CN110114057A - Tlr9激动剂对癌症治疗的免疫调节作用 - Google Patents
Tlr9激动剂对癌症治疗的免疫调节作用 Download PDFInfo
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Abstract
本发明涉及用TLR9激动剂与免疫检查点抑制剂疗法的组合治疗肿瘤(包括转移瘤)的方法。
Description
优先权
本申请要求2016年9月15日提交的美国临时申请号62/394,845,和2017年4月18日提交的美国临时申请号62/486,738的优先权和权益,其各自通过引用以其整体并入本文。
领域
本发明涉及肿瘤学领域,和免疫疗法在治疗癌症中的应用。
背景
Toll-样受体(TLR)存在于免疫系统的许多细胞上并参与先天免疫反应。在脊椎动物中,这个家族由11种称为TLR1-TLR11的蛋白质组成,它们识别细菌、真菌、寄生虫和病毒的病原体相关分子模式。TLR是脊椎动物识别外来分子和增强对外来分子的免疫反应的关键机制,并且还提供先天和适应性免疫反应之间的联系。一些TLR位于细胞表面上以检测和启动对细胞外病原体的反应,而其他TLR位于细胞内以检测和启动对细胞内病原体的反应。
TLR9识别细菌DNA和合成寡核苷酸中未甲基化的CpG基序。虽然TLR9的激动剂和其他TLR激动剂可以启动抗肿瘤免疫反应,但TLR激动剂也能诱导免疫抑制因子,这可能对有效的肿瘤反应起反作用。
需要癌症免疫疗法,其诱导抗肿瘤反应,并保持免疫系统有效参与提高整体反应。
概述
在各个方面,本发明提供一种治疗肿瘤(包括但不限于转移性黑素瘤)的方法,该方法包括瘤内给予癌症患者寡核苷酸TLR9激动剂(如,IMO-2125或本文描述的其他免疫刺激寡核苷酸)与使用免疫检查点抑制剂疗法(如靶向CTLA-4、PD-1/PD-L1/PD-L2、TIM3、LAG3和/或IDO的疗法)的免疫疗法的组合。在瘤内注射时,TLR9激动剂诱导检查点基因(包括IDO1、PDL1、PD1、IDO2、CEACAM1、OX40、TIM3、LAG3、CTLA4和OX40L)的表达的整体增加。通过改变肿瘤微环境中的免疫信号传导,这样的基因表达的改变为提高对检查点抑制剂疗法的反应性(在一些实施方案中包括完全反应)提供了机会。本发明还提供用抑制性信号平衡抗肿瘤反应的机会,从而还最大限度地减少检查点抑制剂疗法的免疫相关的不良事件(irAE)。
在各种实施方案中,患者罹患以前对检查点抑制剂疗法(例如抗-CTLA-4、抗-PD-1,或抗-PD-L1和/或抗-PD-L2药物)没有反应,或对检查点抑制剂疗法已产生抗药性的癌症。本发明发现了用于治疗原发性癌症或转移性癌症,包括源自皮肤、结肠、乳腺或前列腺以及其他组织的癌症的用途。在一些实施方案中,癌症是进行性、局部晚期或者转移性癌。在一些实施方案中,癌症是转移性黑素瘤。
根据本发明的实施方案,瘤内给予免疫刺激寡核苷酸(如,IMO-2125)。瘤内给药改变肿瘤微环境中的免疫信号传导,为有效的抗肿瘤反应启动免疫系统,同时诱导与更有效的检查点抑制剂疗法相一致的变化。例如,TLR9激动剂(如,IMO-2125)可以每剂量从约4 mg到约64 mg瘤内给予,在10-12周内给予约3到约12个剂量。例如,疗法可以以3-5个每周剂量的IMO-2125开始,任选地接着3-8个大约每3周给予的维持剂量。
在IMO-2125 (或其他TLR9激动剂)的方案期间,给予一种或多种检查点抑制剂疗法以利用免疫信号传导的变化。在一些实施方案中,患者接受抗-CTLA-4药物(如,伊匹单抗(ipilimumab)或tremelimumab)和/或抗-PD-1药物(如,纳武单抗(nivolumab)或派姆单抗(pembrolizumab))。免疫检查点抑制剂可胃肠外给予,例如,在一些实施方案中可经皮下、瘤内、静脉内给予。例如,在各个实施方案中,免疫检查点抑制剂以从约1 mg/kg到约5 mg/kg的剂量经静脉内给予。免疫检查点抑制剂的初始剂量可在初始TLR9激动剂剂量后至少1周,例如在约第2、3或4周给予。在一些实施方案中,免疫疗法药物给予约2-约6次(例如,约4次,优选每3周)。
在一些实施方案中,将IMO-2125瘤内给予转移性黑素瘤患者,该患者先前已被发现对PD-1阻断疗法无反应或仅有部分反应。例如,IMO-2125以每剂量4-32 mg的剂量在第1、2、3、5、8和11周给予,并以3 mg/kg i.v.给予伊匹单抗。伊匹单抗可在第2周开始,每3周给予。或者,派姆单抗可在第2周开始,每3周i.v.给予2 mg/kg。
在各种实施方案中,本方法允许一种强有力的抗肿瘤免疫反应(其在某些实施方案中是完全反应),而这种免疫反应并不是以严重的副作用为代价的,例如相对于在没有TLR9激动剂的情况下使用一种或多种免疫疗法时所观察到的副作用。这样的副作用包括常见的影响各种组织和器官(包括皮肤、胃肠道、肾脏、外周和中枢神经系统、肝脏、淋巴结、眼睛、胰腺和内分泌系统)的免疫相关不良事件,如下垂体炎、结肠炎、肝炎、肺炎、皮疹和风湿病(以及其他)。
其他方面和实施方案将从以下详细描述中清楚地显示。
附图简述
图1显示用IMO-2125单一疗法在CT26.CL25肿瘤模型中肿瘤生长的减少。显示了治疗的肿瘤和远处肿瘤的肿瘤体积。
图2显示,在小图A中,来自图1所示实验的第28天的肿瘤结节中的肿瘤浸润淋巴细胞。放大倍数为x 400。在小图B中,FACS数据显示使用IMO-2125单一疗法(0.5 mg/kg)的CD8+ T细胞肿瘤浸润。
图3显示证实特异性细胞毒性T细胞对肿瘤抗原的反应的分析。
图4显示,在小图A中,评估肿瘤内IMO-2125抗肿瘤活性与浸润CD4+和CD8+ T细胞的关系的研究设计。小图B显示CD4+和CD8+ T细胞耗尽在治疗的肿瘤和远处肿瘤中的影响。
图5显示,在小图A中,评估经瘤内IMO-2125治疗诱导的抗肿瘤反应的持续时间和特异性的研究设计。小图B显示用CT26或A20和瘤内IMO-2125再攻击的小鼠的肿瘤生长。
图6显示在A20模型中比较瘤内和皮下给药的肿瘤研究。小图A显示研究设计和肿瘤动力学,而小图B显示肿瘤-浸润性淋巴细胞(TIL)的存在和各种检查点基因的基因表达变化。
图7显示,在小图A中,评估瘤内IMO-2125与抗-CTLA-4 mAb组合对治疗的肿瘤及全身肺转移的抗肿瘤活性的研究设计。图7,小图B显示瘤内IMO-2125和抗-CTLA-4 mAb单独或组合的抗-肿瘤作用。
图8显示IMO-2125和抗-CTLA-4 mAb单独或组合对全身肺转移的抗-肿瘤活性。小图A显示各个治疗组中肺肿瘤结节的数量,而小图B显示各个治疗组的肿瘤图像(肿瘤植入后第13天拍摄的照片)。
图9显示各个治疗组中转移性结节中的TIL (CD3 IHC染色 x 400)。
图10显示瘤内IMO-2125与抗-PD-1 mAb组合在CT26结肠癌肿瘤模型中的抗肿瘤活性的评估。小图A显示了研究设计。小图B显示所述组合对治疗部位和远处部位的肿瘤生长动力学的影响。小图C显示所述组合对TIL的影响(放大显示)。小图D显示在用所述组合治疗后,在治疗部位和远处部位的检查点基因表达。
图11显示在B16黑素瘤模型中,瘤内IMO-2125与抗-PD-1 mAb组合对治疗的肿瘤及全身肺转移的抗肿瘤活性的评估。小图A显示了研究设计。小图B显示所述组合对治疗部位的肿瘤生长动力学的影响。小图C显示所述组合对肺转移的影响。小图D显示转移性肺肿瘤的组织病理学(圆圈:大肿瘤结节,箭头:小肿瘤结节,插图:HE染色(x 40),和大图:CD3染色(x 400))。
图12显示评估瘤内IMO-2125与IDO-1抑制剂组合对治疗的肿瘤及全身肺转移的抗肿瘤活性的研究设计。
图13显示瘤内IMO-2125抗-肿瘤活性通过与IDO-1抑制剂共同治疗得到加强。小图A显示在各个治疗组中的肺肿瘤结节数目。小图B显示在治疗方案期间,肿瘤体积在各个治疗组中的变化。
图14提供在成人研究群体中的给药概览,所述成人群体具有用≥12周的PD-1-导向疗法(单独或组合)有进展的无法切除的黑素瘤或转移性黑素瘤。
图15显示对患者003给药前和经i.t. IMO-2125注射(4 mg剂量的IMO-2125)后24小时的树突状细胞成熟结果(小图A);且显示在注射的肿瘤和远处肿瘤中的T-细胞活化结果(小图B)。
图16显示对患者003 (4 mg IMO-2125),远处病变中的顶端细胞克隆的扩增和IFN-γ的诱导。
图17显示对于患者004 (8 mg 2125)治疗前后的肿瘤成像。
详细描述
在各个方面,本发明提供一种治疗肿瘤,例如转移性肿瘤(包括但不限于转移性黑素瘤)的方法,其包括瘤内给予癌症患者寡核苷酸TLR9激动剂(如,IMO-2125)与使用免疫检查点抑制剂疗法,如靶向CTLA-4、PD-1/PD-L1/PD-L2、LAG3、TIM3和/或IDO的疗法的免疫疗法的组合。
示例性免疫检查点抑制剂包括抗-PD-1、抗-PD-L1、抗-PD-L2和抗-CTLA-4药物。PD-1/PD-L1/PD-L2抗体抑制肿瘤细胞上PD-1及其配体(PD-L1和PD-L2)之间的相互作用,以促进免疫-介导的肿瘤破坏。CTLA-4抗体阻断由CTLA-4传导至T-细胞的抑制信号。虽然PD-1抗体和CTLA-4抗体已作为各种癌症的重要治疗选择而出现,但许多患者没有反应。例如,在12周的治疗后,一些黑素瘤患者对抗-PD-1治疗没有反应,或者甚至进展。此外,免疫检查点阻断与各种免疫-相关的不良事件相关,其可影响各种组织和器官,包括皮肤、胃肠道、肾脏、外周和中枢神经系统、肝脏、淋巴结、眼睛、胰腺和内分泌系统。这些免疫-相关的不良事件(irAE)可能是严重的,或者甚至是致命的,可能需要停止治疗。常见irAE的例子有下垂体炎、结肠炎、肝炎、肺炎、皮疹和风湿病。
免疫系统的细胞上各种免疫检查点分子的表达诱导一系列复杂的事件,这些事件决定了免疫反应是否有效地对抗肿瘤,或者是否以其他方式导致免疫耐受。例如,树突状细胞(DC)上PD-1表达的增加促进活化DC (抗肿瘤免疫反应的关键抗原呈递细胞)的凋亡。Park SJ, 诱导型PD-1对活化树突状细胞存活的负面作用(Negative role of induciblePD-1 on survival of activated dendritic cells), J. Leukocyte Biology 95(4):621-629 (2014)。此外,IDO、PD-L1和CTLA-4在黑素瘤患者的外周血中的表达可能与晚期疾病和负面结果相关,且相互关联,提示在某些情况下,多个免疫检查点可能需要靶向来改善治疗。Chevolet I, et al., 黑素瘤中循环免疫细胞中的IDO、色氨酸代谢、PD-L1和CTLA-4的体内免疫网络的特征鉴定(Characterization of the in vivo immune networks ofIDO, tryptophan metabolism, PD-L1, and CTLA-4 in circulating immune cells inmelanoma), Oncoimmunology 4(3) e982382-7 (2015)。
称为IMO-2125的TLR9激动剂,其在本文有更全面描述,在瘤内注射时导致检查点基因表达的整体增加,包括IDO1 (5.3倍)、PDL1 (2.6倍)、PD1 (2.5倍)、IDO2 (5.9倍)、CEACAM1 (2.1倍)、OX40 (1.4倍)、TIM3 (2.9倍)、LAG3 (1.9倍)、CTLA4 (1.8倍)和OX40L(1.5倍),见图6B。通过改变肿瘤微环境中的免疫信号传导,这样的基因表达的改变为提高检查点抑制剂疗法的反应性和获得持久的抗肿瘤免疫力提供了机会。此外,通过靶向从PD-1或CTLA-4的较强抑制信号中选择的单个免疫检查点分子,结合抗原呈递细胞(如,DC)的稳健激活和IMO-2125对T细胞的启动作用,本发明提供了用抑制性信号平衡抗肿瘤反应的机会,从而使检查点抑制剂疗法的irAE最小化。
在各个实施方案中,患者患有以前对检查点抑制剂疗法无反应,或对其产生抗药性的癌症。例如,癌症可能对免疫疗法是难治性的,或者对免疫疗法没有足够的反应,所述免疫疗法例如抗-CTLA-4、抗-PD-1,或抗-PD-L1和/或PD-L2药物,包括例如,伊匹单抗、tremelimumab、派姆单抗和纳武单抗的一种或多种。在各个实施方案中,癌症患者在使用抗-CTLA-4、抗-PD-1,或抗-PD-L1和/或PD-L2药物,包括例如,伊匹单抗、tremelimumab、派姆单抗和纳武单抗(或其相关的药物)的一种或多种治疗后或在治疗过程中已进展,或者显示对这样的治疗没有反应至少约12周。
其他免疫检查点抑制剂可单独(如代替)或与抗-CTLA4或抗-PD-1/抗-PD-L1组合给予,例如IDO (如,IDO-1或IDO-2)、LAG3、TIM3等的抑制剂。这些和其他免疫检查点抑制剂在US 2016-0101128中有描述,其通过引用以其整体并入本文。例如,患者还可接受IDO-1抑制剂例如Epacadostat的治疗方案。
在各个实施方案中,癌症是原发性癌症或转移性癌症。原发性癌症指在临床上可以检测到的原发部位的癌细胞,且可能是原发性肿瘤。“转移”是指癌症从原发部位扩散到身体的其他地方。癌细胞可以从原发性肿瘤中脱离,渗透到淋巴管和血管中,通过血流循环,并在身体其他地方的正常组织中以远处病灶生长(转移)。转移可以是局部的或远处的。
癌症可能来源于任何组织。癌症可能来源于皮肤、结肠、乳腺或前列腺,因此可能由原来分别为皮肤、结肠、乳腺或前列腺的细胞组成。癌症也可能是血液恶性肿瘤,其可能是淋巴瘤。在各个实施方案中,原发性或转移性癌症是肺癌、肾癌、前列腺癌、子宫颈癌、结肠直肠癌、胰腺癌、卵巢癌、尿路上皮癌、胃癌/GEJ癌、头颈部癌、胶质母细胞瘤、Merkel细胞癌、头颈部鳞状细胞癌(HNSCC)、非小细胞肺癌(NSCLC)、小细胞肺癌(SCLC)、膀胱癌、前列腺癌(如激素难治性)和血液恶性肿瘤。
在一些实施方案中,癌症是进行性、局部晚期或转移性癌。在一些实施方案中,癌症是转移性黑素瘤,并可能是复发性的。在一些实施方案中,转移性黑素瘤处于III或IV期,并可能是IVA、IVB或IVC期。转移可能是区域性的或远处的。
IMO-2125和相关免疫刺激寡核苷酸靶向TLR9,并用作TLR9激动剂以改变肿瘤微环境中的免疫信号传导,并诱导抗-肿瘤T细胞反应。
根据各个实施方案,TLR9激动剂包含至少2个通过其3'端连接在一起的寡核苷酸,以致有多个可获得的5'端。组分寡核苷酸3'端的连键与其他寡核苷酸连键无关,并可直接通过3'或2'羟基,或间接地通过非核苷酸接头或核苷(利用核苷的2'或3'羟基位置)。连键还可以使用3'末端核苷酸的官能化的糖或核碱基。示例性TLR9激动剂在美国专利号8,420,615、7,566,702、7,498,425、7,498,426、7,405,285、7,427,405中有描述,包括各自的表1和2A-2D,其全部内容通过引用以其整体并入本文。
在各个实施方案中,TLR激动剂选自:
5'-TCTGACG1TTCT-X-TCTTG1CAGTCT-5' (SEQ ID NO:1)
5'-TCTGTCG1TTCT-X-TCTTG1CTGTCT-5' (SEQ ID NO:2)
5'-TCG1TCG1TTCTG-X-GTCTTG1CTG1CT-5' (SEQ ID NO:3)
5'-TCG1AACG1TTCG1-X-G1CTTG1CAAG1CT-5' (SEQ ID NO:4)
5'-CTGTCoG2TTCTC-X-CTCTTG2oCTGTC-5' (SEQ ID NO:5)
5'-CTGTCG2TTCTCo-X-oCTCTTG2CTGTC-5' (SEQ ID NO:6)
5'-TCG1AACG1TTCG1-X-TCTTG2CTGTCT-5' (SEQ ID NO:7)
5'-TCG1AACG1TTCG1-Y-GACAG1CTGTCT-5' (SEQ ID NO:8)
5'-CAGTCG2TTCAG-X-GACTTG2CTGAC-5' (SEQ ID NO:9)
5'-CAGTCG1TTCAG-X-GACTTG1CTGAC-5' (SEQ ID NO:10)
5'-TCG1AACG1TTCoG-Z-GoCTTG1CAAG1CT-5' (SEQ ID NO:11)
5'-TCG1AACG1TTCG1-Y2-TCTTG1CTGTCTTG1CT-5' (SEQ ID NO:12)
5'-TCG1AACG1TTCG1-Y2-TCTTG1CTGUCT-5' (SEQ ID NO:13)
5'-TCG1AACG1ToTCoG-m-GoCToTG1CAAG1CT-5' (SEQ ID NO:14)
5'-TCG1AACG1TTCoG-Y3-GACTTG2CTGAC-5' (SEQ ID NO:15)
5'-TCG1AACG1TTCG1-Y4-TGTTG1CTGTCTTG1CT-5' (SEQ ID NO:16)
5'-TCG2TCG2TTU1Y-M-YU1TTG2CTG2CT-5' (SEQ ID NO:17)
5'-CAGTCG2TTCAG-Y3-TCTTG1CTGTCT-5' (SEQ ID NO:18)
5'-TCG1TACG1TACG1-X-G1CATG1CATG1CT-5' (SEQ ID NO:19)
5'-TCG1AACG1TTCG-Z-GCTTG1CAAG1CT-5' (SEQ ID NO:20)
5'-TCG1AACG1TTCoG-Y3-CTTG2CTGACTTG1CT-5' (SEQ ID NO:21)
5'-TCG1AACG1oTTCG1-X2-G1CTToG1CAAG1CT-5' (SEQ ID NO:22)
5'-TCG1AACG1TTCG1-Y4-CATTG1CTGTCTTG1CT-5' (SEQ ID NO:23)
5'-TCG1AACG1TTCG1-m-G1CTTG1CAAG1CT-5' (SEQ ID NO:24)
5'-TCoG1oAACoG1TTCoG1o-X2-oG1oCTTG1oCAAoG1oCT-5' (SEQ ID NO:25)
5'-ToCG1oAACoG1TTCoG1o-X2-oG1oCTTG1oCAAoG1CoT-5' (SEQ ID NO:26)
5'-TCoG1oAACoG1TTCoG1o-m-oG1oCTTG1oCAAoG1oCT-5' (SEQ ID NO:27)
5'-TCoG2oAACoG2TTCoG2o-X2-oG2oCTTG2oCAAoG2oCT-5' (SEQ ID NO:28)
5'-TCoG1oAACoG1TTCoGo-Z-oGoCTTG1oCAAoG1oCT-5' (SEQ ID NO:29)和
5'-ToCG1oAACoG1TTCoGo-Z-oGoCTTG1oCAAoG1CoT-5' (SEQ ID NO:30),
其中G1是2'-脱氧-7-脱氮鸟苷;G2是2'-脱氧-阿糖鸟苷;G、C或U是2'-O-甲基核糖核苷酸;U1是2'-脱氧-U;o是磷酸二酯键;X是甘油接头;X2是异丁烷三醇接头,Y是C3-接头;m是顺式,反式-1,3,5-环己三醇接头;Y2是1,3-丙二醇接头;Y3是1,4-丁二醇接头;Y4是1,5-戊二醇接头;Z是1,3,5-戊三醇接头;和M是顺式,顺式-1,3,5-环己三醇接头。
在各个实施方案中,TLR9激动剂选自5'-TCG1AACG1TTCG1-X-G1CTTG1CAAG1CT-5'(SEQ ID NO:4), 5'-CTGTCoG2TTCTC-X-CTCTTG2oCTGTC-5' (SEQ ID NO:5), 5'-CTGTCG2TTCTCo-X-oCTCTTG2CTGTC-5' (SEQ ID NO:6), 5'-TCG1AACG1TTCG1-Y-TCTTG2CTGTCT-5' (SEQ ID NO:7),和5'-TCG1AACG1TTCG1-Y-GACAG1CTGTCT-5' (SEQ ID NO:8),其中X是甘油接头,Y是C3-接头,G1是2′-脱氧-7-脱氮鸟苷,G2是阿糖鸟苷,和o是磷酸二酯键。
在各个实施方案中,TLR9激动剂是5'-TCG1AACG1TTCG1-X-G1CTTG1CAAG1CT-5' (SEQID NO:4),其中X是甘油接头和G1是2′-脱氧-7-脱氮鸟苷,也称为IMO-2125。
可供选择的TLR9激动剂是在US 8,871,732中公开的免疫刺激寡核苷酸,其通过引用以其整体并入本文。这样的激动剂包含至少8个核苷酸的回文序列和至少一个CG二核苷酸。
根据本发明的实施方案,免疫刺激寡核苷酸(如,IMO-2125)经瘤内给予。在一些实施方案中,瘤内给予是在原发性或继发性肿瘤(如,转移性黑素瘤病变)内进行。瘤内给予改变肿瘤微环境中的免疫信号传导,为有效的抗-肿瘤反应启动免疫系统,同时诱导与更有效的检查点抑制剂疗法相一致的变化。
适合于瘤内给予的示例性剂型包括溶液、混悬液、分散液、乳液等。TLR9激动剂可以无菌固体组合物(如冻干组合物)的形式提供,其在临用前可在无菌注射介质中溶解或悬浮。它们可含有例如本领域已知的助悬剂或分散剂。
在各个实施方案中,TLR9激动剂是IMO-2125且以每剂量从约4 mg到约64 mg,或在一些实施方案中每剂量从约8 mg到约64 mg,或每剂量从约12 mg到约64 mg,或每剂量从约16 mg到约64 mg,或每剂量从约20 mg到约64 mg,经瘤内给予。在一些实施方案中,IMO-2125以每剂量从约20 mg到约48 mg,或每剂量约20 mg到约40 mg给予。例如,在各个实施方案中,IMO-2125以每剂量约4 mg,或约8 mg,或约12 mg,或约16 mg,或约20 mg,或约24 mg,或约28 mg,或约32 mg,或约36 mg,或约40 mg,或约44 mg,或约48 mg,或约52 mg,或约56mg,或约60 mg,或约64 mg,例如经瘤内给予。
在各个实施方案中,给予约3到约12个剂量的TLR9激动剂(如IMO-2125) (如约3个剂量,或约4个剂量,或约5个剂量,或约6个剂量,或约7个剂量,或约8个剂量,或约9个剂量,或约10个剂量,或约11个剂量,或约12个剂量)。在各个实施方案中,在10-12周内给予约4到约8个剂量。在一些实施方案中,在10-12周内给予约6个剂量。在一些实施方案中,疗法以3-5个每周剂量的IMO-2125开始,任选地接着3-8个约每3周给予的维持剂量。在一些实施方案中,在第1、2、3、5、8和11周给予IMO-2125剂量。IMO-2125剂量可在相同或不同的病变内给予。
在IMO-2125 (或其他TLR9激动剂)治疗方案期间,给予一种或多种检查点抑制剂疗法以利用免疫信号传导的变化。一种或多种检查点抑制剂可经胃肠外给予,包括静脉内、瘤内,或皮下,以及其他方法。在一些实施方案中,患者接受抗-CTLA-4药物。例如,抗-CTLA-4药物可以是靶向CTLA-4的抗体,例如拮抗性抗体。在各个实施方案中,抗-CTLA-4是伊匹单抗(如YERVOY、BMS-734016、MDX-010、MDX-101)。在各个实施方案中,抗-CTLA-4是tremelimumab (如CP-675,206、MEDIMMUNE)。在其他实施方案中,免疫疗法药物是抗-PD-1药物。例如,抗-PD-1药物可以是靶向PD-1的抗体,例如其抑制PD-1和PD-L1 (和/或PD-L2)之间的相互作用。在各个实施方案中,抗-PD-1药物是纳武单抗(ONO-4538/BMS-936558、MDX1106或OPDIVO)。在各个实施方案中,抗-PD-1药物是派姆单抗(KEYTRUDA或MK-3475)。在各个实施方案中,抗-PD-1药物是pidilizumab (CT-011或MEDIVATION)。
在一些实施方案中,本免疫疗法药物是抗-PD-L1和/或PD-L2药物。例如,在各个实施方案中,抗-PD-L1和/或PD-L2药物是靶向PD-L1和/或PD-L2的抗体,例如,其抑制PD-1和PD-L1和/或PD-L2之间的相互作用。在各个实施方案中,抗-PD-L1和/或PD-L2药物是阿特珠单抗(atezolizumab) (TECENTRIQ, ROCHE)、BMS 936559 (BRISTOL MYERS SQUIBB)或MPDL328OA (ROCHE)。
在各个实施方案中,以约1 mg/kg,或约2 mg/kg,或约3 mg/kg,或约4 mg/kg,或约5 mg/kg的剂量,例如经静脉内给予抗-CTLA-4、抗-PD-1,或抗-PD-L1和/或PD-L2药物(如YERVOY、OPDIVO或KEYTRUDA,或与其相当的药物)。例如,在一些实施方案中,抗-CTLA-4药物,例如YERVOY的剂量是约3 mg/kg。例如,在一些实施方案中,抗-PD-1药物,例如OPDIVO的剂量是约3 mg/kg。例如,在一些实施方案中,抗-PD-1药物,例如KEYTRUDA的剂量是约2 mg/kg。在各个实施方案中,在初始TLR9激动剂剂量后至少1周,例如在约第2、3或4周给予初始剂量的抗-CTLA-4、抗-PD-1,或抗-PD-L1和/或PD-L2药物(如YERVOY、OPDIVO或KEYTRUDA,或与其相当的药物)。
在一些实施方案中,免疫疗法药物是抗-CTLA-4 (如YERVOY)、抗-PD-1 (如OPDIVO或KEYTRUDA),或抗-PD-L1和/或抗-PD-L2药物,其给予约2-约6次(如约2次,或约3次,或约4次,或约5次,或约6次)。在一些实施方案中,免疫疗法药物,例如抗-CTLA-4 (如YERVOY)、抗-PD-1 (如OPDIVO或KEYTRUDA),或抗-PD-L1和/或PD-L2药物给予约4次。
在一些实施方案中,免疫疗法药物是抗-CTLA-4药物,例如YERVOY且约每3周经约90分钟以3 mg/kg i.v.给予。在一些实施方案中,免疫疗法药物是抗-PD-1药物,例如OPDIVO且约每2周经约60分钟以约3 mg/kg i.v.给予。在一些实施方案中,免疫疗法药物是抗-PD-1药物,例如KEYTRUDA且约每3周经约30分钟以约2 mg/kg i.v.给予。
在一些实施方案中,大约每3周给予维持剂量的TLR9激动剂(如IMO-2125),以及给予抗-CTLA-4、抗-PD-1,或抗-PD-L1和/或PD-L2药物(如YERVOY、OPDIVO或KEYTRUDA,或与其相当的药物)。
在各个实施方案中,本免疫刺激寡核苷酸允许免疫疗法的剂量减少到单一疗法剂量的约10%,或约20%,或约30%,或约40%,或约50%,或约60%,或约70%,或约80%,或约90%,或约100%。例如,在一些实施方案中,免疫疗法剂量是约0.1 mg/kg,或约0.3 mg/kg,或约0.5mg/kg,或约0.7 mg/kg,或约1 mg/kg,或约1.5 mg/kg,或约2 mg/kg,或约2.5 mg/kg,或约3mg/kg。
在一些实施方案中,IMO-2125经瘤内给予先前已被发现对PD-1阻断疗法无反应或仅有部分反应的转移性黑素瘤患者。IMO-2125以4-32 mg每剂量(如,约16 mg、约20 mg、约24 mg、约28 mg,或约32 mg)的剂量在第1、2、3、5、8和11周给予,其中以3 mg/kg经i.v.给予伊匹单抗。伊匹单抗可在第2周开始,每3周(例如,第2、5、8和11周)给予。或者,派姆单抗可在第2周开始,每3周(例如,第2、5、8和11周)以2 mg/kg经i.v.给予。
在一些实施方案中,患者还接受Epacadostat (一种IDO-1抑制剂)的治疗方案,其可以以25 mg-300 mg口服给予,每日约两次。治疗方案可给予约5天的周期。可在初始IMO-2125 (或其他TLR9激动剂)瘤内注射后大约1周开始给予第一个剂量的Epacadostat。
在各个实施方案中,不希望受到理论的束缚,本发明在癌症患者,包括具有晚期、转移性疾病的癌症患者中提供更平衡的免疫反应。本文描述的组合疗法可以消除或减少在各自的单一疗法中观察到的缺陷。例如,各种患者对免疫疗法难治,或者这样的单一疗法被广泛的副作用特征阻碍。随着本领域向免疫疗法的组合(如YERVOY和OPDIVO)的进一步发展,这样的副作用可能更成问题。
在各个实施方案中,组合疗法允许树突状细胞(如浆细胞样树突状细胞)的活化和/或成熟,并调节在治疗的肿瘤和远处肿瘤二者中的肿瘤微环境(TME)。例如,在各个实施方案中,组合疗法提供TIL和/或CD8+ T细胞的数量或质量的改进,以促进抗肿瘤活性。例如,观察到启动的T细胞侵袭近端和远处肿瘤。这样的启动的T细胞适合于肿瘤侵袭,特别是在远处部位(例如继发性肿瘤),并且不希望受到理论的束缚,遇到已经在适当的位置降低耐受机制的肿瘤环境。在各个实施方案中,组合疗法提供干扰素(如IFN-α)和各种Th1类细胞因子(如IFN-γ、IL-2、IL-12和TNF-β)的刺激作用。
本发明在各个实施方案中提供用于治疗癌症,包括转移性癌症的方法,其中总体宿主免疫环境重新改造远离肿瘤耐受。例如,局部的TME被创建,它既破坏免疫耐受和抑制的通路,又允许肿瘤消退。本发明的方法在一些实施方案中提供一种能够传播可靠的免疫反应的TME。
在各个实施方案中,癌症患者的DC是不成熟的,且不能摄取、加工或呈递抗原。这些DC也可能被抑制免于迁移到区域淋巴结或可诱导耐受性,特别是当呈递自身抗原时。癌症患者的肿瘤部位也可被调节性T细胞浸润,这些细胞能够介导抗原启动的T细胞的抑制。辅助CD4 T细胞反应也可能向Th2表型倾斜,这抑制了Th1 T细胞的启动和有效的细胞免疫力。肿瘤细胞可表达异常的MHC I类分子或β2-微球蛋白,导致抗原呈递不足,从而导致效应T细胞对肿瘤的识别效率低下。最后,肿瘤细胞和周围的基质可释放许多抑制性细胞因子,例如IL-6、IL-10和TGF-β。这创造了一个不利于局部免疫力的环境,使肿瘤细胞得以逃脱。在各个实施方案中,本方法允许有利于对抗肿瘤的局部免疫力的环境,例如但不限于,DC的成熟和/或调节性T细胞和Th2 CD4 T细胞的减少。
在一些实施方案中,根据本发明的组合疗法改变免疫细胞的平衡,有利于对肿瘤的免疫攻击。例如,在一些实施方案中,本方法改变在临床重要的部位,例如在给药部位或远处部位的免疫细胞的比例,以有利于能够杀死和/或抑制肿瘤的细胞(如T细胞、细胞毒性T淋巴细胞、T辅助细胞、天然杀伤(NK)细胞、天然杀伤T (NKT)细胞、抗-肿瘤巨噬细胞(如M1巨噬细胞)、B细胞、树突状细胞,或其亚群)且反对保护肿瘤的细胞(如髓源性抑制细胞(MDSC)、调节性T细胞(Treg);肿瘤相关中性粒细胞(TAN)、M2巨噬细胞、肿瘤相关巨噬细胞(TAM),或其亚群)。在一些实施方案中,本方法增加效应T细胞与调节性T细胞的比例。在各个实施方案中,这种改变的免疫细胞平衡受到局部/近端和/或全身/远处影响。在各个实施方案中,这种改变的免疫细胞平衡在TME中受到影响。
此外,在各个实施方案中,本方法允许有强有力的抗肿瘤免疫反应,而这种反应不以显著的副作用(如,irAE)为代价,例如相对于在没有TLR9激动剂的情况下使用一种或多种免疫疗法时所观察到的副作用。
例如,组合疗法减少免疫疗法(例如抗-CTLA-4、抗-PD-1,或抗-PD-L1和/或PD-L2药物,包括例如,YERVOY、OPDIVO和KEYTRUDA或与其相关药物的一种或多种)的一种或多种副作用。这样的副作用包括:疲劳、咳嗽、恶心、食欲不振、皮肤疹、瘙痒、皮疹和结肠炎。在一些实施方案中,副作用是可引起肠穿孔的肠道问题(如结肠炎)。结肠炎的体征和症状可包括:腹泻或比平时更多的粪便;大便中有血或黑色、焦油状、粘稠的粪便;和腹痛或压痛。在一些实施方案中,副作用是可能导致肝衰竭的肝脏问题(如肝炎)。肝炎的体征和症状可包括:皮肤变黄或眼白;深色尿;恶心或呕吐;胃右侧疼痛;比正常更容易出血或瘀伤。在一些实施方案中,副作用是可导致严重的皮肤反应的皮肤问题。严重的皮肤反应的体征和症状可包括:皮肤疹伴或不伴有瘙痒;口腔疼痛;和皮肤水泡和/或脱皮。在一些实施方案中,副作用是可能导致瘫痪的神经问题。神经问题的症状可包括:腿、手或面的异常虚弱;和手或脚麻木或刺痛。在一些实施方案中,副作用是激素腺体问题(如垂体、肾上腺和甲状腺)。体征和症状包括:持续性或不寻常的头痛;不寻常的呆滞;时时刻刻感到寒冷;体重增加;情绪或行为改变,如性欲减退、易怒或健忘;头晕或昏晕。在一些实施方案中,副作用是眼睛问题。症状可包括:视力模糊、复视或其他视力问题;和眼睛疼痛或发红。
在一些实施方案中,患者经历结肠炎、克罗恩氏病或根据本发明的其他涉及GI的irAE的较少发生率。
在一些实施方案中,患者获得更长的无进展间隔或更长的生存期(例如,与单一疗法相比),或在一些实施方案中,达到缓解或完全反应。完全反应是指在对治疗反应时,癌症的所有症状消失。
本发明还通过以下非限制实施例加以说明。
实施例
实施例1:免疫刺激寡核苷酸(IMO-2125)的抗-肿瘤作用
免疫单体如本领域已知的进行合成(见,例如,国际专利公布号WO 2016/057898,其全部内容,包括其中的实施例1和图1和2,通过引用并入本文)。
在BALB/c小鼠(每组n=8)的右侧腹s.c.植入2 x 106个CT26.WT细胞(肿瘤1)和在左侧腹s.c.植入2 x 106个CT26.CL25细胞(肿瘤2)。当右侧腹肿瘤体积达到50-150 mm3时,在第5天开始治疗。
仅在第5、8、11和14天,对右侧肿瘤结节(肿瘤1)经瘤内(i.t.)注射(100 μl)给予试验化合物。在第28天收集肿瘤结节。试验化合物为对照DNA、IMO-2125: 0.5 mg/kg、IMO-2125: 2.5 mg/kg和IMO-2125: 5 mg/kg。如在图1中所示,瘤内IMO-2125治疗导致治疗的肿瘤和远处肿瘤二者的肿瘤体积的剂量-依赖性减少。图2显示在肿瘤植入后第28天收集的肿瘤结节。对CD3+ T淋巴细胞表面标记进行免疫组织化学染色。CD3+细胞染色为棕色。来自注射安慰剂的小鼠的邻近正常组织的肿瘤组织内出现很少的CD3+细胞,但来自用IMO-2125,2.5 mg/kg治疗的小鼠的肿瘤组织中出现大量的CD3+细胞。结果示于图2小图A中,这尤其表明,抗肿瘤活性与诱导肿瘤浸润性淋巴细胞(TIL)相关。图2小图B显示瘤内IMO-2125治疗增加CD8+ T细胞在肿瘤中的浸润。
此外,在第28天,从安慰剂-和IMO-2125 (2.5 mg/kg)-治疗的荷瘤小鼠(n = 3)的脾脏收集T细胞。分泌IFN的ELISPOT被用于测定特异性针对在CT26.WT和CT26.CL25二者中存在的肿瘤内部抗原AH1和仅在CT26.CL25中存在的β-gal的T细胞。图3显示瘤内IMO-2125治疗引起对肿瘤抗原的特异性细胞毒性T细胞反应。在图4中,显示了CD8+ T细胞在治疗的肿瘤和远处肿瘤中的关键作用。
图5显示了证实瘤内IMO-2125诱导持久和肿瘤特异性免疫记忆的研究。6只荷瘤小鼠(6/9),其肿瘤在IMO-2125 (5 mg/kg, i.t.)治疗后完全或部分消退(<150mm3),和8只未用过的BALB/c小鼠(n = 8)在第33天用1 x 106个CT26细胞经腹部左右侧s.c.注射再攻击。以相同方式接种的未用过的BALB/c小鼠被用作肿瘤生长对照。排斥CT26肿瘤细胞再攻击的小鼠(6只中的5只)于第73天经s.c. (在后背上部)接种106个同基因、非器官相关的B细胞淋巴瘤A20细胞。见图5,小图A的计划。结果示于图5,小图B。
在图6中,研究比较瘤内IMO-2125比全身(s.c.)治疗更有效,如通过A20淋巴瘤模型中抗肿瘤活性所显示的。在BALB/c小鼠(n=10)中,经s.c.在左右侧腹植入3x106个A20细胞。在第8天在左侧腹,经瘤内注射2.5 mg/kg IMO-2125开始治疗。在第8、10、12和14天给予IMO-2125。在肿瘤植入后第21天收集来自安慰剂(PBS)对照和IMO-2125治疗的荷瘤小鼠的样品。小图A显示研究设计和肿瘤动力学。在小图A中,皮下给药的肿瘤动力学稍好于对照,而瘤内给药显著地减慢肿瘤生长。小图B显示了TIL的存在和各种检查点基因的基因表达的变化。重要的是,IMO-2125增加肿瘤TIL并调节肿瘤检查点表达,从而使TME敏化以供与一种或多种检查点抑制剂组合。
实施例2:IMO-2125和抗-CTLA-4抗体的组合疗法的抗-肿瘤作用
图7显示瘤内IMO-2125与抗-CTLA-4 mAb组合对治疗的肿瘤和全身肺转移的抗肿瘤活性的评价。研究设计示于图7,小图A中,结果示于图7,小图B中。
用2 x 107个CT26细胞在右侧腹s.c.植入BALB/c小鼠。然后在小鼠中经i.v.注射3x 106个CT26细胞以建立肺转移。在第5天开始治疗。2.5 mg/kg IMO-2125经瘤内给予到在右侧腹的CT26实体瘤中,通过腹膜内(i.p.)注射给予10 mg/kg抗-CTLA-4 mAb。在第5、6、8和9天单独给予或者共同-给予IMO-2125和抗-CTLA-4 mAb。收集PBS对照、IMO-4、抗-CTLA-4mAb或IMO-2125和抗-CTLA-4 mAb治疗的荷瘤小鼠的肺和脾脏T细胞。
瘤内IMO-2125和抗-CTLA-4 mAb组合在治疗的肿瘤中显示比用任何一种药物的单一疗法改进的生长抑制作用。
图8显示IMO-2125和抗-CTLA-4 mAb单独或组合对全身肺转移的抗-肿瘤活性。
图9显示瘤内IMO-2125和抗-CTLA-4 mAb组合增加在转移性结节中的TIL。
瘤内IMO-2125和抗-CTLA-4 mAb的组合导致比用任何一种药物的单一疗法改进的肿瘤生长的抑制作用,全身肺转移的消退和TIL浸润。在直接治疗的肿瘤和全身肺转移中观察到该效果。
实施例3:IMO-2125和抗-PD-1抗体的组合疗法的抗-肿瘤作用
图10显示瘤内IMO-2125与抗-PD-1 mAb组合在CT26结肠癌肿瘤模型中抗肿瘤活性的评估。小图A显示了研究设计。用1 x 107个鼠结肠癌CT26细胞在右侧腹(肿瘤1)和左侧腹(肿瘤2)经s.c.植入BALB/c小鼠(每组n=8)。在第7天当肿瘤体积达到200-300 mm3时开始治疗。在第7、8、11和12天,2.5 mg/kg IMO-2125 (50 µg,在100 µL PBS中)在右侧肿瘤结节处经i.t.注射,和抗-PD-1 mAb (10 mg/kg,200 µg/小鼠)单独通过i.p.注射给予或者共同给予,共4次。在第14天收集肿瘤结节。在第21天评价肿瘤生长抑制作用、TIL和检查点基因表达。图10,小图B显示所述组合对治疗部位和远处部位的肿瘤生长动力学的影响。IMO-2125和抗-PD-1的组合证实在治疗部位和远处部位二者的生长抑制作用,其优于任何一种单一疗法。小图C显示所述组合对TIL的影响。瘤内IMO-2125和抗-PD-1 mAb组合增加TIL。PBS对照组显示几个T细胞(棕色);IMO-2125组显示了大量的T细胞;PD-1 mAb组显示比PBS处理组稍微增加的T细胞;组合组显示超过IMO-2125处理组的丰富的T细胞(放大:上排 x 100,中排 x 200,下排 x 400)。小图D显示用IMO-2125和抗-PD-1的组合治疗后,在治疗部位和远处部位的检查点基因表达。
对治疗的肿瘤及全身肺转移,组合测试IMO-2124和抗-PD-1。见图11。
用1 x 107个B 16.F 10细胞在右侧腹经s.c.植入C57BL/6小鼠(n=10) (肿瘤1)。然后用2x106个B16.F10细胞经i.v.注射小鼠以建立肺转移(肿瘤2)。在第5天开始治疗。5mg/kg IMO-2125经瘤内给予到右侧腹的B16实体瘤中,并通过腹膜内(i.p.)注射给予15mg/kg抗-PD-1 mAb。在第5、6、7、8和9天单独给予或共同-给予IMO-2125和抗-PD-1 mAb。从对照、IMO-2125、抗-PD-1 mAb或IMO-2125和抗-PD-1 mAb治疗的荷瘤小鼠收集样品。图11,小图A显示了研究设计。
图11,小图B显示所述组合对治疗部位的肿瘤生长动力学的影响。
图11,小图C显示所述组合对肺转移的影响。瘤内注射IMO-2125与抗-PD-1 mAb的组合诱导对播散性肺转移的有效全身免疫反应。
图11,小图D显示转移性肺肿瘤的组织病理学(圆圈:大肿瘤结节,箭头:小肿瘤结节,插图:HE染色(x 40),和大图:CD3染色(x 400))。用瘤内IMO-2125和抗-PD-1 mAb的组合治疗导致肺肿瘤转移的降低(插图和大图)和TIL皱褶(大图)。
用瘤内IMO-2125与抗-PD-1抗体的组合治疗显示比单用任何一种药物更有效的抗肿瘤活性。在治疗的肿瘤以及远处肿瘤处观察到抗肿瘤活性。治疗的肿瘤和远处肿瘤二者中TIL的浸润水平增加。在临床前模型中,IMO-2125增加在治疗的肿瘤和远处肿瘤中的PD-L1和其他检查点表达。
实施例4:IMO-2125和IDO-1抑制剂的组合疗法的抗-肿瘤作用
图12显示评估瘤内IMO-2125与IDO-1抑制剂的组合在小鼠模型中对治疗的肿瘤及全身肺转移的抗肿瘤活性的研究设计。在第0天植入实体瘤和肺转移(实体瘤,1x107个CT26,s.c., 右侧腹;肺转移,3x106个CT26 i.v.),其中在第4、5、7和8天,经瘤内给予IMO-2125(2.5 mg/kg)。在第4、5、7和8天给予IDO-1抑制剂两次(75 mg/kg i.g.)。
图13显示瘤内IMO-2125抗-肿瘤活性通过与IDO-1抑制剂联合治疗而得到加强。小图A显示各个治疗组中的肺肿瘤结节的数目,表明与每种单独药物比较,IMO-2125和IDO-1抑制剂的改进。小图B显示在治疗方案期间各个治疗组中肿瘤体积的变化。
实施例5:具有用≥12周的PD-1导向疗法(单独或组合)有进展的无法切除或转移性黑素瘤的成人研究群体
图14提供成人研究群体的给药概述,所述成人研究群体具有用≥12周的PD-1导向疗法(单独或组合)有进展的无法切除或转移性黑素瘤。在第1和3周经瘤内单独给予IMO-2125。在第2、5、8和11周一起给予IMO-2125与伊匹单抗或派姆单抗。派姆单抗的给予每三周继续进行,直到有进展为止。
图15显示了对于患者003 (4 mg剂量的IMO-2125;伊匹单抗),在给药前和i.t.注射IMO-2125后24小时的树突状细胞成熟结果(CD1c、CD303和HLA-DR表达) (小图A);且显示了注射的肿瘤和远处肿瘤中T-细胞激活的结果(小图B)。
图16显示远处病变中顶部细胞克隆的扩增,并将无反应的患者与有反应的患者(患者003,4 mg IMO-2125,伊匹单抗)进行比较。最右边的小图显示了对于患者003,IFN-γ的诱导作用。
图17显示了对患者004 (8 mg 2125, 3mg伊匹单抗),治疗前和治疗后的肿瘤成像。注射的病变和远处病变在大约5周的治疗后看不到。
等价方案
虽然已结合本发明的具体实施方案对其进行了描述,但将理解,本发明能够进一步修改,本申请旨在涵盖本发明的任何变化、用途或修改,其总体上遵循本发明的原理,且包括从本公开内容的偏离,所述偏离在本发明所属领域的已知或常规实践内,并可适用于上文所述和如下在所附权利要求的范围内的基本特征。
本领域的技术人员只需使用常规实验将认识到,或能够确定本文中具体描述的特定实施方案的许多等价方案。这样的等价方案意欲包括在以下权利要求的范围内。
通过引用并入
本文提及的所有专利和出版物通过引用以其整体结合到本文中。
Claims (31)
1.一种治疗癌症患者的方法,该方法包括瘤内给予癌症患者寡核苷酸TLR9激动剂,并在初始TLR9激动剂剂量后一周或更长时间开始给予患者免疫检查点抑制剂疗法。
2.权利要求1的方法,其中免疫检查点抑制剂靶向PD-1、PD-L1、PD-L2、CTLA-4、LAG3、TIM3和/或IDO。
3.权利要求1或2的方法,其中患者显示对先前用PD-1阻断疗法的治疗没有反应。
4.权利要求3的方法,其中患者经历至少一次对先前PD-1阻断疗法的免疫-相关的不良事件。
5.权利要求3或4的方法,其中先前的PD-1阻断疗法包括使用纳武单抗或派姆单抗的疗法。
6.权利要求1-5的任一项的方法,其中癌症是原发性癌症。
7.权利要求1-5的任一项的方法,其中癌症是转移性癌症。
8.权利要求6或7的方法,其中癌症起源于皮肤、结肠、乳腺或前列腺。
9.权利要求6或7的方法,其中癌症是黑素瘤、肺癌、肾癌、前列腺癌、子宫颈癌、结肠直肠癌、胰腺癌、卵巢癌、尿路上皮癌、胃癌/GEJ癌、头颈部癌、胶质母细胞瘤、Merkel细胞癌、头颈部鳞状细胞癌(HNSCC)、非小细胞肺癌(NSCLC)、小细胞肺癌(SCLC)、膀胱癌、前列腺癌或血液恶性肿瘤。
10.权利要求9的方法,其中癌症是转移性黑素瘤。
11.权利要求1-10的任一项的方法,其中TLR9激动剂是IMO-2125。
12. 权利要求11的方法,其中IMO-2125以每剂量约4 mg-约64 mg经瘤内给予。
13. 权利要求12的方法,其中IMO-2125以每剂量约4-约12 mg经瘤内给予。
14. 权利要求11的方法,其中IMO-2125以每剂量约8 mg经瘤内给予。
15. 权利要求12的方法,其中IMO-2125以每剂量约20 mg-约64 mg给予。
16. 权利要求15的方法,其中IMO-2125以每剂量约20 mg-约48 mg给予。
17.权利要求1-16的任一项的方法,其中给予约3-约12个剂量的TLR9激动剂。
18.权利要求17的方法,其中在10-12周内给予约4-约8个剂量的TLR9激动剂。
19.权利要求18的方法,其中在10-12周内给予约6个剂量的TLR9激动剂。
20.权利要求18或19的方法,其中疗法以3-5个每周剂量的TLR9激动剂开始,接着3-8个大约每3周给予的维持剂量。
21.权利要求20的方法,其中TLR9激动剂是IMO-2125,其在第1、2、3、5、8和11周给予。
22.权利要求1-21的任一项的方法,其中患者在第2周或第3周开始接受抗-CTLA-4药物。
23.权利要求22的方法,其中抗-CTLA-4药物给予2-6次,且任选约4次。
24.权利要求23的方法,其中抗-CTLA-4药物每3周给予。
25.权利要求22-24的任一项的方法,其中抗-CTLA-4药物是伊匹单抗。
26.权利要求1-21的任一项的方法,其中患者在第2周或第3周开始接受抗-PD-1药物。
27.权利要求26的方法,其中PD-1药物给予2-6次,且任选约4次。
28.权利要求27的方法,其中抗-CTLA-4药物每3周给予。
29.权利要求26-28的任一项的方法,其中抗-PD-1药物是派姆单抗或纳武单抗。
30.权利要求1-29的任一项的方法,其中免疫检查点抑制剂疗法经胃肠外给予,且任选地经静脉内输注、皮下注射或瘤内注射给予。
31. 一种治疗转移性黑素瘤的方法,其包括瘤内给予转移性黑素瘤患者IMO-2125,该患者先前已被发现对PD-1阻断疗法无反应或仅有部分反应;IMO-2125在第1、2、3、5、8和11周以每剂量4-32 mg的剂量给予;其中在第2周开始每3周静脉内给予2-4 mg/kg的伊匹单抗或派姆单抗。
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IL265370A (en) | 2019-05-30 |
US20180125877A1 (en) | 2018-05-10 |
EP3512499A4 (en) | 2020-08-05 |
EP3512499A1 (en) | 2019-07-24 |
US20200054663A1 (en) | 2020-02-20 |
WO2018053242A1 (en) | 2018-03-22 |
KR20190096936A (ko) | 2019-08-20 |
AU2017325981A1 (en) | 2019-04-11 |
US20200138848A1 (en) | 2020-05-07 |
US20210052625A1 (en) | 2021-02-25 |
JP2019529415A (ja) | 2019-10-17 |
MX2019002925A (es) | 2019-09-05 |
JP2022009200A (ja) | 2022-01-14 |
CA3036978A1 (en) | 2018-03-22 |
US20210038630A1 (en) | 2021-02-11 |
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