CN114096278A - 通过体外单采血增加对检查点抑制剂的反应 - Google Patents
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Abstract
本发明提供了用于增强肿瘤对检查点抑制剂的反应的手段、方法和物组合物。在一个实施方案中,本发明教导了体外单采血术的用途,特别是去除各种肿瘤衍生性或肿瘤微环境衍生性免疫“阻断因子”的用途。在一个实施方案中,本发明提供去除可溶性TNF‑α受体(sTNF‑R)作为增强免疫检查点抑制剂功效的手段。在一个具体的实施方案中,sTNF‑R的去除被用来增强PD‑1/PD‑L1途径和/或CD28/CTLA‑4途径的抑制剂的功效。
Description
背景技术
人类癌症的患病率不断增加,其对死亡率的显著贡献意味着对新疗法的持续需求。消除癌症、减小其大小、破坏其支持的脉管系统或减少在血液或淋巴系统中循环的癌细胞数量是当前癌症疗法的目标。从机制上讲,癌症疗法旨在对抗肿瘤或从肿瘤转移的细胞通常依赖于细胞毒活性。该活性可能是活性剂本身具有的细胞毒性作用,或者它可能是活性剂例如通过调节免疫反应间接采用的作用。
已知组织中会发生遗传和表观遗传变化,因为它们转变为具有癌细胞的表型。恶性转化过程中的不同步骤,包括与肿瘤抑制剂活性的丧失相关的突变体表型的获得,通常导致受免疫识别影响的新抗原的生成。
已经进行了各种尝试来帮助免疫系统对抗肿瘤。一种早期方法涉及通过施用细菌(活的或被杀死的)来全面刺激免疫系统以引发也将针对肿瘤的一般免疫反应。现有的先天免疫刺激剂包括BCG[1-10]、A组产脓链球菌的冻干培养混合物(OK-432)[11-26]、CSF-470[27,28],以及可以选择性抑制Treg细胞的化学疗法剂量。
早在1975年[40]就已知,施用非特异性免疫激活剂可诱导局部癌症消退并且在某些情况下诱导全身性的癌症消退。例如,在一项研究中,6名恶性黑色素瘤皮内转移患者用病灶内BCG治疗。四名患者表现出良好的反应,具有注射的病变消退并且在某些情况下具有未注射的病变消退,而另外两名患者发展为转移性内脏疾病并死亡。六名患者中有三名患者的所有病灶完全消退,并且一名患者未治疗的病灶完全消退。所有人都没有疾病。第四名患者具有注射的病灶的完全消退和一些未治疗的病灶的完全消退,但发展为广泛传播并死亡。四名反应者中的三名(即体内治疗的病灶大小减小超过50%超过1个月的患者)表现出淋巴细胞对黑色素瘤抗原的刺激显著增加。所有反应者(四分之四)的植物血凝素(PHA)均显著增加,而无反应者对黑色素瘤抗原或PHA的淋巴细胞刺激没有增加。这些数据表明了另一个重要的观点,即先天免疫激活可以导致对抗原特异性T细胞和B细胞介导的免疫反应的刺激。最近旨在帮助免疫系统特异性识别肿瘤特异性抗原的方法涉及通常与佐剂(一种已知会引起或增强免疫反应的物质)结合用癌症特异性抗原对受试者进行免疫。肿瘤特异性抗原是已知的并且包括在癌组织中重新激活的一组癌症睾丸抗原(CT抗原)或生殖细胞抗原。已知的是,通常缺乏对肿瘤相关抗原(TAA)的强大免疫反应是由多种因素造成的。T细胞在通过T细胞受体(TCR)的抗原识别介导的免疫反应中具有关键作用,并且它们协调共刺激和抑制信号(称为免疫检查点)之间的平衡。这些抑制信号作为免疫系统的天然抑制物起作用,是维持自身耐受性和保护组织在免疫系统对病原体感染做出反应时免受损伤的重要机制。然而,失调的免疫抑制减少了身体本来可以避免肿瘤发展的有益反应。细胞因子、如CpG(刺激树突细胞)之类的其他刺激分子、Toll样受体配体和其他分子佐剂增强免疫反应。使用针对受体(包括OX40、CD28、CD27和CD137)的激动性抗体可以增强直接涉及T细胞的共刺激相互作用。其他免疫系统激活疗法包括阻断和/或消耗抑制性细胞或分子并且包括使用针对所谓免疫检查点的拮抗性抗体[41]。已知的是,免疫细胞表达的蛋白质是控制和下调免疫反应的免疫检查点。这些在T淋巴细胞中得到最好的定义并且包括PD-1、CTLA-4、TIM-3和LAG3。肿瘤细胞表达这些受体的配体。当T细胞将配体与肿瘤细胞上的这些蛋白质结合时,T细胞就会关闭并且不会试图攻击肿瘤细胞。因此,检查点免疫抑制是肿瘤用来逃避患者免疫系统的复杂策略的一部分并负责对免疫疗法的抗性。生物制药公司已成功开发出治疗性检查点抑制剂,其阻断受体/配体相互作用以促进对肿瘤的适应性免疫反应。目前有六种检查点抑制剂获得批准:帕博利珠单抗(pembrolizumab)、纳武单抗(nivolumab)、阿特珠单抗(atezolizumab)、阿维单抗(avelumab)、德瓦鲁单抗(durvalumab)和伊匹单抗(ipilimumab),其针对多种实体瘤,包括黑色素瘤、肺癌、膀胱癌、胃癌等。T细胞是癌症免疫反应的核心,并且该领域对使用肿瘤浸润淋巴细胞(TIL)治疗和了解癌症很感兴趣。通过它们的T细胞受体(TCR),T细胞对肿瘤内的特定抗原起反应。肿瘤细胞携带基因突变,其中许多直接或间接导致恶性肿瘤。表达序列中的突变通常会产生新抗原,这是免疫系统未知的一种抗原并因此被识别为外来物并能够引发免疫反应。TIL的重要性在于它们与良好的患者预后相关,包括胃癌[42]、乳腺癌[43-46]、黑色素瘤[47]、头颈癌[48]中的预后,从而表明免疫系统有助于癌症存活的积极作用。
不幸的是,尽管在理解免疫-癌症相互作用方面取得了巨大进步,并且围绕这一概念开发了新型首创药物,但许多患者仍然对免疫疗法没有反应,并且在某些情况下,那些有反应的患者会复发。本发明教导了通过使用体外手段去除肿瘤衍生和/或肿瘤微环境衍生的免疫阻断因子来增强免疫疗法(特别是检查点抑制剂)的功效的手段。
发明内容
本文的实施方案涉及增强向患有肿瘤的患者施用的免疫检查点抑制剂的功效的方法,该方法包括:鉴定患有肿瘤的患者;向所述患者施用免疫检查点抑制剂以治疗所述肿瘤或改善所述肿瘤的影响;体外去除抑制所述免疫检查点抑制剂效力的免疫阻断因子,其量足以增强所述免疫检查点抑制剂在治疗或改善所述肿瘤的作用中的效力,其中所述体外去除在选自由以下项组成的组的时间进行:在施用所述免疫检查点抑制剂之前、同时和之后。
更具体地,本文公开的是其中所述检查点抑制剂的所述功效基于选自由以下项组成的组的终点的方法:a)肿瘤消退;b)肿瘤稳定;c)肿瘤生长减少;d)转移的抑制;e)转移的稳定;f)转移性生长的减少;g)肿瘤和/或转移的包囊;h)与肿瘤抑制相关的细胞因子的增强;i)与肿瘤进展相关的细胞因子的减少;j)血管生成的抑制;k)肿瘤浸润淋巴细胞的增强;l)瘤内巨噬细胞从M2到M1表型的转换;m)肿瘤浸润树突细胞的增强;n)肿瘤浸润性杀伤T细胞的增强;o)肿瘤相关的T调节细胞的减少;以及p)肿瘤相关骨髓抑制细胞的减少。
根据进一步的实施方案,所述检查点抑制剂是能够抑制选自由以下项组成的组的分子的活性的药剂:PD-1,PD-L1,CTLA-4,PD-L2,LAG3,Tim3,2B4,A2aR,ID02,B7-H3,B7-H4,BTLA,CD2,CD20,CD27,CD28,CD30,CD33,CD40,CD52,CD70,CD112,CD137,CD160,CD226,CD276,DR3,OX-40,GAL9,GITR,ICOS,HVEM,IDO1,KIR,LAIR,LIGHT,MARCO,PS,SLAM,TIGIT,VISTA和VTCN1。
根据其他实施方案,所述免疫阻断因子是可溶性TNF-α受体。
根据进一步的实施方案,本文公开的这些方法,其中所述免疫阻断因子选自由以下项组成的组:a)可溶性HLA-G;b)可溶性MICA;c)白细胞介素-10;d)白细胞介素-20;e)VEGF;f)可溶性IL-2受体;g)可溶性IL-15受体;h)白细胞介素-35;以及i)可溶性干扰素γ受体。
根据更具体的实施方案,可溶性TNF-α受体的所述去除通过对TNF-α三聚体的亲和捕获来进行。
根据进一步的实施方案,所述检查点抑制剂经由选自由以下项组成的组的途径施用:静脉内、肌肉内、肠胃外、鼻内、肿瘤内、骨内、皮下、舌下、直肠内、鞘内、心室内、口服、眼内、局部、或经由吸入、纳米细胞和/或纳米气泡注射。
根据更具体的实施方案,免疫检查点抑制剂选自由PD-1、PD-L1和CTLA-4组成的组。
根据其他实施方案,PD-1的抑制剂是选自由纳武单抗和帕博利珠单抗组成的组的抗PD-1抗体。
进一步的实施方案涉及这些方法,其中PD-L1的抑制剂是选自由以下项组成的组的抗PD-L1抗体:BMS-936559、德瓦鲁单抗、阿特珠单抗、阿维单抗、MPDL3280A、MEDI4736、MSB0010718C和MDX1105-01。
根据其他实施方案,CTLA-4的抑制剂是选自由伊匹单抗和曲美木单抗组成的组的抗CTLA-4抗体。
根据某些实施方案,所述可溶性TNF-α受体的所述去除是使用体外亲和捕获底物进行的,所述体外亲和捕获底物包含选自由以下项组成的组的固定化TNF-α分子:TNF-α三聚体、天然TNF-α分子和TNF-α的突变形式,其中体外亲和捕获底物上的所述固定化TNF-α分子具有能够选择性结合到来自生物流体的可溶性TNFα受体的至少一个结合位点。
进一步的方法包括其中使用利用离心血浆分离的单采血系统进行免疫阻断因子的所述去除的实施方案。
另外的方法包括其中使用利用膜血浆分离的单采血系统进行免疫阻断因子的所述去除的实施方案。
其他方面包括这种方法,其中增强免疫检查点抑制剂的功效是通过执行一种或多种临床程序来实现的,该临床程序涉及去除肿瘤衍生的阻断因子以准备和/或调理患者。
更进一步的实施方案包括其中通过对TNF-α三聚体的亲和捕获来进行可溶性TNF-α受体的所述去除的方法。
根据更具体的实施方案,所述检查点抑制剂经由静脉内、肌肉内、肠胃外、鼻内、肿瘤内、骨内、皮下、舌下、直肠内、鞘内、心室内、口服、局部或经由吸入、纳米细胞和/或纳米泡注射施用。
根据进一步的实施方案,免疫阻断因子的所述体外去除使抗原呈递细胞在施用检查点抑制剂之后具有产生白介素-12的增强能力。
进一步的实施方案涉及用于治疗患者肿瘤的方法中的免疫检查点抑制剂,该方法包括:鉴定患有肿瘤的患者;向所述患者施用免疫检查点抑制剂以治疗所述肿瘤或改善所述肿瘤的影响;以及体外去除抑制所述免疫检查点抑制剂有效性的免疫阻断因子,其中所述体外去除在选自由以下项组成的组的时间进行:在施用所述免疫检查点抑制剂之前、同时和之后。本文公开的所有方法都可以与所述免疫检查点抑制剂一起使用。
具体实施方式
本发明公开了通过以体外手段去除免疫阻断因子来增强免疫检查点抑制剂的治疗能力的手段。在一个实施方案中,本发明涉及癌症治疗领域,特别是增强癌症治疗功效的手段。特别地,本发明提供了生成能够促进抑制癌症以及直接杀死癌症的T细胞群的方法。
如本文所用,术语“治疗”是指试图改变被治疗的个体或细胞的自然过程的临床干预,并且可用于预防或在临床病理过程中进行。预期效果包括预防疾病的发生或复发、缓解症状和减轻疾病的任何直接或间接病理后果、预防转移、降低疾病进展速度、改善或缓解疾病状态以及诱导缓解或改善预后。
术语“体外手段”定义为使用体外装置或系统,通过该装置或系统,从患者获得的血液或血液成分通过用于去除免疫抑制剂的装置,并且其中耗尽免疫抑制剂的血液或血液成分被重新注入患者体内。体外装置由选择性结合并捕获特定抑制剂以防止它们重新注入患者体内的材料组成。
术语“亲和捕获”是指通过化学吸引力选择性结合特定物质或分子。
术语“亲和捕获底物”是指包含亲和捕获分子的材料。
术语“抗体”包括适用于治疗患者的治疗性抗体;例如阿巴伏单抗(abagovomab)、阿德木单抗(adecatumumab)、阿夫土珠(afutuzumab)、阿仑单抗(alemtuzumab)、阿妥莫单抗(altumomab)、阿麦妥单抗(amatuximab)、马安莫单抗(anatumomab)、阿西莫单抗(arcitumomab)、巴维昔单抗(bavituximab)、贝妥莫单抗(bectumomab)、贝伐单抗(bevacizumab)、比伐珠单抗(bivatuzumab)、博纳吐单抗(blinatumomab)、本妥昔单抗(brentuximab)、坎妥珠单抗(cantuzumab)、卡妥索单抗(catumaxomab)、西妥昔单抗(cetuximab)、西他土珠(citatuzumab)、西妥木单抗(cixutumumab)、克利妥珠单抗(clivatuzumab)、可那木单抗(conatumumab)、达雷妥尤单抗(daratumumab)、曲齐妥单抗(drozitumab)、杜利他单抗(duligotumab)、度司妥单抗(dusigitumab)、地莫单抗(detumomab)、dacetuzumab、dalotuzumab、依美昔单抗(ecromeximab)、埃罗妥珠单抗(elotuzumab)、恩妥昔单抗(ensituximab)、厄妥索单抗(ertumaxomab)、埃达组单抗(etaracizumab)、法里妥组单抗(farietuzumab)、非拉妥组单抗(ficlatuzumab)、芬妥木单抗(figitumumab)、法兰妥单抗(flanvotumab)、伏妥昔单抗(futuximab)、盖尼塔单抗(ganitumab)、吉妥珠单抗(gemtuzumab)、吉妥昔单抗(girentuximab)、格巴妥木单抗(glembatumumab)、替伊莫单抗(ibritumomab)、伊戈伏单抗(igovomab)、伊马曲单抗(imgatuzumab)、英妥昔单抗(indatuximab)、英妥珠单抗(inotuzumab)、英妥木单抗(intetumumab)、伊匹单抗(ipilimumab)、伊妥木单抗(iratumumab)、拉贝妥珠单抗(labetuzumab)、来沙木单抗(lexatumumab)、林妥珠单抗(lintuzumab)、洛沃妥珠单抗(lorvotuzumab)、卢卡木单抗(lucatumumab)、马帕木单抗(mapatumumab)、马妥珠单抗(matuzumab)、米拉组单抗(milatuzumab)、明瑞莫单抗(minretumomab)、米妥莫单抗(mitumomab)、鲁磨西替(moxetumomab)、那呐妥单抗(narnatumab)、那普妥莫单抗(naptumomab)、耐昔妥珠单抗(necitumumab)、尼妥珠单抗(nimotuzumab)、诺伐木单抗(nofetumomabn)、奥卡妥珠单抗(ocaratuzumab)、奥法木单抗(ofatumumab)、奥拉木单抗(olaratumab)、奥那妥组单抗(onartuzumab)、莫妥组单抗(oportuzumab)、奥戈伏单抗(oregovomab)、帕尼单抗(panitumumab)、帕沙妥组单抗(parsatuzumab)、帕曲妥单抗(patritumab)、平妥单抗(pemtumomab)、帕妥珠单抗(pertuzumab)、平妥莫单抗(pintumomab)、普林木单抗(pritumumab)、雷妥莫单抗(racotumomab)、雷曲妥单抗(radretumab)、利妥木单抗(rilotumumab)、利妥昔单抗(rituximab)、罗妥木单抗(robatumumab)、沙妥莫单抗(satumomab)、西罗珠单抗(sibrotuzumab)、塞妥昔单抗(siltuximab)、辛妥珠单抗(simtuzumab)、索利托单抗(solitomab)、替组单抗(tacatuzumab)、他利妥莫单抗(taplitumomab)、替妥莫单抗(tenatumomab)、替妥木单抗(teprotumumab)、替加组单抗(tigatuzumab)、托珠单抗(tocilizumab)、托西莫单抗(tositumomab)、曲妥珠单抗(trastuzumab)、tucotuzumab、乌妥昔单抗(ublituximab)、维妥珠单抗(veltuzumab)、沃瑟妥珠单抗(vorsetuzumab)、伏妥莫单抗(votumumab)、扎鲁木单抗(zalutumumab)、CC49和3F8。在一些实施方案中,本发明教导了体外去除阻断因子作为增强提到的抗体的治疗功效手段的组合用途。在其他实施方案中,抗体的组合连同阻断因子的体外去除一起进一步与检查点抑制剂的施用组合。本发明对于其作用由抗体依赖性细胞毒性介导的治疗性抗体特别重要。提到的抗体可以单独使用或组合使用。此外,在本发明的范围内设想了其他免疫调节剂的施用。免疫调节剂可以是先天免疫的激活剂,例如toll样受体激动剂。其他免疫调节剂刺激适应性免疫,如T细胞和B细胞。此外,通过利用耗尽髓源性抑制细胞、Th3细胞、T调节细胞、2型中性粒细胞、2型巨噬细胞和嗜酸性粒细胞的方法去除免疫抑制细胞来实现免疫刺激。
术语“抗原呈递细胞”、“APC”或“APCs”包括完整的全细胞以及能够诱导一种或多种抗原呈递(优选与I类MHC分子结合)的其他分子(均为同种异体来源)抗原,以及能够诱导同种异体免疫反应的所有类型的单核细胞。优选地,全活细胞用作APC。合适的APC的示例是但不限于全细胞,例如单核细胞、巨噬细胞、DC、单核细胞衍生的DC、巨噬细胞衍生的DC、B细胞和骨髓性白血病细胞,例如细胞系THP-1、U937、HL-60或CEM-CM3。据说骨髓性白血病细胞提供所谓的前单核细胞。在本发明的一些实施方案中,肿瘤诱导的抗原呈递细胞的不成熟通过体外去除肿瘤相关阻断因子来克服。所述去除导致抗原呈递细胞响应于检查点抑制剂的施用而成熟的倾向。
术语“癌症”、“瘤”和“肿瘤”可互换使用,并以单数或复数形式出现在本说明书和权利要求书中,是指已经发生恶性转化的细胞,该恶性转化使细胞对于宿主生物体来说成为病理性的。通过成熟的技术,特别是组织学检查,可以很容易地将原代癌细胞(即从恶性转化部位附近获得的细胞)与非癌细胞区分开来。如本文所用,癌细胞的定义不仅包括原代癌细胞,还包括源自癌细胞祖先的任何细胞。这包括转移的癌细胞,以及源自癌细胞的体外培养物和细胞系。当提到一种通常表现为实体瘤的癌症时,“临床可检测”肿瘤是指例如通过诸如CAT扫描、磁共振成像(MRI)、X射线、超声或触诊等程序,基于肿瘤质量可检测到的肿瘤。与本发明相关的肿瘤/癌症的非限制性示例是癌(例如乳腺癌、前列腺癌、肺癌、结肠直肠癌、肾癌、胃癌和胰腺癌)、肉瘤(例如骨癌和滑膜癌)、神经-内分泌肿瘤(例如胶质母细胞瘤、髓母细胞瘤和神经母细胞瘤)、白血病、淋巴瘤和鳞状细胞癌(例如宫颈癌、阴道癌和口腔癌)。此外,与本发明相关的肿瘤/癌症的非限制性示例是神经胶质瘤、成纤维细胞瘤、神经肉瘤、子宫癌、黑色素瘤、睾丸肿瘤、星形细胞瘤、异位激素产生肿瘤、卵巢癌、膀胱癌、维尔姆氏瘤、血管活性肠肽分泌肿瘤、头颈部鳞状细胞癌、食道癌或转移癌。特别优选前列腺癌和乳腺癌。
对于本发明的实践,术语“化学疗法”意在包括可用于治疗癌症的任何非蛋白质(即,非肽)化合物。化学治疗剂的示例包括活性氧剂,例如青蒿素(artimesinin);和烷化剂,例如噻替哌和环磷酰胺(CYTOXAN.RTM.);烷基磺酸盐,例如白消安、英丙舒凡和哌泊舒凡;氮丙啶,例如苯并多巴(benzodopa)、卡波醌(carboquone)、甲基优瑞多巴(meturedopa)和优瑞多巴(uredopa);乙烯亚胺和甲基蜜胺,包括甲氨蝶呤(alfretamine)、三烯丙基胺(triemylenemelamine)、三亚乙基磷酰胺、三亚乙基硫代磷酰胺和三羟甲基蜜胺;多聚乙酰(尤其是布拉它辛和布拉它辛酮);喜树碱(包括合成类似物托泊替康);苔藓抑素;卡利斯他汀;CC-1065(包括其阿多来新、卡折来新和比折来新合成类似物);念珠藻素(特别是念珠藻素1和念珠藻素8);多拉司他汀;倍癌霉素(包括合成类似物,KW-2189和CBI-TMI);软珊瑚醇;水鬼蕉碱;匍枝珊瑚醇;海绵抑制素;氮芥,例如苯丁酸氮芥、萘氮芥、氯磷酰胺(cholophosphamide)、雌莫司汀、异环磷酰胺、氮芥(mechlorethamine)、盐酸氧氮芥、美法仑、新恩比兴、苯芥胆甾醇、泼尼莫司汀、曲磷胺(trofosfamide)、尿嘧啶芥;亚硝基脲,例如卡莫司汀(carmustine)、氯脲霉素、前莫司汀(foremustine)、洛莫司汀、尼莫司汀、雷尼莫司汀;抗生素,例如烯二炔抗生素(例如卡奇霉素,尤其是卡奇霉素γII和卡奇霉素phiI1,参见例如Agnew,Chem.Intl.Ed.Engl,33:183-186(1994);达内霉素,包括达内霉素A;双膦酸盐,例如氯膦酸盐;埃斯培拉霉素(esperamicin);以及新制癌菌素发色团和相关的色蛋白烯二炔抗生素发色团)、阿卡拉菌素(aclacinomysins)、放线菌素、安曲霉素、重氮丝氨酸、博来霉素、放线菌素C、卡拉霉素、洋红霉素(carninomycin)、嗜癌菌素、色霉素、放线菌素D、道诺霉素、地托比星、6-重氮-5-氧代-L-正亮氨酸、亚德里亚霉素(甲烯土霉素..TM..)(包括吗啉代-亚德里亚霉素、氰基吗啉代-亚德里亚霉素、2-吡咯啉代-亚德里亚霉素和脱氧亚德里亚霉素)、表柔比星、依索比星、伊达比星、马塞罗霉素、丝裂霉素(例如丝裂霉素C)、霉酚酸、诺加霉素、橄榄霉素、培洛霉素、potfiromycin、嘌呤霉素、三铁阿霉素、罗多比星、链黑霉素、链佐星、杀结核菌素、乌苯美司、净司他丁、佐柔比星;抗代谢物,如甲氨蝶呤和5-氟尿嘧啶(5-FU);叶酸类似物,例如德莫蝶呤(demopterin)、甲氨蝶呤、蝶罗呤、三甲曲沙(trimetrexate);嘌呤类似物,如氟达拉滨,6-巯嘌呤、硫咪嘌呤、硫鸟嘌呤;嘧啶类似物,例如安西他滨、阿扎胞苷、6-氮尿苷、卡莫氟、阿糖胞苷、二脱氧尿苷、多西氟尿苷、依诺他滨、氟尿苷;雄激素,例如卡鲁睾酮、丙酸屈他雄酮、环硫雄醇、美雄烷、睾酮内酯;抗肾上腺素,如氨鲁米特(aminoglutethimide)、米托坦、曲洛司坦;叶酸补充剂,如亚叶酸(frolinicacid);醋葡醛内酯;醛磷酰胺糖苷(aldophosphamide glycoside);氨基乙酰丙酸;恩尿嘧啶(eniluracil);安吖啶;黑斯特拉布奇(hestrabucil);比生群;依达曲沙(edatrexate);地磷酰胺(defofamine);地美可辛(demecolcine);地吖醌;elformthine;依利醋铵(elliptinium acetate);埃博霉素;依托格鲁(etoglucid);硝酸镓;羟基脲;香菇多糖;醛氢叶酸(leucovorin);氯尼达明(lonidamine);美登醇,如美登素和安丝菌素;米托胍腙;米托蒽醌;莫哌达醇;二胺硝吖啶(nitracrine);喷司他汀;蛋氨氮芥(phenamet);吡柔比星;洛索蒽醌;氟嘧啶;醛叶酸(folinic acid);鬼臼酸;2-乙基酰肼;丙卡巴肼(procarbazine);PSK;雷佐生(razoxane);根瘤菌素;西佐喃(sizofiran);螺旋锗;细交链孢菌酮酸(tenuazonic acid);三亚胺醌;2,2',2”-tricUorotriemylamine;单端孢霉烯(尤其是T-2毒素、疣孢菌素A、杆孢菌素A和蛇形菌素);尿烷;长春地辛;达卡巴嗪;甘露醇氮芥;二溴甘露醇;二溴卫矛醇;哌泊溴烷;加胞嘧啶(gacytosine);阿拉伯糖苷("Ara-C");环磷酰胺;thiopeta;紫杉烷,例如紫杉醇(TAXOL.RTM.,Bristol Meyers Squibb Oncology,新泽西普林斯顿)和多西紫杉醇(TAXOTERE.RTM.,Rhone-Poulenc Rorer,法国安东尼);苯丁酸氮芥;吉西他滨(GEMZAR.RTM.);6-硫鸟嘌呤;巯嘌呤;甲氨蝶呤;铂类似物,如顺铂和卡铂;长春花碱;铂;依托泊苷(VP-16);异环磷酰胺;米托蒽醌;长春新碱;长春瑞滨(NAVELBINE.RTM.);诺肖林;替尼泊苷;依达曲沙;道诺霉素;氨基蝶呤;昔洛达(xeoloda);伊班膦酸盐;CPT-11;拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO);类视黄酸,如视黄酸;卡培他滨;FOLFIRI(氟尿嘧啶、醛氢叶酸和伊立替康)以及上述任何物质的药学上可接受的盐、酸或衍生物。在一些实施方案中,化学疗法的功效通过利用阻断因子的体外去除来增强。此外,上述化学疗法的组合可以与检查点抑制剂一起使用。本发明在化学疗法的功效与免疫活性相关的情况下尤其相关。
术语“体外系统”和“体外去除”是指从全血和/或血浆中耗尽一定浓度的物质的一种或多种方法,其中所述物质是免疫抑制性的。用于从血浆中耗尽物质的方法可以利用使用离心力进行血浆分离或经由膜分离的系统,包括但不限于切向流系统和/或毛细管装置。在一个实施方案中,所述体外手段是基于单链TNF-α的亲和柱,称为“LW-02”装置,其可与Terumo Optia单采血系统结合使用。
术语“骨髓抑制细胞”等同于未成熟的骨髓祖细胞、骨髓衍生的抑制细胞、天然抑制细胞或未成熟的中性粒细胞/单核细胞前体。
术语“疫苗”、“免疫原”或“免疫原性组合物”在本文中用于指当施用于人或动物受试者时能够赋予一定程度的特异性免疫的化合物或组合物。如在本公开中所使用的,“细胞疫苗”或“细胞免疫原”是指包含任选地被灭活的至少一种细胞群作为活性成分的组合物。本发明的免疫原和免疫原性组合物是有活性的,这意指它们能够刺激至少部分由宿主的免疫系统介导的特定免疫反应(例如抗肿瘤抗原或抗癌细胞反应)。免疫反应可以包括抗体、免疫反应细胞(例如辅助/诱导或细胞毒性细胞)或其任何组合,并且优选针对存在于治疗针对的肿瘤上的抗原。反应可以通过施用单剂量或多剂量在受试者中被引发或重新刺激。如果化合物或组合物能够:a)在初治(naive)个体中生成针对抗原(例如肿瘤抗原)的免疫反应;或b)重建、加强或维持个体的免疫反应超出如果不施用化合物或组合物会发生的反应,则该化合物或组合物是“免疫原性的”。如果组合物在以单剂量或多剂量施用时能够达到这些标准中的任何一个,则该组合物是免疫原性的。
术语“T细胞反应”是指由肽在体外或体内诱导的效应子功能的特异性增殖和激活。对于MHC I类限制性细胞毒性T细胞,效应子功能可以是裂解肽脉冲、肽前体脉冲或天然肽呈递靶细胞,分泌细胞因子,优选干扰素-γ、TNF-α或肽诱导的IL-2,分泌效应分子,优选由肽诱导的颗粒酶或穿孔素,或脱粒。
术语“肽”在本文中用于表示通常通过相邻氨基酸的α-氨基和羰基基团之间的肽键相互连接的一系列氨基酸残基。肽的长度优选为9个氨基酸,但长度可以短至8个氨基酸,长至10、11、12个氨基酸或甚至更长,并且在MHC II类肽的情况下(例如本发明的肽的伸长变体),它们的长度可以长达15、16、17、18、19、20或23个或更多个氨基酸。此外,术语“肽”应包括通常通过相邻氨基酸的α-氨基和羰基基团之间的肽键相互连接的一系列氨基酸残基的盐。优选地,盐是肽的药学上可接受的盐,例如氯化物或乙酸盐(三氟-乙酸盐)。必须注意,根据本发明的肽的盐与处于其体内状态的肽显著不同,因为肽在体内不是盐。术语“肽”还应包括“寡肽”。术语“寡肽”在本文中用于表示通常通过相邻氨基酸的α-氨基和羰基基团之间的肽键相互连接的一系列氨基酸残基。寡肽的长度对本发明并不重要,只要其中保持正确的一个或多个表位即可。寡肽的长度通常小于约30个氨基酸残基,并且长度大于约15个氨基酸。
有需要的人可以是患有或怀疑患有癌症的个体。在一些变体中,有患癌症风险的人例如是在遗传上或以其他方式易患癌症的人并且已经或没有被诊断出患有癌症。如本文所用,“有风险”的受试者是处于患有癌症(例如,血液学恶性肿瘤)的风险中的受试者。受试者可能有或可能没有可检测的疾病,并且在本文所述的治疗方法之前可能已经或可能没有表现出可检测的疾病。有风险的受试者可能具有一种或多种所谓的风险因素,这些因素是如本文所述的与癌症的发展相关的可测量参数。具有这些风险因素中的一种或多种的受试者比没有这些风险因素的个体具有更高的发展癌症的可能性。这些风险因素可以包括例如年龄、性别、种族、饮食、既往疾病史、先兆疾病的存在、基因(例如遗传)考虑和环境暴露。在一些实施方案中,有患癌症风险的人包括,例如,其亲属已经受该疾病的人,以及其风险通过遗传或生化标记分析确定的人。患有癌症既往史也可能是癌症复发的风险因素。在一些实施方案中,本文提供了一种用于治疗表现出一种或多种与癌症(例如,血液学恶性肿瘤)相关的症状的人的方法。在一些实施方案中,人处于癌症的早期。在其他实施方案中,人处于癌症的晚期。
总生存期(OS)定义为从治疗开始直到任何原因死亡所经过的时间。无进展生存期(PFS)(RECIST 1.1)是从治疗开始直到疾病进展或死亡计算的。客观缓解率[CR(完全反应)或PR(部分反应)或SD(稳定的疾病)]被定义为具有使用CT或MRI确认的并由中央阅读器根据RECIST 1.1确定的最佳反应CR或PR或SD的患者的百分比。反应必须通过间隔大于或等于4周的后续测定来确认。在某些情况下,使用PET。评估和测量在筛选时进行,然后以8周的间隔从首次治疗开始,直到PD(进行性疾病)或开始另一种或额外的抗肿瘤治疗,以先发生者为准。此外,在每次长期随访时进行扫描,直到进展。
在本发明的一个实施方案中,选择体内存在高度癌症相关免疫抑制的患者。使用本领域已知的不同手段评估免疫抑制,并且可以包括循环中免疫细胞数量的量化、循环中免疫细胞活性的量化、肿瘤内发现的免疫细胞数量的量化、肿瘤内发现的免疫细胞活性的量化,肿瘤周围发现的免疫细胞数量的量化,以及肿瘤周围发现的免疫细胞活性的量化。在本发明的一些实施方案中,免疫细胞的量化包括鉴定和评估具有肿瘤细胞溶解和/或肿瘤抑制活性的细胞的活性,此类细胞包括天然杀伤细胞(NK)、γδT细胞、天然杀伤T细胞(NKT)、先天淋巴细胞、细胞毒性T淋巴细胞(CTL)和辅助T细胞(Th)。免疫细胞的活性可以是刺激其他免疫细胞的能力、杀伤活性、肿瘤生长抑制活性以及抑制血管生成的能力。其他评估免疫抑制的手段包括免疫抑制细胞的量化。例如,未成熟树突状细胞、Th2细胞、Th3细胞、骨髓抑制细胞、M2巨噬细胞、T调节细胞、N2中性粒细胞的升高,以及具有免疫抑制特性的间充质干细胞的浸润,都是用于选择具有免疫抑制的患者的衡量标准。
在一些实施方案中,阻断因子的体外去除用于降低骨髓抑制细胞的免疫调节活性,作为诱导免疫激活的手段。骨髓抑制细胞被认为类似于由Singhal小组在1970年代描述的“天然抑制”细胞。天然抑制细胞被发现是骨髓衍生细胞,其在免疫激活后具有抗原非特异性抑制T细胞增殖的能力[49-55],并且通过癌症和怀孕上调[56-63]。这些特性类似于目前描述的骨髓衍生抑制细胞的特性[64]。
在本发明的一些实施方案中,将维生素D3加入到阻断因子的体外去除中以便增强所述骨髓衍生性抑制细胞的分化和/或免疫抑制能力的丧失。出版物[65,66]描述了利用维生素D3来减少癌症相关的免疫抑制并通过引用并入。
本发明教导了在具有预先存在的免疫抑制的患者中,可以使用体外阻断因子的去除来增加检查点抑制剂药物的功效。对于本发明的实践,各种检查点抑制剂可以与免疫阻断因子的体外去除一起使用以增强治疗活性。此类检查点抑制剂的示例包括:a)程序性死亡1的抑制剂(PD-1,CD279),例如纳武单抗(OPDIVO.RTM.,BMS-936558,MDX1106或MK-34775)和帕博利珠单抗(KEYTRUDA.RTM.,MK-3475,SCH-900475,兰洛利珠单抗(lambrolizumab),CAS登记号1374853-91-4),以及美国专利号7,488,802,7,943,743,8,008,449,8,168,757,8,217,149,WO 03042402,WO 2008156712,WO 2010089411,WO2010036959,WO 2011066342,WO 2011159877,WO 2011082400和WO 201116169中描述的PD-1阻断剂;b)程序性死亡--配体1抑制剂(PD-L1,也称为B7-H1和CD274),包括抗体,例如BMS-936559,MPDL3280A),MEDI4736,MSB0010718C和MDX1105-01);还包括:阿特珠单抗、德瓦鲁单抗和阿维单抗;c)CTLA-4的抑制剂,例如伊匹单抗(YERVOY.RTM.,MDX-010,BMS-734016和MDX-101)、曲美木单抗、抗体克隆BNI3(Abcam);RNA抑制剂,包括WO 1999/032619,WO 2001/029058,U.S.2003/0051263,U.S.2003/0055020,U.S.2003/0056235,U.S.2004/265839,U.S.2005/0100913,U.S.2006/0024798,U.S.2008/0050342,U.S.2008/0081373,U.S.2008/0248576,U.S.2008/055443,美国专利号6,506,559,7,282,564,7,538,095和7,560,438(每个均通过引用并入本文)中描述的那些;d)PD-L2的抑制剂(B7-DC、CD273),例如AMP-224(Amplimune,Inc.)和rHIgM12B7;以及e)检查点蛋白抑制剂,包括:LAG3,例如IMP321;TIM3(HAVCR2);2B4;A2aR,ID02;B7H1;B7-H3或B7H3,例如抗体MGA271;B7H4;BTLA;CD2;CD20,例如替伊莫单抗(ibritumomab tiuxetan)、奥法木单抗(ofatumumab)、利妥昔单抗(rituximab)、阿托珠单抗(Obinutuzumab)和托西莫单抗(tositumomab);CD27,如CDX-1127;CD28;CD30,如本妥昔单抗(brentuximab vedotin);CD33,如吉妥珠单抗奥佐米星(gemtuzumab ozogamicin);CD40;CD52,如阿仑单抗;CD70;CD80;CD86;CD112;CD137;CD160;CD226;CD276;DR3;OX-40(TNFRSF.亚.4和CD134);GAL9;GITR;如TRX518;HAVCR2;HVEM;IDO1;ICOS(诱导型T细胞共刺激剂;CD278);例如MEDI570(MedImmune LLC)和AMG557(Amgen);KIR;LAIR;LIGHT;MARCO(具有胶原结构的巨噬细胞受体);PS(磷脂酰丝氨酸);SLAM;TIGIT;VISTA;以及VTCN1;或其组合。在另一个变体中,检查点抑制剂是选自PD-1、PD-L1和CTLA-4的组的检查点蛋白的抑制剂。在另一个变体中,检查点抑制剂选自抗PD-1抗体,以及抗PD-L1抗体,以及抗CTLA-4抗体的组。在一个变体中,抗PD-1抗体选自纳武单抗、帕博利珠单抗和兰洛利珠单抗的组。在另一个变体中,抗PD-L1抗体选自BMS-936559,MPDL3280A,MEDI4736,MSB0010718C和MDX1105-01的组。在其他变体中,抗PD-L1抗体选自由德瓦鲁单抗、阿特珠单抗和阿维单抗的组。在另一个变体中,抗CTLA-4抗体选自伊匹单抗和曲美木单抗的组。在一个实施方案中,检查点抑制剂选自由纳武单抗、帕博利珠单抗、兰洛利珠单抗、BMS-936559,MPDL3280A,MEDI4736,MSB0010718C,MDX1105-01、德瓦鲁单抗、阿特珠单抗、阿维单抗、伊匹单抗和曲美木单抗。在某些实施方案中,检查点抑制剂选自由纳武单抗、帕博利珠单抗、兰洛利珠单抗、德瓦鲁单抗、阿特珠单抗、阿维单抗、伊匹单抗和曲美木单抗。在一个实施方案中,检查点抑制剂选自纳武单抗、帕博利珠单抗、德瓦鲁单抗、阿特珠单抗和阿维单抗组成的组。列出的所述检查点抑制剂可以经由多种方法施用,包括但不限于静脉内、肌肉内、肠胃外、鼻内、瘤内、骨内、皮下、舌下、直肠内、鞘内、心室内、口服、眼内、局部或经由吸入、纳米细胞和/或纳米气泡注射。对于本发明的实践,免疫检查点抑制剂功效的增强可以通过进行涉及去除肿瘤衍生阻断因子以准备和/或调理患者的一个或多个临床程序来实现。所述去除可以在施用所述检查点抑制剂之前的不同时间点进行。在一些实施方案中,基于患者的免疫学和/或肿瘤学评估来进行去除时间点的确定。在某些情况下,评估患者的免疫活性,并将其用作确定施用检查点抑制剂之前体外治疗的量和频率的基础。在某些情况下,可能需要在施用检查点抑制剂的同时继续进行体外治疗。此外,在某些情况下,可能需要在施用检查点抑制剂后继续进行体外治疗。
在一些实施方案中,通过去除体外阻断因子来增加检查点抑制剂药物的功效。所述检查点抑制剂可用于通过添加一种或多种癌症疫苗来进一步提高功效,这被称为“主动免疫”。在本发明的一些实施方案中,检查点抑制剂的施用与主动免疫一起进行。免疫可以采取肽、蛋白质、改变的肽配体和细胞疗法的形式。
已知在癌症上发现并且对本发明的实践有用的抗原包括:表皮生长因子受体(EGFR,EGFR1,ErbB-1,HER1);ErbB-2(HER2/neu),ErbB-3/HER3,ErbB-4/HER4,EGFR配体家族;胰岛素样生长因子受体(IGFR)家族、IGF结合蛋白(IGFBP)、IGFR配体家族(IGF-1R);血小板衍生生长因子受体(PDGFR)家族,PDGFR配体家族;成纤维细胞生长因子受体(FGFR)家族、FGFR配体家族、血管内皮生长因子受体(VEGFR)家族、VEGF家族;HGF受体家族;TRK受体家族;肝配蛋白(EPH)受体家族;AXL受体家族;白细胞酪氨酸激酶(LTK)受体家族;TIE受体家族,血管生成素1,2;受体酪氨酸激酶样孤儿受体(ROR)受体家族;盘菌素域受体(DDR)家族;RET受体家族;KLG受体家族;RYK受体家族;MuSK受体家族;转化生长因子α(TGF-α),TGF-α受体;转化生长因子-β(TGF-β),TGF-β受体;白细胞介素β受体α2链(IL13Rα2);白细胞介素-6(IL-6),1L-6受体;白细胞介素-4、IL-4受体;细胞因子受体,I类(促红细胞生成素家族)和II类(干扰素/1L-10家族)受体;肿瘤坏死因子(TNF)家族,TNF-α;肿瘤坏死因子(TNF)受体超家族(TNTRSF);死亡受体家族,TRAIL-受体;癌-睾丸(CT)抗原;谱系特异性抗原;分化抗原;α-辅肌动蛋白-4;ARTC1,断点簇区域-Abelson(Bcr-abl)融合产物;B-RAF;半胱氨酸蛋白酶-5(CASP-5);半胱氨酸蛋白酶-8(CASP-8);β-连环蛋白(CTNNB1);细胞分裂周期27(CDC27);细胞周期蛋白依赖性激酶4(CDK4);CDKN2A;COA-1;dek-can融合蛋白;EFTUD-2;伸长因子2(ELF2);Ets变异基因6/急性髓细胞性白血病1基因ETS(ETC6-AML1)融合蛋白;纤连蛋白(FN);GPNMB;低密度脂质受体/GDP-L岩藻糖;β-D-半乳糖2-α-L岩藻糖基转移酶(LDLR/FUT)融合蛋白;HLA-A2;MLA-Al1;热休克蛋白70-2突变(HSP70-2M);KIAA0205;MART2;黑色素瘤泛在突变1,2,3(MUM-1,2,3);前列腺酸性磷酸酶(PAP);新-PAP;肌球蛋白1类;NFYC;OGT,OS-9;pml-RARα融合蛋白;PRDX5;PTPRK,K-ras(KRAS2);N-ras(NRAS);HRAS;RBAF600;SIRT12;SNRPD1;SYT-SSX1或-SSX2融合蛋白;磷酸丙糖异构酶;BAGE;BAGE-1;BAGE-2,3,4,5;GAGE-1,2,3,4,5,6,7,8;GnT-V(异常N-乙酰氨基葡萄糖转移酶V;MGAT5),HERV-K MEL,KK-LC,KM-HN-1,LAGE,LAGE-1,CTL-识别的黑色素瘤抗原(CAMEL),MAGE-A1(MAGE-1);MAGE-A2;MAGE-A3;MAGE-A4;MAGE-AS;MAGE-A6;MAGE-A8;MAGE-A9;MAGE-A10;MAGE-A11;MAGE-A12;MAGE-3;MAGE-B1;MAGE-B2;MAGE-B5;MAGE-B6;MAGE-C1;MAGE-C2;黏蛋白1(MUC1);MART-1/草木犀浆-A(MLANA);gp100;gp100/Pme117(S1LV);酪氨酸酶(TYR);TRP-1;HAGE;NA-88;NY-ESO-1;NY-ESO-1/LAGE-2;SAGE,Sp17;SSX-1,2,3,4;TRP2-1NT2;癌胚抗原(CEA);激肽释放酶4;乳腺球蛋白-A;OA1;前列腺特异性抗原(PSA);前列腺特异性膜抗原;TRP-1/,75;TRP-2亲脂蛋白;黑色素瘤2(AIM-2)中不存在的干扰素诱导蛋白;BING-4;CPSF;细胞周期蛋白D1;上皮细胞粘附分子(Ep-CAM);EpbA3;成纤维细胞生长因子-5(FGF-5);糖蛋白250(gp250肠道羧基酯酶(iCE);甲胎蛋白(AFP);M-CSF;mdm-2;MUCI;p53(TP53);PBF;PRAME;PSMA;RAGE-1;RNF43;RU2AS;SOX10;STEAP1;存活蛋白(BIRCS);人端粒酶逆转录酶(hTERT);端粒酶;Wilms'肿瘤基因(WT1);SYCP1;BRDT;SPANX;XAGE;ADAM2;PAGE-5;LIP1;CTAGE-1;CSAGE;MMA1;CAGE;BORIS;HOM-TES-85;AF15q14;HCA66I;LDHC;MORC;SGY-1;SPO11;TPX1;NY-SAR-35;FTHLI7;NXF2 TDRD1;TEX 15;FATE;TPTE;免疫球蛋白特异型;Bence-Jones蛋白;雌激素受体(ER);雄激素受体(AR);CD40;CD30;CD20;CD19;CD33;CD4;CD25;CD3;癌抗原72-4(CA 72-4);癌抗原15-3(CA 15-3);癌抗原27-29(CA 27-29);癌抗原125(CA 125);癌抗原19-9(CA 19-9);β-人绒毛膜促性腺激素;1-2微球蛋白;鳞状细胞癌抗原;神经元特异性烯醇化酶;热休克蛋白gp96;GM2,沙格司亭(sargramostim);CTLA-4;707丙氨酸脯氨酸(707-AP);由T细胞4识别的腺癌抗(ART-4);癌胚抗原肽-1(CAP-1);钙激活氯通道-2(CLCA2);亲环素B(Cyp-B);以及人印戒肿瘤-2(HST-2)。
在一个实施方案中,本发明教导了去除体外阻断因子以增加浸润肿瘤的树突细胞数量的用途。树突细胞作为免疫疗法的用途是本领域已知的,并且使用树突细胞疗法的方式针对以下项的下述示例中定义:黑色素瘤[67-118]、软组织肉瘤[119]、甲状腺[120-122]、神经胶质瘤[123-144]、多发性骨髓瘤[145-153]、淋巴瘤[154-156]、白血病[157-164],以及肝[165-170]、肺[171-184]、卵巢[185-188]和胰腺癌[189-191]。在其他实施方案中,本发明教导了免疫阻断因子的体外去除用于增加现有树突细胞以浸润肿瘤的用途。评估树突细胞浸润的手段是本领域已知的并且在针对以下项的下述示例中描述:胃癌[192-195]、头颈癌[196-200]、宫颈癌[201]、乳腺癌[202-204]、肺癌[205]、结直肠癌[206-208]、肝癌[209,210]、胆囊癌[211,212]和胰腺癌[213]。
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Claims (18)
1.一种增强向患有肿瘤的患者施用的免疫检查点抑制剂的功效的方法,所述方法包括:
识别患有肿瘤的患者;
向所述患者施用免疫检查点抑制剂以治疗所述肿瘤或改善所述肿瘤的影响;
体外去除抑制所述免疫检查点抑制剂的效力的免疫阻断因子,其量足以增强所述免疫检查点抑制剂在治疗或改善所述肿瘤的影响中的效力,其中所述体外去除在选自由以下项组成的组的时间下进行:在所述免疫检查点抑制剂的所述施用之前、同时和之后。
2.根据权利要求1所述的方法,其中所述免疫检查点抑制剂的所述功效基于选自由以下项组成的组的终点:a)肿瘤消退;b)肿瘤稳定;c)肿瘤生长减少;d)转移的抑制;e)转移的稳定;f)转移性生长的减少;g)肿瘤和/或转移的包囊;h)与肿瘤抑制相关的细胞因子的增强;i)与肿瘤进展相关的细胞因子的减少;j)血管生成的抑制;k)肿瘤浸润淋巴细胞的增强;l)瘤内巨噬细胞从M2到M1表型的转换;m)肿瘤浸润树突细胞的增强;n)肿瘤浸润性杀伤T细胞的增强;o)肿瘤相关的T调节细胞的减少;以及p)肿瘤相关骨髓抑制细胞的减少。
3.根据权利要求1所述的方法,其中所述检查点抑制剂是能够抑制选自由以下项组成的组的分子的活性的药剂:PD-1,PD-L1,CTLA-4,PD-L2,LAG3,Tim3,2B4,A2aR,ID02,B7-H3,B7-H4,BTLA,CD2,CD20,CD27,CD28,CD30,CD33,CD40,CD52,CD70,CD112,CD137,CD160,CD226,CD276,DR3,OX-40,GAL9,GITR,ICOS,HVEM,IDO1,KIR,LAIR,LIGHT,MARCO,PS,SLAM,TIGIT,VISTA和VTCN1。
4.根据权利要求1所述的方法,其中所述免疫阻断因子是可溶性TNF-α受体。
5.根据权利要求1所述的方法,其中所述免疫阻断因子选自由以下项组成的组:a)可溶性HLA-G;b)可溶性MICA;c)白细胞介素-10;d)白细胞介素-20;e)VEGF;f可溶性IL-2受体;g)可溶性IL-15受体;h)白细胞介素-35以及i)可溶性干扰素γ受体。
6.根据权利要求4所述的方法,其中可溶性TNF-α受体的所述去除通过对TNF-α三聚体的亲和捕获来进行。
7.根据权利要求6所述的方法,其中所述检查点抑制剂经由选自由以下项组成的组的途径施用:静脉内、肌肉内、肠胃外、鼻内、肿瘤内、骨内、皮下、舌下、直肠内、鞘内、心室内、口服、眼内、局部、或经由吸入、纳米细胞和/或纳米气泡注射。
8.根据权利要求1所述的方法,其中所述免疫检查点抑制剂选自由PD-1、PD-L1和CTLA-4组成的组。
9.根据权利要求8所述的方法,其中PD-1的抑制剂是选自由纳武单抗和帕博利珠单抗组成的组的抗PD-1抗体。
10.根据权利要求8所述的方法,其中PD-L1的抑制剂是选自由以下项组成的组的抗PD-L1抗体:BMS-936559、德瓦鲁单抗、阿特珠单抗、阿维单抗、MPDL3280A、MEDI4736、MSB0010718C和MDX1105-01。
11.根据权利要求8所述的方法,其中CTLA-4的抑制剂是选自由伊匹单抗和曲美木单抗组成的组的抗CTLA-4抗体。
12.根据权利要求4所述的方法,其中所述可溶性TNF-α受体的所述去除是使用体外亲和捕获底物进行的,所述体外亲和捕获底物包含选自由以下项组成的组的固定化TNF-α分子:TNF-α三聚体、天然TNF-α分子和TNF-α的突变形式,其中所述体外亲和捕获底物上的所述固定化TNF-α分子具有能够选择性结合到来自生物流体的可溶性TNFα受体的至少一个结合位点。
13.根据权利要求1所述的方法,其中使用利用离心血浆分离的单采血系统进行免疫阻断因子的所述去除。
14.根据权利要求1所述的方法,其中使用利用膜血浆分离的单采血系统进行免疫阻断因子的所述去除。
15.根据权利要求1所述的方法,其中增强免疫检查点抑制剂的功效是通过执行一种或多种临床程序来实现的,所述临床程序涉及去除肿瘤衍生的阻断因子以准备和/或调理所述患者。
16.根据权利要求15所述的方法,其中通过对TNF-α三聚体的亲和捕获来进行可溶性TNF-α受体的所述去除。
17.根据权利要求16所述的方法,其中所述检查点抑制剂经由静脉内、肌肉内、肠胃外、鼻内、肿瘤内、骨内、皮下、舌下、直肠内、鞘内、心室内、口服、局部或经由吸入、纳米细胞和/或纳米泡注射施用。
18.根据权利要求1所述的方法,其中免疫阻断因子的体外去除使抗原呈递细胞在施用检查点抑制剂之后具有产生白介素-12的增强能力。
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