改善,或是细胞增殖或细胞增生性病症如肿瘤形成、肿瘤或癌症或转移相关或所致不良症状发生、程度、持续时间或频次的降低。这可使生存得到改善。例如以下情形时认为本发明方法获得了令人满意的临床终点:一种或多种相关异常、不良症状或并发症的严重程度、持续时间或频率越来越低或部分降低;细胞增殖或细胞增生性病症如肿瘤形成、肿瘤或癌症或转移的一种或多种生理学、生物化学或细胞性表现或特征被抑制或逆转。所以,疗效或改善可以是但不限于:目标增殖性细胞(如肿瘤形成、肿瘤或癌症或转移)被摧毁,或细胞增殖或细胞增生性病症如肿瘤形成、肿瘤或癌症或转移相关或所致一种、多种、大部分或全部异常、不良症状或并发症消减。然而,疗效或改善不必是痊愈或所有目标增殖性细胞(如肿瘤形成、肿瘤或癌症或转移)的完全消灭,也不必是细胞增殖或细胞增生性病症如肿瘤形成、肿瘤或癌症或转移相关或所致的所有异常、不良症状或并发症的完全消除。例如,抑制肿瘤或癌症发展或恶化所致肿瘤或癌细胞团块的部分消灭,或肿瘤或癌症质量、尺寸或细胞数量的稳定就能够降低死亡率,延长生存期,哪怕是数天、数周或数月,即便肿瘤或癌症的质量、尺寸或细胞数量仍有部分或大部分留存。
疗效的具体非限制性例子有:肿瘤形成、肿瘤或癌症或转移的量(尺寸或细胞质量)或细胞数量减少,抑制或避免肿瘤形成、肿瘤或癌症的量的增加(如实现稳定),减缓或抑制肿瘤形成、肿瘤或癌症发展、恶化或转移,或抑制肿瘤形成、肿瘤或癌症的增殖、生长或转移。
本发明实施方式之一中,检查点抑制剂治疗在与免疫调节剂(最好是全细胞热灭活分枝杆菌)的联合疗法中,根据irRC(由不同时间的效果评价和肿瘤负荷得出),产生可测或可量的改善或整体效果,这包括以下之一或多项:(i)irCR–所有病灶完全消失,不论可测或非可测,且无新的病灶(以有记录首日起至少4周的重复、连续评价来确认),(ii)irPR-肿瘤负荷相比基线降低≥50%(以有记录首日起至少4周的连续评价来确认)。
本发明方法可能不是即时起效。例如,治疗开始后可能出现肿瘤形成、肿瘤或癌细胞数量或质量上升,但经一段时间后最终会令对象的肿瘤细胞质量、尺寸或数量被稳定或减少。
能得到抑制、减轻、减少、推迟或避免的其他肿瘤形成、肿瘤、癌症和转移相关不良症状或并发症包括例如:恶心,食欲不振、嗜睡、疼痛和不适。所以,细胞增殖性疾病相关或所致不良症状或并发症程度、持续时间或频率的部分或完全消减,对象生活质量和/或幸福感的改善,例如体能、食欲、精神状态的改善,这些都是疗效的具体非限定性例子。
所以,疗效或改善包括接受治疗的对象生活质量的主观改善。其他实施方式中,本发明方法延长对象的生存期(存活)。另一实施方式中,本发明方法改善对象的生活质量。
最佳实施方式中,给予检查点抑制剂治疗在与免疫调节剂(最好是全细胞热灭活分枝杆菌)的联合疗法中在以下一项或多项疾病状态和发展标志上获得临床相关性改善:(i):总生存期,(ii):无恶化生存期,(iii):总响应率,(iv):转移性疾病下降,(v):肿瘤抗原循环水平,所述肿瘤抗原例如糖抗原19.9(CA19.9)和癌胚抗原(CEA)或基于肿瘤的其他抗原,(vii):营养状况(体重、食欲、血清白蛋白),(viii):疼痛的控制或镇痛药的使用,(ix):CRP/白蛋白比例。
热灭活全细胞牝牛分枝杆菌和奥布分枝杆菌治疗引发较为复杂的免疫,不仅包括先天免疫和1型免疫还包括免疫调节,后者更有效地恢复正常免疫功能。
按照本发明,免疫调节剂与检查点抑制剂联用。
优选实施方式之一中,检查点抑制治疗包括给予选自以下所述的阻抑剂:针对CTLA-4、PD-1、PD-L1、TIM-3、BTLA、VISTA和/或LAG-3的抗体或其抗原结合片段、肽、蛋白质、细胞,及其各种组合。
另一优选实施方式之一中,检查点抑制治疗包括给予亚治疗量和/或亚疗程的选自以下所述的阻抑剂:针对CTLA-4、PD-1、PD-L1、TIM-3、BTLA、VISTA和/或LAG-3的抗体或其抗原结合片段、肽、蛋白质、细胞,及其各种组合。
另一优选实施方式之一中,检查点抑制治疗包括给予选自以下所述的阻抑剂:针对PD-1和/或PD-L1的抗体或其抗原结合片段、肽、蛋白质、细胞。
另一优选实施方式之一中,检查点抑制治疗包括给予选自以下所述的阻抑剂:针对PD-1和/或PD-L1的抗体或其抗原结合片段、肽、蛋白质、细胞,同时、分别或依次给予针对CTLA-4的阻抑性抗体或其抗原结合片段。
“联合”或“联用”在此表示包括与分枝杆菌同时、分别或依次给予检查点抑制剂。因此,检查点抑制剂与分枝杆菌可以共存于同一药物制剂或分处不同药物制剂,同时或在不同时刻给予。
这样,分枝杆菌和检查点抑制剂可以是彼此分开、用来同时或者不同时刻给药的药物。
较好的是,分枝杆菌和检查点抑制剂是用来不同时刻给药的彼此分开的药物。分别且在不同时刻给药时,可以先给分枝杆菌也可先给检查点抑制剂;然而,先给检查点抑制剂然后给分枝杆菌为宜。此外,这两者可以同日也可以非同日给予,并且,治疗周期内,它们的给药计划可以相同也可以不同。
本发明实施方式之一中,治疗周期的构成为:每日、每周、隔周或每月给予分枝杆菌,同时每周给予检查点抑制剂。或者,检查点抑制剂给药之前和/或之后给予分枝杆菌。
本发明另一实施方式中,检查点抑制剂给药之前和之后都给患者施用分枝杆菌。即,实施方式之一中,检查点抑制剂给药之前和之后都给患者施用该免疫调节剂。
根据患者个体对治疗的耐受性,可进行推迟给药和/或减量和调整给药计划。
或者,可在给予有效量分枝杆菌的同时给予检查点抑制剂。
免疫调节剂(优选全细胞热灭活分枝杆菌)可经以下途径给予患者:肠胃外、经口、舌下、经鼻或经肺途径。优选实施方式之一中,免疫调节剂经选自以下所述的肠胃外途径给予:皮下、皮内、真皮下(subdermal)、腹膜内、静脉和囊内注射。更好的是,肠胃外途径给药不包括瘤内注射分枝杆菌胞壁提取物。
按本发明接受检查点抑制治疗的对象可同时、分别或依次接受免疫调节剂(优选全细胞热灭活分枝杆菌)给药。
本发明内容之一中,有效量的免疫调节剂可单剂给出,或者分多个(重复)剂次,例如两次或更多次、三次或更多次、四次或更多次、五次或更多次、十次或更多次、或二十次或更多次。免疫调节剂给药可比检查点抑制治疗早约4周至1日,如约4周至1周、或约3周至1周、或约3周至2周。给药可以是单剂次或是多剂次。
本发明优选实施方式之一中,提供了用于与检查点抑制剂联合治疗肿瘤疾病的分枝杆菌,其在给予检查点抑制剂之前、并行和/或之后给予对象。
本发明另一优选实施方式之一是治疗、减轻、抑制或控制对象体内肿瘤形成、肿瘤或癌症的方法,该方法包括同时、分别或依次给予对象(i)检查点抑制剂和(ii)免疫调节剂,优选全细胞热灭活分枝杆菌,所述方法的疗效高于单用该检查点抑制剂或免疫调节剂。
本发明另一优选实施方式之一是治疗、减轻、抑制或控制对象体内肿瘤形成、肿瘤或癌症的方法,该方法包括同时、分别或依次给予对象(i)检查点抑制剂和(ii)免疫调节剂,优选全细胞热灭活分枝杆菌;其中,所述检查点抑制治疗包括给予选自以下所述的阻抑剂:针对CTLA-4、PD-1、PD-L1、TIM-3、BTLA、VISTA和/或LAG-3的抗体或其抗原结合片段、肽、蛋白质、细胞,及其各种组合。
本发明另一优选实施方式之一是治疗、减轻、抑制或控制对象体内肿瘤形成、肿瘤或癌症的方法,该方法包括同时、分别或依次给予对象(i)检查点抑制剂和(ii)免疫调节剂,优选全细胞热灭活分枝杆菌;其中,所述检查点抑制治疗包括给予选自以下所述的阻抑剂:针对PD-1和/或PD-L1的抗体或其抗原结合片段、肽、蛋白质、细胞。
本发明另一优选实施方式之一是治疗、减轻、抑制或控制对象体内肿瘤形成、肿瘤或癌症的方法,该方法包括同时、分别或依次给予对象(i)检查点抑制剂和(ii)免疫调节剂,优选全细胞热灭活分枝杆菌;其中,所述检查点抑制治疗包括给予选自以下所述的阻抑剂:针对CTLA-4、PD-1、PD-L1、TIM-3、BTLA、VISTA和/或LAG-3的抗体或其抗原结合片段、肽、蛋白质、细胞,及其各种组合;其中,所述检查点抑制治疗包括给予亚治疗量和/或亚疗程的所述阻抑性抗体或其抗原结合片段。
本发明另一优选实施方式之一是治疗、减轻、抑制或控制对象体内肿瘤形成、肿瘤或癌症的方法,该方法包括同时、分别或依次给予对象(i)两种或更多种检查点抑制剂和(ii)免疫调节剂,优选全细胞热灭活分枝杆菌;其中,所述检查点抑制治疗包括给予选自以下所述的阻抑剂:针对CTLA-4、PD-1、PD-L1、TIM-3、BTLA、VISTA和/或LAG-3的抗体或其抗原结合片段、肽、蛋白质、细胞,及其各种组合;所述检查点抑制治疗可选性地包括给予亚治疗量和/或亚疗程的选自细胞、蛋白质、肽、抗体或其抗原结合片段的所述阻抑剂。
本发明实施方式之一中,分枝杆菌可以是以一定剂型给予患者的药物的形式。
本发明某些情形中的容器可以是小瓶、安瓿、注射器、胶囊、片剂或管。某些情形中,分枝杆菌被冻干并配制成供临用前重悬。而其他一些情形中,分枝杆菌悬溶于一定体积的药学上可接受的液体中。某些最佳实施方式中,有一容器,其中包含单个剂量单位的悬溶于药学上可接受载体中的分枝杆菌,所述单位剂量含约1x 106至约1x 1010个微生物。一些非常特定的实施方式中,分枝杆菌悬溶液的体积是约0.1ml至10ml、或约0.3ml至2ml、或约0.5ml至2ml。上述组合物能提供对本文所述免疫治疗应用来说理想的单位剂量。
就本发明方法和/或组合物而言的实施方式也可用于本文所述的其他方法或组合物。因此,就一种方法或组合物而言的实施方式也可用于本发明的其他方法和组合物。
某些情形中,将非病原性热灭活分枝杆菌给到对象的特定部位上或特定部位中。例如,可将本发明分枝杆菌组合物例如包含奥布分枝杆菌的组合物给到肿瘤附近或淋巴结附近,例如肿瘤周围的排出组织(drain tissue)。这样,某些情形中,分枝杆菌组合物定点给药可以是靠近颈后、扁桃体、腋窝、腹股沟、颈前、下颌下、颏下或锁骨上路(superclavicular)淋巴结。
免疫调节剂给药的持续时间可以是患者体内有癌症或肿瘤存在期间,或直至癌症消减或稳定。也可以在患者癌症或肿瘤消减或稳定之后继续使用免疫调节剂。
本发明分枝杆菌组合物包含有效量的分枝杆菌,通常是分散于药学上可接受载体中的分枝杆菌。“药学上可接受的或药理学上可接受的”指适当给予动物(例如人)不会产生不良、过敏或其他不期望的反应的分子或组合物。结合本文所揭示的内容,本领域技术人员知道如何制备含分枝杆菌的药物组合物,例如可参考Remington's PharmaceuticalSciences(《雷明顿药物科学》),第18版,Mack Printing Company(麦克印刷公司),1990。并且,就动物(如人)给药而言,制剂应符合无菌、无热源、常规安全和纯度标准。药理学上可接受的载体的例子之一在此是硼酸盐缓冲液或无菌盐水溶液(0.9%NaCl)。
“药学上可接受的载体”在此包括各种即所有溶剂、分散介质、包衣、表面活性剂、抗氧化剂、防腐剂(如抗细菌剂、抗真菌剂)、等渗剂、吸收延迟剂、盐、防腐剂、药物、药物稳定剂、凝胶、粘合剂、赋形剂、崩解剂、润滑剂、甜味剂、调味剂、染料之类物质,及它们的各种组合,正如本领域技术人员可知(见,例如Remington's Pharmaceutical Sciences(《雷明顿药物科学》),第18版,Mack Printing Company(麦克印刷公司),1990,第1289-1329页)。
优选实施方式之一中,免疫调节剂经选自以下所述的肠胃外途径给予:皮下、皮内、真皮下、腹膜内、静脉和囊内注射。皮内注射能够将整份分枝杆菌组合物递送到真皮层,真皮层受到免疫监控因而能够激发抗癌症免疫反应并促进局部淋巴结处的免疫细胞增殖。
虽然本发明分枝杆菌组合物在非常优选的实施方式中为直接皮内注射,某些情况中也可用其他给药方法。因此,某些情境中,本发明热灭活分枝杆菌可以以下所述方式给予:注射、输液、连续输液、静脉注射、皮内、动脉内、腹腔内、病灶内、玻璃体内、阴道内、直肠内、局部、瘤内、肌肉内、腹腔内、皮下、结膜下、囊内、粘膜、心包内、脐内、眼内、口服、颅内、关节内、前列腺内、胸膜内、气管内、鼻内、局部(topically)、区域(locally)、吸入(例如气雾剂吸入)、通过导管、通过灌洗或用其他方法,或以上所述的各种组合,正如本领域技术人员可知(见,例如Remington's Pharmaceutical Sciences(《雷明顿药物科学》),第18版,Mack Printing Company(麦克印刷公司),1990)。更好的是,肠胃外途径给药不包括瘤内注射分枝杆菌胞壁提取物。
以上提到的出版物均通过引用纳入本文。以上所述本发明方法和系统的各种修改和变化形式对本领域技术人员来说是显而易见的,且显然属于本发明构思和范围之内。尽管以上结合优选实施方式对本发明进行了说明,应当认为,权利要求要求保护的本发明不限于这些具体的实施方式。事实上,对于生物化学、免疫学及相关领域的技术人员而言,本发明实施方式除以上所述之外的各种改变和变化形式是显而易见的,应纳入权利要求保护范围之内。
进一步通过以下非限定性实施例来说明本发明。
实施例1
成年C57BL/6小鼠侧腹皮下注射105个源自KPC小鼠胰腺癌细胞系的细胞(Hingorani等,Cancer Cell,2005,7:469-48)。这些鼠胰腺癌细胞带有Kras、p53和Pdx-Cre内突变(Hingorani等,Cancer Cell,2005,7:469-48)。
当注射的肿瘤细胞长成可触及肿瘤(第0日),小鼠接受无治疗或以下治疗:
1)0.1mg奥布分枝杆菌NTCT 13365/鼠,整个研究过程中,按日轮换地在颈后和尾根皮下注射,5日注射、2日暂歇;
2)10mg/kg抗PDL-1单抗,腹膜内注射,每周一次;
3)抗PDL-1联合奥布分枝杆菌NTCT 13365,剂量和计划与以上单用相同。
全程监测肿瘤生长以确定所施的治疗对于缩小肿瘤和改善生存是否有效。
图1数据显示:接受抗PDL-1与奥布分枝杆菌NTCT 13365联合治疗的小鼠其肿瘤持续缩小,看起来控制住了肿瘤。与分别接受两种治疗单用的小鼠相比,肿瘤缩小更明显。无治疗小鼠肿瘤非控生长,很快病亡。
Claims (26)
1.一种包含非病原性热灭活全细胞奥布分枝杆菌(M.obuense)和针对CTLA-4、TIM-3、BTLA、VISTA、LAG-3和/或其组合的检查点抑制剂的产品,所述检查点抑制剂和非病原性热灭活全细胞奥布分枝杆菌共存于同一药物制剂或分处不同药物制剂、同时或在不同时刻给予。
2.如权利要求1所述的产品,其中,所述检查点抑制剂选自细胞、蛋白质、肽、抗体或其抗原结合片段。
3.如权利要求1所述的产品,其中,所述非病原性热灭活奥布分枝杆菌为粗糙型变体。
4.如权利要求1所述的产品,其中,所述非病原性热灭活奥布分枝杆菌为用于经肠胃外、经口、舌下、经鼻或经肺途径给药的形式。
5.如权利要求4所述的产品,其中,所述肠胃外途径选自:皮下、皮内、真皮下、腹膜内或静脉。
6.如权利要求2所述的产品,所述检查点抑制剂是单克隆抗体或其抗原结合片段。
7.(i)针对CTLA-4、TIM-3、BTLA、VISTA、LAG-3和/或其组合的检查点抑制剂和(ii)非病原性热灭活奥布分枝杆菌用于制备药物的用途,所述药物用于治疗、减轻、抑制或控制对象的胰腺癌相关肿瘤形成、肿瘤或癌症,所述治疗、减轻、抑制或控制包括同时、分别或依次给予对象所述检查点抑制剂和所述非病原性热灭活奥布分枝杆菌,其中,所述治疗、减轻、抑制或控制的疗效高于检查点抑制剂或非病原性热灭活分枝杆菌各自单用。
8.如权利要求7所述的用途,其中,所述检查点抑制剂选自细胞、蛋白质、肽、抗体或其抗原结合片段。
9.如权利要求7所述的用途,其中,所述胰腺癌相关肿瘤形成、肿瘤或癌症是转移性的。
10.如权利要求7所述的用途,其中,所述非病原性热灭活奥布分枝杆菌包含全细胞奥布分枝杆菌。
11.如权利要求7所述的用途,其中,所述非病原性热灭活奥布分枝杆菌是粗糙型变体。
12.如权利要求7所述的用途,其中,所述非病原性热灭活奥布分枝杆菌为用于经肠胃外、经口、舌下、经鼻或经肺途径给药的形式。
13.如权利要求12所述的用途,其中,所述肠胃外途径选自:皮下、皮内、真皮下、腹膜内或静脉。
14.如权利要求10所述的用途,其中,给药时所述药物中非病原性热灭活奥布分枝杆菌的量是107至109个细胞。
15.如权利要求7所述的用途,其中,根据总生存期延长确定疗效增强。
16.如权利要求7所述的用途,其中,根据无恶化生存期增加确定疗效增强。
17.如权利要求7所述的用途,其中,根据肿瘤尺寸缩小或稳定确定疗效增强。
18.如权利要求7所述的用途,其中,根据生活质量改善确定疗效增强。
19.非病原性热灭活奥布分枝杆菌用于制备药物的用途,所述药物用于治疗、减轻、抑制或控制接受针对CTLA-4、TIM-3、BTLA、VISTA、LAG-3和/或其组合的检查点抑制剂的对象的胰腺癌相关肿瘤形成、肿瘤或癌症。
20.如权利要求19所述的用途,其中,所述检查点抑制剂选自细胞、蛋白质、肽、抗体或其抗原结合片段。
21.如权利要求19所述的用途,其中,所述胰腺癌相关肿瘤形成、肿瘤或癌症是转移性的。
22.如权利要求19所述的用途,其中,所述非病原性热灭活奥布分枝杆菌包含全细胞奥布分枝杆菌。
23.如权利要求19所述的用途,其中,所述非病原性热灭活奥布分枝杆菌是粗糙型变体。
24.如权利要求19所述的用途,其中,所述非病原性热灭活奥布分枝杆菌为用于经肠胃外、经口、舌下、经鼻或经肺途径给药的形式。
25.如权利要求24所述的用途,其中,所述肠胃外途径选自:皮下、皮内、真皮下、腹膜内或静脉。
26.如权利要求22所述的用途,其中,给药时所述药物中非病原性热灭活奥布分枝杆菌的量是107至109个细胞。
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