CN109195600A - 反式-[四氯双(1h-吲唑)钌(iii)酸盐]用于治疗癌症的用途 - Google Patents
反式-[四氯双(1h-吲唑)钌(iii)酸盐]用于治疗癌症的用途 Download PDFInfo
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- CN109195600A CN109195600A CN201780027237.0A CN201780027237A CN109195600A CN 109195600 A CN109195600 A CN 109195600A CN 201780027237 A CN201780027237 A CN 201780027237A CN 109195600 A CN109195600 A CN 109195600A
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Abstract
反式‑[四氯双(1H‑吲唑)钌(III)酸]钠IT‑139是一种静脉内施用的小分子化合物。在临床前抗肿瘤和作用机制研究中，IT‑139显示出针对多种肿瘤类型的活性，包括对标准抗癌剂(例如铂、长春花生物碱、紫杉烷、蒽环霉素)具有抗性的那些肿瘤类型。这种活性被认为是由IT‑139的靶向GRP78路径的新型作用机制产生的。发现GRP78的上调是关键的癌细胞存活路径。使用IT‑139对GRP78的下调消除了这种抗性路径，使得化学疗法和免疫‑肿瘤剂在治疗癌症方面更有效。
Description
技术领域
本发明一般涉及反式-[四氯双(1H-吲唑)钌(III)酸盐]及其在癌症治疗中的用途。
背景技术
近年来在癌症的治疗方面已经取得了许多进展。然而，在转移性疾病的大多数情况下，治疗不是治愈性的，因为肿瘤细胞发展出克服并经受住由抗癌剂引起的损伤的机制。靶向和克服肿瘤细胞的这些存活/抗性机制是抗癌靶向的一个领域，也是活跃研究的主题。因此，仍然存在开发用于治疗癌症，特别是治疗抗性的治疗剂的未满足的需求。
发明内容
现已发现，本发明的化合物及其组合物可用于治疗癌症，并且特别是可用于靶向肿瘤细胞的存活和抗性机制。
更具体地，现已发现IT-139抑制肿瘤细胞中GRP78的应激上调。这种作用对肿瘤细胞是特异性的，因为IT-139不影响正常细胞中的GRP78表达。在非应激和应激条件下用IT-139治疗正常细胞已表明：1)IT-139不影响非应激正常细胞中的基础GRP78水平；和2)由于这些相同的正常细胞中的应激，IT-139不会影响GRP78的上调。因此，无论应激条件如何，相信IT-139都不会影响正常细胞中的GRP78水平。
附图说明
图1描绘了在A)非应激细胞；和B)用毒胡萝卜素(thapsigargin)应激的细胞中用IT-139治疗之前和之后的GRP78蛋白水平。
图2描绘了在A)非应激细胞；和B)用毒胡萝卜素应激的细胞中用IT-139治疗之前和之后的GRP78 mRNA水平。
图3描绘了用IT-139和PD-1抗体治疗后的由皮下同系模型产生的结果。
图4描绘了在A)受控的未治疗细胞；和B)用IT-139治疗的HCT116细胞中的HCT116细胞的透射电子显微镜图像。
图5描绘了在以下情况中IT-139对RNA聚合酶II与GRP78启动子结合的影响：A)chip seq结果；B)通过凝胶电泳的Pol II引物定量；和C)GRP78引物的定量。
图6描绘了用A)盐水和B)IT-139治疗的HT-29肿瘤(离体)的免疫组织化学染色。
图7描绘了在有和没有IT-139治疗的情况下在应激和非应激条件下对肾293T细胞的治疗。
图8描绘了参照A)GRP78 mRNA水平；和B)相对GRP78 mRNA表达，在有和没有IT-139治疗的情况下在应激和非应激条件下对肾293T细胞的治疗。
图9描绘了在多种细胞系中用IT-139治疗后线粒体电位的影响。
图10描绘了用IT-139治疗后正常外周血单核细胞的细胞活力。
图11描绘了用IL-2或IL-2和IT-139治疗后正常外周血单核细胞的细胞活力。
图12描绘了用以下物质治疗的GRP78蛋白水平的表达：DMSO；150μM IT-139；1μM毒胡萝卜素(Tg)；150μM IT-139和1μM Tg的同时治疗；1μM Tg治疗6小时，随后150μM IT-139治疗24小时；以及对于泳道1-5，分别用150mM IT-139治疗24小时，随后用1mM Tg治疗24小时。泳道6-12是再孵育24小时的相同治疗。
图13描绘了用以下物质体外治疗48小时的ASPC20细胞：DMSO(对照)；150μM IT-139；5μM吉西他滨(gemcitabine)；同时150μM IT-139和5μM吉西他滨；5μM吉西他滨24小时，随后150μM IT-139；和150μM IT-139，随后5μM吉西他滨24小时。
图14描绘了用以下物质体外治疗48小时的PANC-1细胞：DMSO(对照)；150μM IT-139；5μM吉西他滨；同时150μM IT-139和5μM吉西他滨；5μM吉西他滨24小时，随后150μM IT-139；和150μM IT-139，随后5μM吉西他滨24小时。
图15描绘了A20小鼠模型中8个治疗组的中值肿瘤体积。
图16描绘了显示肿瘤中效应T细胞的中值％的散点图。
图17描绘了显示肿瘤中调节因子T细胞的中值％的散点图。
具体实施方式
1.总体描述：
反式-[四氯双(1H-吲唑)钌(III)酸]钠IT-139是一种静脉内施用的小分子化合物。IT-139也称为KP1339或NKP1339。在临床前抗肿瘤和作用机制研究中，IT-139显示出针对多种肿瘤类型的活性，包括对标准抗癌剂(例如铂、长春花生物碱、紫杉烷、蒽环霉素)具有抗性的那些肿瘤类型。这种活性被认为是由靶向GRP78路径的IT-139的新型作用机制产生的。
GRP78(葡萄糖调节蛋白78)(也称为BiP或HSPA5)是内质网(ER)应激反应的调节因子。其还在肿瘤细胞存活、抗凋亡和治疗剂抗性中起关键作用。在正常细胞中，发现GRP78水平很低并且位于内质网的腔中。在应激细胞中，GRP78在细胞质、细胞核、线粒体中、细胞表面上和分泌时被显著上调，并且也在ER外部被发现。在多种癌症类型中的GRP78表达的升高与肿瘤细胞增殖、转移、血管生成和肿瘤细胞存活和抗性增加相关。高水平的GRP78蛋白与例如顺铂(cisplatin)、5-FU、替莫唑胺(temozolomide)、长春碱(vinblastine)、紫杉醇(paclitaxel)、硼替佐米(bortezomib)、索拉非尼(sorafenib)、喜树碱(camptothecin)、依托泊苷(etoposide)和多柔比星(doxorubicin)的药剂的抗性相关。此外，用这些药剂中的若干种治疗肿瘤细胞系导致GRP78蛋白的另外上调。与这些抗癌药物相比，IT-139抑制肿瘤细胞中GRP78的上调。IT-139抑制GRP78转录。这种抑制对肿瘤细胞是有选择性的，并且在应激下在肿瘤细胞中最为明显。无论是在非应激或应激条件下，IT-139对正常细胞中的GRP78水平都没有影响。由于GRP78上调是产生抗性的主要原因之一，因此预计当IT-139与其它抗癌剂组合时显示出协同作用。临床前研究表明，当IT-139与迄今为止测试的所有不同类别的抗癌药物组合使用时都具有明显的协同作用。
GRP78是热休克蛋白的Hsp70家族的成员。在正常细胞中，GRP78主要位于内质网(EndRet)中，在其中促进蛋白质的正确折叠和组装，包括穿过ER膜的易位和靶向错误折叠的蛋白以进行降解。参见西提亚,R.(Sitia,R.)和I.布拉克曼(I.Braakman)的内质网蛋白工厂的质量控制(Quality control in the endoplasmic reticulum protein factory).自然(Nature),2003.426(6968):第891-4页和徐,C.(Xu,C.)、B.贝利梅特(B.Bailly-Maitre)和J.C.雷德(J.C.Reed)的内质网应激：细胞生死决定(Endoplasmic reticulumstress:cell life and death decisions).临床研究杂志(J Clin Invest),2005.115(10):第2656-64页。正常的无应激细胞具有低水平的错误折叠蛋白并且表达低基础水平的GRP78。在应激条件下，产生更高水平的错误折叠蛋白并且激活未折叠蛋白反应(UPR)。UPR通过三种EndRet跨膜受体介导：蛋白激酶RNA类内质网激酶(PERK)、激活转录因子6(ATF6)和肌醇需要酶1(inositol-requiring enzyme；IRE1)。在无应激细胞中，所有三种ER应激分子伴侣通过GRP78的结合维持在非活性形式。参见马,Y.(Ma,Y.)和L.M.亨德肖特(L.M.Hendershot)的未折叠蛋白反应在肿瘤研发中的作用：朋友还是敌人？(The role ofthe unfolded protein response in tumour development:friend or foe？)自然癌症综述(Nat Rev Cancer),2004.4(12):第966-77页。
在应激过程中，错误折叠的蛋白数量增加，并且GRP78与其结合，释放出这些跨膜蛋白，导致下游活动的级联的开始，包括翻译衰减和ER应激靶向基因的上调。参见赖,E.(Lai,E.)、T.特奥多罗(T.Teodoro)和A.沃住客(A.Volchuk)的内质网应激：发出未折叠蛋白反应的信号。生理学(Physiology)(贝塞斯达(Bethesda)),2007.22:第193-201页。通过这些功能，GRP78是应激条件下细胞存活的主要调节因子。
体内模型显示纯合GRP78(-/-)基因敲除是胚胎致死的，而杂合GRP78(+/-)基因敲除小鼠正常发育并发挥功能。这些数据表明胚胎发生需要一些GRP78，但正常细胞可以忍受GRP78的高度下调而没有副作用。参见罗,S.(Luo,S.)等人的在早期小鼠胚胎发育期间，GRP78/BiP是细胞增殖和保护内细胞团免于凋亡所必需的(GRP78/BiP is required forcell proliferation and protecting the inner cell mass from apoptosis duringearly mouse embryonic development)。分子细胞生物学(Mol Cell Biol),2006.26(15):第5688-97页。
在肿瘤细胞中，GRP78承担关键肿瘤细胞存活和抗性因子的角色。癌细胞中的GRP78与正常细胞的不同之处在于肿瘤细胞中的GRP78水平显著高于正常应激细胞中，并且GRP78定位的模式不同于正常应激细胞的模式。与GRP78主要局限于EndRet的正常细胞不同，肿瘤细胞在细胞质、细胞核、线粒体和细胞表面中都具有显著水平的GRP78。此外，肿瘤细胞将GRP78分泌到肿瘤周围环境中。GRP78在癌细胞中的水平增加和异常定位的组合导致肿瘤细胞增殖增加，肿瘤中GRP78表达水平的升高已在多种癌症类型中有所显示，所述癌症类型包括肺癌、胃癌、乳腺癌、肝细胞癌、甲状腺癌、黑色素瘤、胶质瘤、结肠直肠癌、胰腺癌，膀胱癌和各种白血病(表1)。在这些肿瘤类型中，在源自肿瘤的细胞系中或在患者肿瘤标本中用于检测GRP78的方法是可变的，其中利用免疫组织化学(IHC)分析、用于GRP78蛋白水平的蛋白印迹分析、RNA印迹分析、或用于GRP78 mRNA水平的RT-PCR。
在肿瘤活组织检查研究中，与邻近的非癌组织相比，肿瘤细胞中的GRP78表达水平升高。
在肝细胞癌(HCC)研究中，与邻近的非癌组织相比，13个HCC组织中有11个中的GRP78 mRNA显著更高(p<0.05)[14]。此外，如通过GRP78 siRNA实验所测定，HCC细胞对索拉非尼的敏感性与GRP78的水平相关。参见邱,J.F.(Chiou,J.F.)等人的葡萄糖调节蛋白78是获得肝细胞癌中索拉非尼抗性的新贡献者(Glucose-regulated protein 78 is a novelcontributor to acquisition of resistance to sorafenib in hepatocellularcarcinoma).外科肿瘤学纪事(Ann Surg Oncol)2010.17(2):第603-12页。
在脑肿瘤中，IHC和蛋白印迹研究显示，与正常成人脑相比，GRP78在恶性神经胶质瘤标本和人恶性神经胶质瘤细胞系中显著升高。研究还表明，高GRP78水平与肿瘤细胞增殖率增加相关。参见皮科,P.(Pyrko,P.)等人的未折叠蛋白反应调节因子GRP78/BiP作为用于增加恶性胶质瘤中化学敏感性的新靶标(The unfolded protein response regulatorGRP78/BiP as a novel target for increasing chemosensitivity in malignantgliomas).癌症研究(Cancer Res)2007.67(20):第9809-16页和维尔雷,J.J.(Virrey,J.J)等人,应激伴随蛋白GRP78/BiP赋予肿瘤相关内皮细胞化学抗性(Stress chaperoneGRP78/BiP confers chemoresistance to tumor-associated endothelial cells)分子癌症研究(Mol Cancer Res)2008.6(8):第1268-75页。
在使用新鲜活组织检查分离物的黑素瘤研究中，与正常黑素细胞相比，显示黑素瘤肿瘤细胞表达升高的GRP78。此外，与培养的黑素瘤细胞系相比，通过蛋白印迹测得新鲜黑素瘤肿瘤分离物具有高达4倍的GRP78水平。参见江,C.C.(Jiang,C.C.)等人的葡萄糖调节蛋白78拮抗人黑素瘤细胞中的顺铂和阿霉素(Glucose-regulated protein 78antagonizes cisplatin and adriamycin in human melanoma cells)。癌变(Carcinogenesis),2009.30(2):第197-204页。
在乳腺癌研究中，通过IHC测得约65％的预治疗肿瘤标本表达高水平的GRP78。参见李,E.(Lee,E.)等人的GRP78作为乳腺癌化疗反应性的新预测因子(GRP78 as a novelpredictor of responsiveness to chemotherapy in breast cancer)。癌症研究(CancerRes),2006.66(16):第7849-53页。这和费尔南德斯(Fernandez)等人先前发表的报告一致，所述报告显示，与0/5良性乳腺病变相比，3/5雌激素受体阳性乳腺肿瘤和6/9雌激素受体阴性乳腺肿瘤中的GRP78 mRNA过表达1.8至20倍。参见费尔南德斯,P.M.(Fernandez,P.M.)等人的在恶性而非良性人乳腺病变中葡萄糖调节的应激基因GRP78的过度表达(Overexpression of the glucose-regulated stress gene GRP78 in malignant butnot benign human breast lesions)。乳腺癌研究治疗(Breast Cancer Res Treat),2000.59(1):第15-26页。
在一项甲状腺癌的研究中，王(Wang)等人表明，如通过实时RT-PCR和蛋白印迹评估，甲状腺癌细胞表达高基础水平的GRP78。此外，如通过GRP78 siRNA实验所测定，甲状腺癌细胞对蛋白酶体抑制的敏感性与GRP78的水平相关。王,H.Q.(Wang,H.Q.)等人的GRP78和CHOP的不同诱导作为甲状腺癌细胞中蛋白酶体抑制剂敏感性的预测因子(Differentinduction of GRP78 and CHOP as a predictor of sensitivity to proteasomeinhibitors in thyroid cancer cells)。内分泌学(Endocrinology),2007.148(7):第3258-70页。
在胃癌和结肠直肠癌中已显示肿瘤活组织检查中的高GRP78表达水平与不良存活率的相关性。参见邢,X.(Xing,X.)等人的结肠癌中葡萄糖调节蛋白78的过表达(Overexpression of glucose-regulated protein 78 in colon cancer).国际临床化学杂志(Clin Chim Acta),2006.364(1-2):第308-15页。张(Zhang)等人报道了来自86名原发性胃癌患者的活组织检查的IHC分析，证明与邻近的无肿瘤胃粘膜相比，GRP78在肿瘤细胞中过表达。参见张,J.(Zhang,J.)等人的升高的GRP78表达与胃癌患者淋巴结转移增加和不良预后的关联(Association of elevated GRP78 expression with increased lymphnode metastasis and poor prognosis in patients with gastric cancer)。临床实验癌转移(Clin Exp Metastasis),2006.23(7-8):第401-10页。肿瘤GRP78染色的强度分为阴性、弱或强。GRP78表达水平显示与中位总存活率的显著相关性，肿瘤被染色为阴性、弱或强的患者的中位存活率分别为2489、1242和432天(阴性GRP78肿瘤表达对比强GRP78肿瘤表达的总存活率p<0.001)。类似地，淋巴结中的GRP78表达与较差的总存活率相关(在淋巴结中，阴性对比任何GRP78表达的总存活率p＝0.037)。
在更近期的研究中，恒美(Tsunemi)等人通过IHC评估了GRP78表达在胃癌组织和正常胃粘膜中的定位。在正常胃粘膜中，偶尔在深部固有腺中观察到GRP78染色，但在浅表上皮中没有观察到。在胃癌组织中，GRP78在癌细胞的细胞质中以高水平表达，而不管表面的深度如何。在同一研究中，在胃癌患者和正常个体的血清中评估循环GRP78蛋白。针对重组GRP78的蛋白印迹显示来自17/60(28.3％)胃癌患者和0/20(0.0％)健康个体的血清中的反应性。参见恒美,S.(Tsunemi,S.)等人的基于蛋白组学的肿瘤相关抗原的鉴定及其在胃癌中的相应自身抗体(Proteomics-based identification of a tumor-associatedantigen and its corresponding autoantibody in gastric cancer)肿瘤学报道(OncolRep),2010.23(4):第949-56页。
根据IT-139在各种抗性肿瘤细胞系中的活性来选择IT-139，并且因此预期其靶标是影响抗性的靶标。现在已确认IT-139的主要靶标是GRP78。现在已经发现，令人惊讶的是，IT-139抑制了肿瘤细胞中GRP78的应激上调。这种作用对肿瘤细胞是特异性的，因为IT-139不影响正常细胞中的GRP78表达。在非应激和应激条件下用IT-139治疗正常细胞已经表明：1)IT-139不影响非应激正常细胞中的基础GRP78水平；和2)由于这些相同的正常细胞中的应激，IT-139不会影响GRP78的上调。因此，无论应激条件如何，相信IT-139都不会影响正常细胞中的GRP78水平。
不希望受任何特定理论的束缚，相信IT-139不是UPR的通用抑制剂，而是GRP78诱导的特异性抑制剂。GRP78诱导的主要路径是通过转录。如通过用IT-139治疗的肿瘤细胞的RNA印迹分析所见，GRP78的IT-139抑制是以剂量依赖性方式处于转录水平。在一些实施例中，本发明涵盖IT-139抑制应激诱导剂诱导GRP78这一发现。
令人惊讶地发现，IT-139不阻断UPR的其它臂，例如诱导XBP-1剪接形式、ATF6的诱导、加工和核输入，以及eIF2a的磷酸化。因此，IT-139引起ER应激和部分UPR，但抑制GRP78(UPR的生存臂)的诱导。
通过GRP78启动子研究证实了转录水平下的GRP78诱导的IT-139抑制。由于GRP78启动子含有内质网应激元件(ERSE)的多个拷贝，因此细胞中GRP78蛋白水平的调节主要通过转录控制。ERSE是应激诱导的转录因子的结合位点。已显示IT-139抑制与荧光素酶报告基因连接的GRP78启动子片段(-169至-29；含有3个ERSE)的应激诱导。
GRP78的诱导是细胞在应激条件下的存活反应。这是细胞自我修复和预防细胞凋亡的尝试。因此，当细胞受到应激/死亡时，可以看到GRP78诱导。肿瘤细胞中GRP78的IT-139抑制在应激肿瘤细胞中最为突出。体内肿瘤细胞总是经历各种应激。在体外非应激的肿瘤细胞中，IT-139在不同的肿瘤系中将GRP78水平抑制到不同的水平。
高水平的GRP78蛋白与诸如以下药剂的抗性相关：顺铂(江,C.C.等人的葡萄糖调节的蛋白78拮抗人黑色素瘤细胞中的顺铂和阿霉素癌变,2009.30(2):第197-204页)；5-FU(皮科,P.等人的未折叠蛋白反应调节因子GRP78/BiP作为用于增加恶性胶质瘤化疗敏感性的新靶标癌症研究2007.67(20):第9809-16页)；替莫唑胺(皮科,2007)；长春碱(王,J.(Wang，J.)等人的阻断GRP78使乳腺癌细胞对诱导未折叠的蛋白反应的微管-干扰剂敏感(Blockade of GRP78 sensitizes breast cancer cells to microtubules-interferingagents that induce the unfolded protein response)细胞与分子医学杂志(J CellMol Med),2009.13(9B):第3888-97页)；紫杉醇(迈达特N.M.(Mhaidat，N.M.)等人的通过下调GRP78抑制MEK使紫杉醇诱导的人结肠直肠癌细胞凋亡敏感(Inhibition of MEKsensitizes paclitaxel-induced apoptosis of human colorectal cancer cells bydownregulation of GRP78)抗癌药物(Anticancer Drugs),2009.20(7):第601-6页)；硼替佐米(科恩,J.(Kern,J.)等人的通过肿瘤细胞分泌的GRP-78阻断硼替佐米的抗血管生成活性(GRP-78 secreted by tumor cells blocks the antiangiogenic activity ofbortezomib)血液(Blood),2009.114(18):第3960-7页)；索拉非尼(邱，J.F.等人的葡萄糖调节蛋白78是获得肝细胞癌中索拉非尼抗性的新贡献者外科肿瘤学纪事2010.17(2):第603-12页)；喜树碱(雷德,R.K.等人的内质网伴随蛋白GRP78保护细胞免受拓扑异构酶抑制剂诱导的细胞凋亡：ATP结合位点在抑制卡斯蛋白酶-7激活中的作用(Endoplasmicreticulum chaperone protein GRP78 protects cells from apoptosis induced bytopoisomerase inhibitors:role of ATP binding site in suppression of caspase-7activation)生物化学杂志(J Biol Chem),2003.278(23):第20915-24页)；依托泊苷(王,Y.(Wang，Y.)等人的GRP78的下调与化疗对小细胞肺癌NCI-H446细胞中VP-16的敏感性有关(Down-regulation of GRP78 is associated with the sensitivity of chemotherapyto VP-16 in small cell lung cancer NCI-H446 cells)生物医学癌症中心(BMCCancer),2008.8:第372页)和多柔比星(江,C.C.等人的葡萄糖调节的蛋白78拮抗人黑色素瘤细胞中的顺铂和阿霉素癌变,2009.30(2):第197-204页)。此外，用这些药剂中的若干种治疗肿瘤细胞系进一步上调GRP78蛋白的水平。参见江2009和雷德2003。抗癌剂诱导的GRP78的此额外上调被认为是肿瘤细胞存活和抗性的显著决定因素。IT-139优先防止GRP78在“应激”肿瘤细胞中的诱导，此表明当与许多不同类别的抗癌剂组合使用时，IT-139将具有协同作用。
在应激诱导后产生多种GRP78转录因子，包括NF-Y、TFII-I、ATF6α和YY-1。NF-Y结合在应激和非应激GRP78转录中得以保留。TFII-I结合在应激转录中得到增强。ATF6在毒胡萝卜素(Tg)应激治疗的1小时内被裂解成ATF6α，并且仅在ER应激后产生。此复合物(ATF6α/YY1)将PRMT1与甲基化组蛋白H4、p300、GCN5和组蛋白乙酰转移酶一起募集到启动子。ATF6α通过将一系列RNA聚合酶II共调节复合物募集到ER应激反应增强子元件(至少部分地)起作用，所述RNA聚合酶II共调节复合物包括调节物和多种组蛋白乙酰转移酶的复合物(Spt-Ada-Gcn5乙酰转移酶(SAGA)和含Ada-2-A(Ada-Two-A-containing；ATAC)的复合物)。不希望受任何特定理论的束缚，我们提出IT-139抑制此POL II复合物在GRP78启动子区域上的加载。
本发明的一个实施例是IT-139的作用机制是对GRP78转录的影响。本发明的另一个实施例是IT-139抑制应激诱导的GRP78转录。GRP78的转录激活是未折叠蛋白反应的指示。UPR诱导核小体的特异性乙酰化和甲基化修饰。理论上，ERSE是介导GRP78启动子的应激诱导的最关键元件。
本发明的另一方面是治疗有需要的受试者的癌症的方法，其包含组合施用IT-139或其药学上可接受的组合物与一或多种免疫-肿瘤学治疗剂。肿瘤传播的ER应激从一开始就将BMDC印迹成一种表型，所述表型概括了归因于肿瘤浸润性骨髓细胞的几种炎症/抑制特征，突出了肿瘤UPR作为抗肿瘤免疫的关键控制因子和用于癌症中的免疫调节的新靶标(参见马哈迪温(Mahadevan)等人,PlosONe 2012年12月)。可以在内质网驻留蛋白ERp5和GRP78易位至肿瘤细胞表面时诱导慢性淋巴细胞白血病细胞将NKG2D配体MICA脱落(参见癌症免疫与免疫疗法(Cancer Immunol Immunother)(2012)61:1201)。表面LAP/TGF-β与GRP78形成复合物，并且GRP78的敲低降低了Treg上的表面LAP/TGF-β的表达水平(参见人类免疫学(Hum.Immunol)62,764-770,2001)。因此，不希望受任何理论束缚，我们认为包含IT-139和免疫肿瘤剂的组合疗法将导致比单独的免疫-肿瘤剂更有效的治疗。
2.定义：
如本文所述，短语免疫-肿瘤剂是指任何癌症免疫治疗剂，其中利用免疫系统来治疗癌症。此类药剂包括但不限于抗体、PD-1疗法、PD-L1疗法、细胞因子治疗剂和检查点抑制剂。具体实例包括但不限于纳武单抗(nivolumab)、阿仑单抗(alemtuzumab)、阿特珠单抗(atezolizumab)、伊匹单抗(ipilimumab)、奥法木单抗(ofatumumab)、帕博利珠单抗(pembrolizumab)、利妥昔单抗(rituximab)、干扰素(interferon)和白细胞介素(interleukin)。免疫-肿瘤剂的靶标包括但不限于CD52、PD-L1、CTLA4、CD20或PD-1受体。
如本文所述，短语化学治疗剂(chemotherapy agent)或化学治疗剂(chemotherapeutic agent)描述了用于治疗癌症的化学物质。此类药剂包括细胞毒素和细胞抑制药物。化学治疗剂(chemotherapy agent)或化学治疗剂(chemotherapeutic agent)也可以指抗体或单克隆抗体(MAB)。化学治疗剂的类别包括但不限于：紫杉烷、蒽环霉素、含铂药物、埃坡霉素(epothilones)、抗有丝分裂剂(anti-mitotic agents)、喜树碱(camptothecins)、叶酸衍生物(folic acid derivatives)、HDAC抑制剂、有丝分裂抑制剂、微管稳定剂、DNA嵌入剂、拓扑异构酶(topoisomerase)抑制剂或分子靶向治疗剂。短语化学治疗剂(chemotherapy agent)或化学治疗剂(chemotherapeutic agent)还可以指组合在一起以治疗癌症的一或多种化学物质。所述化学物质的一个非限制性实例可包括吉西他滨和纳米颗粒白蛋白紫杉醇。
如本文所用，术语IT-139是指反式-[四氯双(1H-吲唑)钌(III)酸]钠。IT-139也称为KP1339或NKP1339。
长春花生物碱在文献中是众所周知的并且是一组抗有丝分裂剂。长春花生物碱包括长春碱(vinblastine)、长春新碱(vincristine)、长春地辛(vindesine)和长春瑞滨(vinorelbine)，并用于防止微管形成。示例性长春花生物碱如下所示。
抗肿瘤植物生物碱喜树碱(CPT)是一种靶向DNA拓扑异构酶I的广谱抗癌剂。尽管CPT已经显示有希望的体外和体内抗肿瘤活性，但由于其疗效低并且毒性严重，因此尚未在临床上使用。在CPT类似物中，伊立替康盐酸盐(CPT-11)最近显示对结肠直肠癌、肺癌和卵巢癌具有活性。CPT-11本身是一种前药，并且在体内通过羧酸酯酶转化为7-乙基-10-羟基-CPT(称为SN-38)，这是CPT-11的生物活性代谢物。多种喜树碱衍生物正在研发中，其结构如下所示。
已经生产了若干种蒽环霉素衍生物，并且已经在临床中用于治疗白血病、霍奇金氏淋巴瘤(Hodgkin's lymphoma)以及膀胱癌、乳腺癌、胃癌、肺癌、卵巢癌、甲状腺癌和软组织肉瘤。此类蒽环霉素衍生物包括柔红霉素(daunorubicin)(也称为道诺霉素(Daunomycin)或道诺霉素柔毛霉素(daunomycin cerubidine))、多柔比星(也称为DOX，羟基柔红霉素或阿霉素(adriamycin))、表柔比星(epirubicin)(也称为艾伦斯(Ellence)或法玛新(Pharmorubicin))、伊达比星(idarubicin)(也称为4-脱甲氧基柔红霉素、善唯达(Zavedos)或艾达霉素(Idamycin))和伐柔比星(valrubicin)(也称为N-三氟乙酰基阿霉素-14-戊酸盐或瓦尔斯塔尔(Valstar))。
基于铂的治疗剂在文献中是众所周知的。铂治疗剂广泛用于肿瘤学中，并用于交联导致细胞死亡(细胞凋亡)的DNA。卡铂(Carboplatin)、吡铂(picoplatin)、顺铂和奥沙利铂(oxaliplatin)是示例性铂治疗剂，并且结构如下所示。
另外的分子靶向治疗剂也在研发中。实例包括E7016、XL765、TG101348、E7820、艾日布林(eribulin)、INK 128、TAK-385、MLN2480、TAK733、MLN-4924、莫特塞尼(motesanib)、埃沙佐米(ixazomib)、TAK-700、达克替尼(dacomitinib)和舒尼替尼(sunitinib)。每种结构如下所示。
分子靶向治疗剂的其它实例包括克唑替尼(crizotinib)、阿西替尼(axitinib)、PF 03084014、PD 0325901、PF 05212384、PF 04449913、利达利莫司(ridaforlimus)、MK-1775、MK-2206，GSK2636771、GSK525762、艾曲波帕(eltrombopag)、达瑞芬尼(dabrefenib)和弗雷替尼(foretinib)。每种结构如下所示。
分子靶向治疗剂的其它实例包括拉帕替尼(lapatinib)、帕唑帕尼(pazopanib)、CH5132799、RO4987655、RG7338、A0379、厄洛替尼(erlotinib)、皮克立西(pictilisib)、GDC-0032、维罗非尼(venurafenib)、GDC-0980、GDC-0068、arry-520、帕瑞肽(pasireotide)、多韦替尼(dovitinib)和考比替尼(cobmetinib)。每种结构如下所示。
分子靶向治疗剂的其它实例包括布帕昔布(buparlisib)、AVL-292、罗米地辛(romidepsin)、arry-797、来那度胺(lenalidomide)、沙利度胺(thalidomide)、阿普司特(apremilast)、AMG-900、AMG208、如卡帕瑞(rucaparib)、NVP-BEZ 235、AUY922、LDE225和米哚妥林(midostaurin)。每种结构如下所示。
3.示例性实施例的描述：
本发明提供了一种治疗有需要的患者的癌症的方法，其包含组合施用IT-139或其药学上可接受的组合物与化学治疗剂或免疫-肿瘤剂。
根据另一个实施例，本发明涉及一种治疗癌症的方法，所述癌症选自乳腺癌、卵巢癌、子宫颈癌、前列腺癌、睾丸癌、泌尿生殖道癌、食道癌、喉癌、成胶质细胞瘤、神经母细胞瘤、胃癌、皮肤癌、角化棘皮瘤、肺癌、表皮样癌、大细胞癌、小细胞癌、肺腺癌、骨癌、结肠癌、腺瘤、胰腺癌、腺癌、甲状腺癌、滤泡癌、未分化癌、乳头状癌、精原细胞瘤、黑色素瘤、肉瘤、膀胱癌、肝癌和胆道癌、肾癌、骨髓病症、淋巴病症、霍奇金氏病、毛细胞癌、颊腔和咽(口腔)癌、唇癌、舌癌、口腔癌、咽癌、小肠癌、结肠-直肠癌、大肠癌、直肠癌、脑癌和中枢神经系统癌和白血病，所述方法包含组合施用IT-139或其药学上可接受的组合物与化学治疗剂或免疫-肿瘤剂。
另一个实施例提供了一种通过在施用IT-139后减少癌细胞中GRP78的量来治疗癌症的方法。
根据另一个实施例，本发明提供了一种通过在组合施用IT-139与化学治疗剂或免疫-肿瘤剂后减少癌细胞中GRP78的量来治疗癌症的方法，其中与仅施用化学治疗剂或免疫-肿瘤剂相比，施用IT-139或其药学上可接受的组合物导致GRP78的量减少。
应仔细考虑治疗剂的施用顺序。不希望受任何特定理论束缚，GRP78的作用机制和下调决定了应首先施用任何化学治疗剂，然后再施用IT-139以获得最大治疗效益。如上所述，用一系列化学治疗剂治疗导致ER应激增加，其诱导GRP78的产生。此过程是细胞存活机制。IT-139的施用降低了应激诱导的GRP78的水平，此消除了细胞存活路径。最终结果是增加癌细胞死亡并且增加抗肿瘤效果。
根据本发明的一个实施例，提供了一种用于治疗有需要的患者的癌症的方法，其包含以下步骤：
1)给患者施用化学治疗剂；
2)随后给患者施用IT-139或其药学上可接受的组合物；和
3)任选地重复步骤1和2。
在某些实施例中，在化学治疗剂之后1天施用IT-139或其药学上可接受的组合物。在其它实施例中，在化学治疗剂之后1周向患者施用IT-139或其药学上可接受的组合物。在另外其它实施例中，在化学治疗剂之后1至7天之间向患者施用IT-139。
在某些实施例中，IT-139或其药学上可接受的组合物与化学治疗剂同时施用。在某些实施例中，IT-139或其药学上可接受的组合物和化学治疗剂在彼此间隔约20-28小时内，或在彼此间隔约22-26小时内，或在彼此间隔约24小时内施用。
在某些实施例中，IT-139或其药学上可接受的组合物在化学治疗剂之前施用。在某些实施例中，IT-139或其药学上可接受的组合物在化学治疗剂之前至少约8-16小时，或在化学治疗剂之前至少约10-14小时，或在化学治疗剂之前至少约12小时施用。
在某些实施例中，IT-139或其药学上可接受的组合物在化学治疗剂之前至少约20-28小时，或在化学治疗剂之前至少约22-26小时，或在化学治疗剂之前至少约24小时施用。
在某些实施例中，IT-139或其药学上可接受的组合物在化学治疗剂之前至少约44-52小时，或在化学治疗剂之前至少约46-50小时，或在化学治疗剂之前至少约48小时施用。
在某些实施例中，IT-139或其药学上可接受的组合物在化学治疗剂之前至少约64-80小时，或在化学治疗剂之前至少约70-74小时，或在化学治疗剂之前至少约72小时施用。
在某些实施例中，IT-139或其药学上可接受的组合物在化学治疗剂之前施用。在某些实施例中，IT-139或其药学上可接受的组合物在化学治疗剂之后至少约8-16小时，或在化学治疗剂之后至少约10-14小时，或在化学治疗剂之后至少约12小时施用。
在某些实施例中，IT-139或其药学上可接受的组合物在化学治疗剂之后至少约20-28小时，或在化学治疗剂之后至少约22-26小时，或在化学治疗剂之后至少约24小时施用。
在某些实施例中，IT-139或其药学上可接受的组合物在化学治疗剂之后至少约44-52小时，或在化学治疗剂之后至少约46-50小时，或在化学治疗剂之后至少约48小时施用。
在某些实施例中，IT-139或其药学上可接受的组合物在化学治疗剂之后至少约64-80小时，或在化学治疗剂之后至少约70-74小时，或在化学治疗剂之后至少约72小时施用。
在某些实施例中，化学治疗剂选自由以下组成的群组：吉西他滨、纳米颗粒白蛋白紫杉醇、紫杉醇、多西他赛、卡巴他赛、奥沙利铂、顺铂、卡铂、多柔比星、柔红霉素、索拉非尼、依维莫司和维罗非尼。在某些实施例中，化学治疗剂是吉西他滨。
根据本发明的一个实施例，提供了一种治疗有需要的患者的胰腺癌的方法，其包含以下步骤：
1)施用吉西他滨和白蛋白纳米颗粒紫杉醇；
2)随后施用IT-139或其药学上可接受的组合物；和
3)任选地重复步骤1和2。
在某些实施例中，IT-139或其药学上可接受的组合物与吉西他滨同时施用。在某些实施例中，IT-139或其药学上可接受的组合物和吉西他滨在彼此间隔约20-28小时内，或在彼此间隔约22-26小时内，或在彼此间隔约24小时内施用。
在某些实施例中，在吉西他滨之前施用IT-139或其药学上可接受的组合物。在某些实施例中，IT-139或其药学上可接受的组合物在吉西他滨之前至少约8-16小时，或在吉西他滨之前至少约10-14小时，或在吉西他滨之前至少约12小时施用。
在某些实施例中，IT-139或其药学上可接受的组合物在吉西他滨之前至少约20-28小时，或在吉西他滨之前至少约22-26小时，或在吉西他滨之前至少约24小时施用。
在某些实施例中，IT-139或其药学上可接受的组合物在吉西他滨之前至少约44-52小时，或在吉西他滨之前至少约46-50小时，或在吉西他滨之前至少约48小时施用。
根据本发明的一个实施例，提供了一种治疗有需要的患者的癌症的方法，其包含组合施用IT-139或其药学上可接受的组合物与免疫-肿瘤剂。在某些实施例中，在施用IT-139或其药学上可接受的组合物之前，将免疫-肿瘤剂施用给患者。
在某些实施例中，IT-139或其药学上可接受的组合物与免疫-肿瘤剂同时施用。在某些实施例中，IT-139或其药学上可接受的组合物和免疫-肿瘤剂在彼此间隔约20-28小时内，或在彼此间隔约22-26小时内，或在彼此间隔约24小时内施用。
在某些实施例中，IT-139或其药学上可接受的组合物在免疫-肿瘤剂之前施用。在某些实施例中，IT-139或其药学上可接受的组合物在免疫-肿瘤剂之前至少约8-16小时，或在免疫-肿瘤剂之前至少约10-14小时，或在免疫-肿瘤剂之前至少约12小时施用。
在某些实施例中，IT-139或其药学上可接受的组合物在免疫-肿瘤剂之前至少约20-28小时，或在免疫-肿瘤剂之前至少约22-26小时，或在免疫-肿瘤试剂之前至少约24小时施用。
在某些实施例中，IT-139或其药学上可接受的组合物在免疫-肿瘤剂之前至少约44-52小时，或在免疫-肿瘤剂之前至少约46-50小时，或在免疫-肿瘤剂之前至少约48小时施用。
在某些实施例中，IT-139或其药学上可接受的组合物在免疫-肿瘤剂之前至少约64-80小时，或在免疫-肿瘤剂之前至少约70-74小时，或在免疫-肿瘤剂之前至少约72小时施用。
在某些实施例中，在免疫-肿瘤剂后施用IT-139或其药学上可接受的组合物。在某些实施例中，IT-139或其药学上可接受的组合物在免疫-肿瘤剂之后至少约8-16小时，或在免疫-肿瘤剂之后至少约10-14小时，或在免疫-肿瘤剂之后至少约12小时施用。
在某些实施例中，IT-139或其药学上可接受的组合物在免疫-肿瘤剂之后至少约20-28小时，或在免疫-肿瘤剂之后至少约22-26小时，或在免疫-肿瘤剂之后至少约24小时施用。
在某些实施例中，IT-139或其药学上可接受的组合物在免疫-肿瘤剂之后至少约44-52小时，或在免疫-肿瘤剂之后至少约46-50小时，或在免疫-肿瘤剂之后至少约48小时施用。
在某些实施例中，IT-139或其药学上可接受的组合物在免疫-肿瘤剂之后至少约64-80小时，或在免疫-肿瘤剂之后至少约70-74小时，或在免疫-肿瘤剂之后至少约72小时施用。
在某些实施例中，免疫-肿瘤剂选自由以下组成的群组：细胞因子、检查点抑制剂和除PD-1抗体之外的抗体。在某些实施例中，免疫-肿瘤剂选自由以下组成的群组：干扰素、白细胞介素、PD-L1抗体、阿仑单抗，伊匹单抗、奥法木单抗、阿特珠单抗和利妥昔单抗。
根据本发明的一个实施例，提供了一种治疗有需要的患者的癌症的方法，其包含组合施用IT-139或其药学上可接受的组合物与PD-1抗体。在某些实施例中，PD-1抗体在施用IT-139或其药学上可接受的制剂之前施用。
根据本发明的一个实施例，提供了一种治疗有需要的患者的癌症的方法，其包含组合施用IT-139或其药学上可接受的组合物与PD-L1抗体。在某些实施例中，PD-L1抗体在施用IT-139或其药学上可接受的制剂之前施用。
根据本发明的一个实施例，提供了一种治疗有需要的患者的癌症的方法，其包含组合施用IT-139或其药学上可接受的组合物与除PD-1抗体之外的免疫-肿瘤剂。在某些实施例中，在施用IT-139或其药学上可接受的制剂之前施用除PD-1抗体之外的免疫-肿瘤剂。
为了可以更全面地理解本文所述的本发明，阐述了以下实例。应理解，这些实例仅出于说明性目的并且不应解释为以任何方式限制本发明。
范例
实例1.如通过ATCC所述，维持所有人原发性和转移性细胞系。将细胞接种在6孔板中，随后用仅培养基(对照)、仅IT-139(200μM)、仅毒胡萝卜素(300nM，用于诱导细胞应激)或IT-139加毒胡萝卜素治疗。在16小时时收集细胞裂解物，通过蛋白印迹分析抗-GRP78抗体，并通过GAPDH使其标准化。图1所示结果表明，IT-139对无应激细胞几乎没有影响(图1A)，而在应激细胞(IT-139加毒胡萝卜素)中用IT-139治疗则减少应激细胞中存在GRP78的量(图1B)。
实例2.如通过ATCC所述，维持所有人原发性和转移性细胞系。将细胞接种在6孔板中，随后用仅培养基(对照)、仅IT-139(200μM)、仅毒胡萝卜素(300nM，用于诱导细胞应激)或IT-139加毒胡萝卜素治疗。在24小时时收集细胞裂解物并提取总RNA。将GRP78转录物的定量实时PCR分析标准化为GAPDH。图2所示结果表明，在无应激细胞中的IT-139治疗通常对grp78 mRNA水平几乎没有影响(图2A)，而在应激细胞(IT-139加毒胡萝卜素)中用IT-139治疗则减少GRP78 mRNA的表达量(图2B)。
实例3.将CT26细胞(1百万)皮下植入具有免疫能力的小鼠体内并使其生长直至形成可触知肿瘤(第3天)。用以下4种总剂量每周治疗两次每组四只的多组小鼠：1)盐水，2)仅IT-139(KP1339,30mg/kg)，3)RPM1-14(PD-1抗体，5mg/kg)，或4)RPM1-14和IT-139(分别为5mg/kg和30mg/kg)。静脉内施用IT-139并且腹膜内施用RPM1-14。施用在同一天进行。到第18天测量肿瘤体积。根据盐水对照，用PD-1抗体治疗显示没有变化。IT-139显示出抗肿瘤活性，然而与仅PD-1抗体或仅IT-139相比，PD-1抗体和IT-139的组合显示出增加的抗肿瘤活性。图3所示的结果表明，IT-139增加了PD-1抗体的抗肿瘤功效。
实例4.根据ATCC指南，在治疗前一天接种HCT116细胞系。用IT-139(200μM)治疗后24小时，固定经治疗的细胞和未治疗的细胞以用于电子显微镜评估。如图4所示，当与未治疗细胞(图4A)相比时，用IT-139治疗的HCT116细胞(图4B)显示出显著的空泡化、ER扩大和细胞内细胞器的结构紊乱，表明ER应激。
实例5.进行染色质免疫沉淀(ChIP)测定以检查用IT-139治疗的应激和未应激细胞中的聚合酶II与Pol II和GRP78启动子区域的结合。使HCT116细胞生长至80％汇合，然后用1.5μg/mL衣霉素和200μM IT-139或DMSO治疗16小时。使用甲醛使染色质交联。用胰蛋白酶收获细胞，并对分离的细胞核进行超声处理，以得到200-1000bp之间的片段。将等量的染色质与抗Pol II抗体一起孵育过夜，然后用Staph A细胞下拉(pull down)。逆转交联并使用得自西格玛(Sigma)的GeneElute PCR cleanup试剂盒纯化DNA。对纯化的DNA和输入样品进行30个PCR循环，其使用扩增Grp78和Pol II的启动子区的引物。产物在4％琼脂糖凝胶上跑胶并用溴化乙锭染色使其可视化。在非应激细胞中，IT-139对聚合酶II与Pol II启动子的结合具有最小影响，但在Tu应激细胞中将此结合降低至40％。引人注目的是，在非应激细胞和Tu应激细胞中，IT-139将聚合酶II与Grp78启动子的结合降至零。这些结果显示在图5A-C中。
实例6.进行免疫组织化学分析以分析与盐水治疗的肿瘤相比，用IT-139以30mg/kg(q4d)治疗的HT-29异种移植肿瘤中GRP78的表达。与经过IT-139治疗的肿瘤中的非常弱的染色(图6B)相比，在盐水治疗的肿瘤中观察到GRP78的强免疫染色(图6A)。这些结果表明IT-139抑制GRP78的体内表达。
实例7.正常人胚胎肾293T细胞未被应激(用正常培养基治疗)或被应激(用300nMEndRet应激和GRP78诱导剂毒胡萝卜素治疗)。细胞培养物不用药物(对照)或200μM IT-139治疗。通过蛋白印迹测定GRP78水平；β-肌动蛋白是加载对照。结果如图7所示。
实例8.前列腺癌LnCaP-FGC细胞未被治疗(仅DMSO对照)或用300nM毒胡萝卜素(Tg)治疗。将细胞与指定浓度的IT-139一起孵育，并对细胞裂解物进行RNA印迹分析。β-肌动蛋白是加载对照。图显示了RNA印迹。对条带进行定量，并且条形图显示相对于β-肌动蛋白加载对照标准化的GRP78 mRNA水平的相对水平。如通过用IT-139治疗的肿瘤细胞的RNA印迹分析所见，GRP78的IT-139抑制以剂量依赖性方式处于转录水平。结果如图8所示。
实例9.如通过ATCC所述，维持所有人原发性和转移性细胞系。在仅用IT-139治疗之前24小时，将所有细胞系(HCT116、HT-29、LNCaP、A549和A375)接种在6个孔板中。所有细胞系均用30μM、50μM、100μM和200μM治疗，但具有以下例外：对于HCT116和HT29细胞系，分别省略用30μM和200μM的治疗。用药物孵育24小时后，对细胞进行胰蛋白酶化并再悬浮于温PBS中，并在37C下在黑暗中用JC-1染料染色30分钟。然后洗涤细胞并再悬浮于温PBS中。通过流式细胞术分析，通过在488nm激发染料并通过其在530nm处的发射检测JC-1单体来测量JC-1染料的荧光，其中在580nm下测量JC-1的聚集体。用50μM抗霉素A治疗的所有细胞系作为阳性对照。结果显示HCT116和HT29细胞系在较低浓度(分别为50μM和30μM)的IT-139下显示出线粒体电位损失的增加。然而，前列腺(LNCaP)、肺(A549)和黑素瘤(A375)细胞在高浓度的IT-139下显示线粒体去极化的增加。数据如图9所示。
实例10.如通过ATCC所述，维持前列腺癌细胞系MiaPaca2。与用增加浓度的IT-139(50、100和200μM)治疗24小时的正常外周血单核细胞(PBMC)共培养的MiaPaca2细胞未显示对细胞活力的任何影响，如图10所示。MiaPaca2细胞未经过治疗或用IT-139(100μM)预治疗，并与不同剂量的IL-2激活PBMC共培养。使用6000IU的IL-2激活PBMC 24小时。IT-139显示与激活PBMC共培养的MiaPaca2细胞中细胞死亡的增加，如图11所示。
实例11.组合IT-139和吉西他滨(GEM)治疗延长了ASPC小鼠模型的中位存活率和总存活率。同样，在48小时时在体外ASPC-1细胞中组合给药吉西他滨与IT-139导致当首先给药IT-139时的存活率的显著变化。体外ASPC20细胞用以下治疗48小时：DMSO(对照)；150μM IT-139；5μM吉西他滨；150μM IT-139和5μM吉西他滨同时给药；5μM吉西他滨持续24小时，随后150μM IT-139；或150μM IT-139，随后5μM吉西他滨持续24小时。收获细胞并通过台盼蓝计数以计算死细胞相对于活细胞的数量。在ASPC20细胞中，用于与IT-139组合诱导应激的毒胡萝卜素(Tg)的给药顺序影响30小时时GRP78表达的水平。结果显示在图12中。此外，给药顺序也影响细胞死亡的量，因为当IT-139在吉西他滨之前给药时观察到细胞死亡增加。结果显示在图13中。用以下物质在体外对PANC-1细胞治疗48小时：DMSO(对照)；150μM IT-139；5μM吉西他滨；150μM IT-139和5μM吉西他滨同时给药；5μM吉西他滨持续24小时，随后150μM IT-139；和150μM IT-139，随后5μM吉西他滨持续24小时，DMSO(对照)；150μM IT-139；5μM吉西他滨；150μM IT-139和5μM吉西他滨同时给药；5μM吉西他滨持续24小时，随后150μM IT-139；和150μM IT-139，随后5μM吉西他滨持续24小时。结果显示在图14中。在PANC-1细胞中，48小时时的细胞毒性效应表明没有依赖于吉西他滨和IT-139的给药顺序的差异。
实例12.在A20淋巴瘤小鼠模型中，在小鼠右腹对104Balb/c小鼠皮下接种淋巴瘤A20细胞。当肿瘤达到80-120mm3的平均体积时，将小鼠随机分成8组，每组10只小鼠。每天监测小鼠的行为和存活，并且每周两次监测体重和肿瘤生长。通过将含有基质胶(50:50，v:v，参考：356237，碧迪生物科学公司(BD Biosciences)，法国(France))的200μL RPMI 1640培养基中的5x106个A20细胞皮下注入一百零四(104)只Balb/C小鼠右腹来诱导肿瘤。检查点抑制剂是抗-PD-L1(克隆10F.9G2；参考：Bioxcell同种型大鼠IgG2b)和抗-CTLA4抗体(克隆9H10；参考：BE0131，bioxcell；同种型仓鼠IgG1)，两者均每3天以10mg/kg腹膜内给药。IT-139每4天静脉注射30mg/kg。剂量时间表如下表1所示。实验过程中的平均肿瘤体积显示在图15中。收集来自每组的5个肿瘤用于FACS分析(40个肿瘤样品)。一组为Treg和T效应细胞(CD45、CD3、CD4、CD8和FoxP3)运行，一组为MDSC(CD45、CD3、CD11b、Gr-1、Ly-6g、Ly-6C、Arg1、NOS2)运行，和一组用于肿瘤相关巨噬细胞(CD54、CD11b、Gr-1、CD68、CD80和CD206)。当在IT-139施用之前24小时给药PD-L1时，存在显著的抗肿瘤功效和肿瘤的效应T细胞浸润的10％增加，如图16和图17所示。在任何其它组中都没有看到这种效果。随着这个组合组中肿瘤生长的减少，存在抗PD-L1抗体的免疫调节效果的证据。
表1.A20免疫疗法研究设计和分组
虽然我们已经描述了本发明的许多实施例，但显而易知，可以改变我们的基础实例以提供利用本发明的化合物和方法的其它实施例。因此，应了解，本发明的范围应该由所附权利要求书而不是举例表示的特定实施例来限定。
Claims (22)
1.一种用于治疗有需要的患者的癌症的方法，其包含组合施用IT-139或其药学上可接受的组合物与除PD-1抗体之外的化学治疗剂或免疫-肿瘤剂。
2.根据权利要求1所述的方法，其中所述IT-139或其药学上可接受的组合物与所述化学治疗剂组合施用。
3.根据权利要求1所述的方法，其中所述IT-139或其药学上可接受的组合物与所述免疫-肿瘤剂组合施用。
4.根据权利要求1、2或3中任一权利要求所述的方法，其中在将所述化学治疗剂或所述免疫-肿瘤剂施用给所述患者后，将所述IT-139或其药学上可接受的组合物施用给所述患者。
5.根据权利要求1或2中任一权利要求所述的方法，其中所述化学治疗剂选自由以下组成的群组：吉西他滨、纳米颗粒白蛋白紫杉醇、紫杉醇、多西他赛、卡巴他赛、奥沙利铂、顺铂、卡铂、多柔比星、柔红霉素、索拉非尼、依维莫司和维罗非尼。
6.根据权利要求1、3或4中任一权利要求所述的方法，其中所述免疫-肿瘤剂选自由以下组成的群组：细胞因子、检查点抑制剂和非PD-1抗体的抗体。
7.根据权利要求1、3或4中任一权利要求所述的方法，其中所述免疫-肿瘤剂选自由以下组成的群组：干扰素、白细胞介素、PD-L1抗体、阿仑单抗、伊匹单抗、帕博利珠单抗(pembrolizumab)、奥法木单抗、阿特珠单抗和利妥昔单抗。
8.根据权利要求1、2、3、4、5、6或7中任一权利要求所述的方法，其中所述癌症选自选自乳腺癌、卵巢癌、子宫颈癌、前列腺癌、睾丸癌、泌尿生殖道癌、食道癌、喉癌、成胶质细胞瘤、神经母细胞瘤、胃癌、皮肤癌、角化棘皮瘤、肺癌、表皮样癌、大细胞癌、小细胞癌、肺腺癌、骨癌、结肠癌、腺瘤、胰腺癌、腺癌、甲状腺癌、滤泡癌、未分化癌、乳头状癌、精原细胞瘤、黑色素瘤、肉瘤、膀胱癌、肝癌和胆道癌、肾癌、骨髓病症、淋巴病症、霍奇金氏病、毛细胞癌、颊腔和咽(口腔)癌、唇癌、舌癌、口腔癌、咽癌、小肠癌、结肠-直肠癌、大肠癌、直肠癌、脑癌和中枢神经系统癌和白血病。
9.根据权利要求1、2、3、4、5、6或7中任一权利要求所述的方法，其中与施用单独的所述化学治疗剂或单独的所述免疫-肿瘤剂相比，IT-139或其药学上可接受的组合物的所述施用导致GRP78的量减少。
10.根据权利要求8所述的方法，其中所述癌症是胰腺癌。
11.根据权利要求8所述的方法，其中所述癌症是神经内分泌癌。
12.根据权利要求2所述的方法，其中所述化学治疗剂是吉西他滨。
13.根据权利要求12所述的方法，其中所述IT-139或其药学上可接受的组合物与所述吉西他滨同时施用给所述患者。
14.根据权利要求12所述的方法，其中所述IT-139或其药学上可接受的组合物和所述吉西他滨彼此间隔约24小时内施用给所述患者。
15.根据权利要求12所述的方法，其中在将所述吉西他滨施用给所述患者之前，将所述IT-139或其药学上可接受的组合物施用给所述患者。
16.根据权利要求12所述的方法，其中在将所述吉西他滨施用给所述患者之前至少约12小时，将所述IT-139或其药学上可接受的组合物施用给所述患者。
17.根据权利要求12所述的方法，其中在将所述吉西他滨施用给所述患者之前至少约24小时，将所述IT-139或其药学上可接受的组合物施用给所述患者。
18.根据权利要求12所述的方法，其中在将所述吉西他滨施用给所述患者之前至少约48小时，将所述IT-139或其药学上可接受的组合物施用给所述患者。
19.根据权利要求3所述的方法，其中在将所述免疫-肿瘤剂施用给所述患者之前，将所述IT-139或其药学上可接受的组合物施用给所述患者。
20.根据权利要求3所述的方法，其中在将所述免疫-肿瘤剂施用给所述患者之前至少约12小时，将所述IT-139或其药学上可接受的组合物施用给所述患者。
21.根据权利要求3所述的方法，其中在将所述免疫肿-瘤剂施用给所述患者之前至少约24小时，将所述IT-139或其药学上可接受的组合物施用给所述患者。
22.根据权利要求3所述的方法，其中在将所述免疫-肿瘤剂施用给所述患者之前至少约48小时，将所述IT-139或其药学上可接受的组合物施用给所述患者。
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