CN106714836A - Gm‑csf/cd40l疫苗和检查点抑制剂联合治疗 - Google Patents
Gm‑csf/cd40l疫苗和检查点抑制剂联合治疗 Download PDFInfo
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Abstract
公开了一种用于在受试者中治疗癌症的方法。该方法包括给受试者施用包含治疗有效量的检查点抑制剂和治疗有效量的肿瘤疫苗的组合物。在一些实施方案中,肿瘤疫苗包含辐射的自体肿瘤细胞和工程化以表达粒细胞巨噬细胞集落刺激因子(GM‑CSF)和分化簇40(CD40)配体的细胞系。在一些实施例中,检查点抑制剂包括抗程序性死亡‑1(抗PD‑1)抗体(例如,BMS 936558)、抗程序性死亡配体‑1(抗PD‑L1)的抗体(例如,cloneMIHI)、抗细胞毒性T淋巴细胞抗原‑4(抗CTLA‑4)抗体(例如,伊匹单抗,BMS),或它们的任意组合。
Description
本申请要求提交于2015年6月5日的美国临时申请号62/171,829的权益,其全部内容通过引用并入本文。
背景技术
已经表明,癌症具有多种机制来阻止免疫应答的激活并逃避免疫应答。因此,单一处理,如用疫苗免疫,可能不足以满足临床效力。
发明概述
公开了用于治疗一施用对象(受试者)中癌症的方法。该方法包括向该对象施用一组合物,所述组合物包含治疗有效量的检查点抑制剂和治疗有效量的肿瘤疫苗。在一些实施方案中,肿瘤疫苗包含经辐射(照射)的自体肿瘤细胞和经工程改造的表达GM-CSF和CD40配体的细胞系。
在一些情况下,所述疫苗包含一株、两株或更多个人肺腺癌细胞系以及经工程化以分泌GM-CSF和表达CD40配体(GM.CD40L)的和旁邻细胞系的混合物。预计在疫苗位点的GM-CSF分泌会募集并分化树突状细胞(DC),其将通过它们与旁邻细胞表面上的CD40配体的相遇而被激活。这些激活的和负载抗原的DC将迁移到引流淋巴结并激活肿瘤抗原特异性T细胞(CD4和CD8)。这些活化的T细胞然后将再循环至(癌细胞)转移性的位点并杀死肿瘤细胞。
细胞系可进一步工程化以表达选自下组的一个或多个因子:IL-1、IL-2、IL-3、IL-4、IL-5、IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-15、促红细胞生成素、GCSF、M-CSF、血小板衍生生长因子(PDGF)、MSF、FLT-3配体、EGF,成纤维细胞生长因子(FGF)、bFGF(FGF-2)、FGF-3、FGF-4、FGF-5、FGF-6、FGF-7、胰岛素样生长因子(IGF-1)、胰岛素样生长因子2(IGF-2);血管内皮生长因子(VEGF)、IFN-γ、IFN-α、IFN-β、白血病抑制因子(LIF)、睫状神经营养因子(CNTF)、抑瘤素M、干细胞因子(SCF)、TGF-a、和TGF-β1。所述细胞系优选是MHC阴性的,并且可以是肿瘤细胞系。
所公开的疫苗与免疫检查点的组合可以放大T细胞应答并增强肿瘤浸润性T细胞的功效,因此与单一试剂相比产生更有效的抗肿瘤效果。在一些实施方案中,所述检查点抑制剂包括抗PD-1抗体(例如BMS936558)、抗PD-L1抗体(例如克隆M1H1)、抗CTLA-4抗体(例如伊匹单抗-Ipilimumab,BMS)、或其组合。
在附图和下面的描述中阐述了本发明的一个或多个实施方式的细节。从说明书和附图以及从权利要求书中,本发明的其它特征、目的和优点将是显而易见的。
详细描述
肿瘤疫苗通常具有非常少的单一药剂活性,因为即使它们有效地了扩增淋巴区(lymphoid compartment)中的肿瘤特异性T细胞,由于暴露于PD-L1,这些T细胞在肿瘤微环境中变得无活性。因此,有必要将肿瘤疫苗与针对肿瘤微环境的药剂进行组合。
为了积极驱动抗肿瘤免疫应答,开发了治疗性的癌症疫苗。与预防性地用于治疗感染性疾病的预防性疫苗不同,治疗性疫苗被设计为通过刺激针对特异性肿瘤相关抗原的免疫应答来治疗已发生的癌症。许多肿瘤相关抗原是本领域已知的,并且用于检测它们的方法是公知的。
在一些实施方案中,所述肿瘤疫苗包括作为表达GM-CSF和CD40配体来源的“基因修饰的通用生产细胞”。在一些实施方案中,所述细胞系是MHC分子阴性细胞系,例如K562细胞系(可从美国典型培养物保藏中心获得,马纳萨斯,VA)-这种细胞的使用应该降低引入机体后对细胞的同种异体反应的发生率。在一些情况下,转化的细胞表达外源GM-CSF和CD40配体转基因。
在一些实施方案中,所述细胞系是MHC分子阴性细胞系,例如K562细胞系(可从美国典型培养物保藏中心获得,Manassas,VA)-这种细胞的使用应该降低引入机体后对细胞的同种异体反应的发生率。在一些情况下,转化的细胞表达外源的GM-CSF和CD40配体转基因。
在一些实施方案中,“基因修饰的通用生产细胞”还可以含有和表达编码选自下组的一种或多种化合物的转基因:IL-1、IL-2、IL-3、IL-4、IL-5、IL-IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-15、促红细胞生成素、G-CSF、M-CSF、血小板衍生生长因子(PDGF)、MSF、FLT-3配体、EGF、成纤维细胞生长因子(FGF;例如aFGF(FGF-1)、bFGF(FGF-2)、FGF-3、FGF-4、FGF-5、FGF-6或FGF-7)、胰岛素样生长因子(例如IGF-1、IGF-2);血管内皮生长因子(VEGF);干扰素(例如IFN-γ、IFN-α、IFN-β);白血病抑制因子(LIF);睫状神经营养因子(CNTF);抑瘤素M;干细胞因子(SCF);转化生长因子(例如TGF-α、TGF-~1、TGF-~1、TGF-~1)。DNA分子可以编码上述化合物的哺乳动物(包括人或鼠)版本。
在一些实施方案中,将患有肿瘤、癌症、或恶性疾病的个体的外周血淋巴细胞与抗原呈递细胞(例如树突细胞)、表达GM-CSF/CD40L的细胞(或源自GM-CSF/CD40L细胞系的细胞)、以及任选的凋亡自体肿瘤、癌症或恶性细胞(或来源于它们的抗原)一起培养。然后将培养的细胞作为自体治疗的形式再给予患者(参见,例如,美国专利号5,192,537[通过引用整体并入本文])。该方法也适用于经历肿瘤、癌症或恶性疾病复发的患者。在另一个实施方案中,从个体的外周血淋巴细胞除去抑制性T细胞,并将剩余的细胞悬浮在含有表达GM-CSF/CD40L的细胞和经辐照的自体肿瘤或癌细胞(或由其衍生的抗原)的组织培养基中。然后将细胞在约37℃至约40℃的温度下孵育一段时间,以使它们被活化。克隆扩增对肿瘤抗原具有特异性的那些细胞,任选地,对其进行处理以再去除各种类型的抑制细胞和/或提高其活性。活化的细胞可以与表达GM-CSF/CD40L的细胞和/或与一种或多种细胞因子共同施用。
在一些情况下,所述肿瘤疫苗包括(1)提供共享肿瘤抗原来源的经辐射的肿瘤细胞(例如自体肿瘤细胞)和(2)经工程化以分泌GM-CSF并在其表面表达CD40配体的旁邻细胞系(GM.CD40L)。在疫苗位点的GM-CSF分泌可以募集并分化DC细胞,其将通过它们与旁邻细胞表面上的CD40配体的相遇而被激活。然后来自辐射的肿瘤细胞的凋亡小体将由DC细胞处理。
肿瘤疫苗可以与检查点抑制剂组合使用。两个已知的抑制性检查点途径涉及通过细胞毒性T淋巴细胞抗原-4(CTLA-4)和程序性死亡1(PD-1)受体的信号传导。这些蛋白质是协调分子(cosignaling)CD28-B7家族的成员,其在T细胞功能的所有阶段中发挥重要作用。PD-1受体(也称为CD279)在活化的T细胞的表面上表达。其配体PD-L1(B7-H1;CD274)和PD-L2(B7-DC;CD273)在APC细胞的表面上表达,例如树突细胞或巨噬细胞。PD-L1是主要配体,而PD-L2具有更受限制的表达模式。当配体结合PD-1时,抑制性信号传递到T细胞中,这减少了细胞因子的产生并抑制了T细胞增殖。临床试验中免疫检查点靶向抗体的列表提供在表2中。
针对程序性死亡受体1(PD-1)的人单克隆抗体和单独使用抗PD-1抗体或与其它免疫治疗剂组合治疗癌症的方法描述于美国专利8,008,449中,对这些抗体通过引用并入本文。抗PD-L1抗体及其用途描述于美国专利8,552,154中,对于这些抗体通过引用并入本文。包含抗PD-1抗体或抗PD-L1抗体的抗癌剂描述于美国专利号8,617,546中,对于这些抗体通过引用并入本文。
在一些实施例中,所述PDl1抑制剂包括特异性结合于PDL1的抗体,例如BMS-936559(百时美施贵宝-Bristol-Myers Squibb)或MPDL3280A(罗氏-Roche)。在一些实施例中,所述PD1抑制剂包括特异性结合于PD1的抗体,例如lambrolizumab(默克-Merck)、纳武单抗(百时美施贵宝)或MEDI4736(阿斯利康-AstraZeneca)。针对PD-1的人单克隆抗体和单独使用抗PD-1抗体或与其它免疫治疗剂组合治疗癌症的方法描述于美国专利8,008,449中,对这些抗体通过引用并入本文。抗PD-L1抗体及其用途描述于美国专利8,552,154中,对于这些抗体通过引用并入本文。包含抗PD-1抗体或抗PD-L1抗体的抗癌剂描述于美国专利号8,617,546中,对于这些抗体通过引用并入本文。
所公开的组合物和方法可以与其他癌症免疫治疗组合使用。有两种不同类型的免疫治疗:被动免疫疗法使用免疫系统的组分来指导针对癌细胞的靶向细胞毒活性,而不必在患者中启动免疫应答,而主动免疫疗法主动触发内源性免疫应答。被动策略包括使用由B细胞响应特异性抗原产生的单克隆抗体(mAb)。1970年代的杂交瘤技术的发展和肿瘤特异性抗原的鉴定允许mAb的药物开发,其可以特异性靶向肿瘤细胞以被免疫系统破坏。迄今为止,mAb是免疫治疗的最大成功案例;2012年最畅销抗癌药的前三名是单克隆抗体(mAb)。它们是利妥昔单抗(瑞图宣-Rituxan,基因泰克-Genentech),其结合于在B细胞恶性肿瘤例如非霍奇金淋巴瘤(NHL)的表面上高度表达的CD20蛋白。利妥昔单抗被FDA批准用于与化疗联合治疗NHL和慢性淋巴细胞性白血病(CLL)。另一个重要的单克隆抗体是曲妥珠单抗(赫赛汀Herceptin;基因泰克),其通过靶向HER2的表达彻底改变了HER2(人表皮生长因子受体2)阳性乳腺癌的治疗。
产生最佳“杀伤”CD8T细胞应答还需要T细胞受体活化加上共刺激,其可通过连接肿瘤坏死因子受体家族成员(包括OX40(CD134)和4-1BB(CD137))提供。OX40是特别令人感兴趣的,因为用活化(激动剂)抗OX40mAb的治疗增强了T细胞分化和细胞溶解功能,导致针对多种肿瘤的抗肿瘤免疫增强。
许多抗癌药物可以与本发明的方法和组合物组合使用。以下是可以与辐照联合使用的抗癌(抗肿瘤)药物的非穷举性列表:阿西维辛(Acivicin)、阿柔比星(Aclarubicin)、盐酸阿扎唑(Acodazole Hydrochloride);AcrQnine;阿多来新(Adozelesin);阿地白介素(Aldesleukin);六甲蜜胺(Altretamine);安博霉素;乙酸阿美蒽醌(AmetantroneAcetate);氨鲁米特(Aminoglutethimide);安吖啶(Amsacrine);阿那曲唑;安曲霉素;天冬酰胺酶;曲林菌素(Asperlin);阿扎胞苷;阿扎替派(Azetepa);阿佐霉素(Azotomycin);巴马司他(Batimastat);苯佐替派(Benzodepa);比卡鲁胺(Bicalutamide);盐酸必桑郡(Bisantrene Hydrochloride);双奈法德(Bisnafide Dimesylate);比折来新(Bizelesin);硫酸博来霉素;布喹那钠(Brequinar Sodium);溴匹立明(Bropirimine);白消安;放线菌素;卡普睾酮(Calusterone);卡拉酰胺;卡贝替姆(Carbetimer);卡铂;卡莫司汀;盐酸卡米诺霉素(Carubicin Hydrochloride);卡折来新(Carzelesin);西地芬戈(Cedefingol);苯丁酸氮芥;西罗霉素(Cirolemycin);顺铂;克拉屈滨;甲磺酸克雷斯托(Crisnatol Mesylate);环磷酰胺(Cyclophosphamide);阿糖胞苷;达卡巴嗪;更生霉素;盐酸柔红霉素;地西他滨;右奥马铂(Dexormaplatin);地扎胍宁(Dezaguanine);甲磺酸地扎胍宁;亚丝醌(Diaziquone);多西他赛;多柔比星;盐酸多柔比星;屈洛昔芬;柠檬酸屈洛昔芬;屈他雄酮丙酸酯(Dromostanolone Propionate);达佐霉素(Duazomycin);依达曲沙(Edatrexate);盐酸氨法林(Eflomithine Hydrochloride);依沙芦星(Elsamitrucin);埃洛铂(Enloplatin);恩普氨酯(Enpromate);依匹哌啶(Epipropidine);盐酸表柔比星;厄布洛唑;盐酸依索比星;雌莫司汀;雌莫司汀磷酸钠;依他硝唑(Etanidazole);乙碘油I 131;依托泊苷;磷酸依托泊苷;艾托卜宁(Etoprine);盐酸法倔唑(Fadrozole Hydrochloride);法扎拉滨(Fazarabine);芬维A胺;氟尿苷;磷酸氟达拉滨;氟尿嘧啶;氟西他滨(Flurocitabine);磷喹酮(Fosquidone);福司曲星(Fostriecin)钠;吉西他滨;盐酸吉西他滨;金Au198;羟基脲;盐酸伊达比星;异环磷酰胺;伊莫福星(I lmofosine);异丙铂(Iproplatin);盐酸伊立替康;醋酸兰瑞肽;来曲唑;醋酸亮丙瑞林;盐酸利洛唑(LiarozoleHydrochloride);洛美曲塞钠(Lometrexol Sodium);洛莫司汀;盐酸洛索蒽醌;马索罗酚(Masoprocol);美登素;盐酸氮芥;醋酸甲地孕酮;醋酸美仑孕酮;美法仑;美诺立尔(Menogaril);巯嘌呤;甲氨蝶呤;甲氨蝶呤钠;氯苯氨啶(Metoprine);美妥替哌(Meturedepa);米丁度胺(Mitindomide);迈拓卡素(Mitocarcin);丝裂红素(Mitocromin);米托洁林(Mitogillin);米托马星(Mitomalcin);丝裂霉素(Mitomycin);米托司培(Mitosper);米托坦(Mitotane);盐酸米托蒽醌;霉酚酸;诺考达唑;诺加霉素;奥马铂;奥昔舒仑(Oxisuran);紫杉醇;培门冬酶(Pegaspargase);培利霉素(Peliomycin);戊氮芥(Pentamustine);硫酸培洛霉素(Peplomycin Sulfate);培磷酰胺(Perfosfamide);哌泊溴烷(Pipobroman);哌泊舒凡(Piposulfan);盐酸罗蒽醌(Piroxantrone Hydrochloride);普卡霉素;普洛美司坦(Plomestane);卟吩姆钠(PorfimerSodium);甲基丝裂霉素(Porfiromycin);泼尼氮芥(Prednimustine);盐酸丙卡巴肼(ProcarbazineHydrochloride);嘌呤霉素;盐酸嘌呤霉素;吡唑呋喃(Pyrazofurin);利波腺苷(Riboprine);罗谷亚胺(Rogletimide);沙芬戈(Safmgol);盐酸沙芬戈(SafingolHydrochloride);甲基环己亚硝脲(Semustine);辛曲秦(Simtrazene);司帕福赛特钠盐(Sparfosate Sodium);司帕霉素;盐酸螺旋锗(Spirogermanium Hydrochloride);螺莫司汀(Spiromustine);螺磺铂胺(Spiroplatin);链黑霉素(Streptonigrin);链脲霉素(Streptozocin);氯化锶Sr 89;磺氯苯脲(Sulofenur);他利霉素(Talisomycin);紫杉烷(Taxane);紫杉烷(Taxoid);替可加兰钠(Tecogalan Sodium);替加氟(Tegafur);盐酸拓兰酮(Teloxantrone Hydrochloride);替莫泊芬(Temoporfin);替尼泊苷(Teniposide);替罗昔隆(Teroxirone);睾内酯(Testolactone);硫咪嘌呤(Thiamiprine);硫鸟嘌呤(Thioguanine);噻替哌(Thiotepa);噻唑羧胺核苷(Tiazofurin);替拉扎明;盐酸拓扑替康;柠檬酸托瑞米芬;醋酸曲托龙(Trestolone Acetate);磷酸曲西瑞宾(TriciribinePhosphate);三甲曲沙;三甲曲沙葡糖醛酸酯;曲普瑞林;盐酸妥布氯唑(TubulozoleHydrochloride);尿嘧啶氮芥(UracilMustard);乌瑞替哌(Uredepa);伐普肽(Vapreotide);维替泊芬;硫酸长春花碱;硫酸长春新碱;长春地辛;硫酸长春地辛;硫酸长春匹定(Vinepidine Sulfate);硫酸长春甘酯;硫酸长春罗辛;酒石酸长春瑞滨;硫酸长春罗定;硫酸长春利定;伏罗唑;折尼铂(Zeniplatin);净司他丁(Zinostatin);盐酸佐柔比星。
所公开的方法的癌症可以是受试者经历的不受调节的生长、侵袭或转移的任何细胞。在一些方面,癌症可以是目前使用放射治疗的任何赘生物或肿瘤。或者,癌症可以是使用标准方法对放射疗法不够敏感的赘生物或肿瘤。因此,所述癌症可以是肉瘤、淋巴瘤、白血病、癌,胚细胞瘤或生殖细胞肿瘤。所公开的组合物可用于治疗的癌症的代表性但非限制性的列表包括:淋巴瘤、B细胞淋巴瘤、T细胞淋巴瘤,蕈样肉芽肿病,霍奇金病,骨髓性白血病,膀胱癌,脑癌,神经系统癌,头颈癌,头颈鳞状细胞癌,肾癌,肺癌如小细胞肺癌和非小细胞肺癌(NSCLC),神经母细胞瘤/成胶质细胞瘤,卵巢癌,胰腺癌,前列腺癌,皮肤癌,肝癌,黑色素瘤,口腔、喉、喉头和肺的鳞状细胞癌,结肠癌,宫颈癌,宫颈上皮癌,乳腺癌,上皮癌,肾癌,泌尿生殖器癌,肺癌,食管癌,头颈癌,大肠癌,造血癌;睾丸癌;结肠和直肠癌,前列腺癌和胰腺癌。例如,提供了肿瘤的类别和类型的列表。
组合物、制剂和施用方法
所公开的化合物和包含它们的组合物的体内应用可以通过本领域技术人员目前或预期已知的任何合适的方法和技术来实现。例如,所公开的化合物可以以生理学上或药学上可接受的形式配制并通过本领域已知的任何合适的途径施用,包括例如口服、鼻、直肠、局部和肠胃外施用途径。如本文所用,术语肠胃外包括皮下、皮内、静脉内、肌内、腹膜内和胸骨内施用,例如通过注射。所公开的化合物或组合物的施用可以是单次施用,或者以本领域技术人员容易确定的连续或不同间隔施用。
本文公开的化合物和包含它们的组合物也可以使用脂质体技术、缓释胶囊、可植入泵和可生物降解的容器给药。这些递送方法可以有利地在延长的时间段内提供均匀的剂量。化合物也可以以其盐衍生物形式或结晶形式施用。
本文公开的化合物可以根据已知方法配制来制备药学上可接受的组合物。制剂在本领域技术人员熟知和容易获得的许多来源中有详细描述。例如,E.W.Martin(1995)的雷明顿药物科学(Remington'sPharmaceuticalScience)描述了可以与所公开的方法结合使用的制剂。通常,可以配制本文公开的化合物,使得有效量的化合物与合适的载体组合以便于化合物的有效给药。所使用的组合物也可以是多种形式。这些包括例如固体、半固体和液体剂型,例如片剂、丸剂、粉剂、液体溶液或悬浮液、栓剂、可注射和可输注的溶液剂和喷雾剂。优选的形式取决于预期的施用模式和治疗应用。所述组合物还优选包括本领域技术人员已知的常规药学上可接受的载体和稀释剂。与化合物一起使用的载体或稀释剂的实例包括乙醇、二甲基亚砜、甘油、氧化铝、淀粉、盐水和等效载体和稀释剂。为了给所需治疗性治疗提供的该剂量下的施用,本文公开的组合物可有利地包含基于总重量约0.1%至99%,特别是1至15%的一种或多种主题化合物,基于包括载体或稀释剂的总组合物的重量。
适于施用的制剂包括例如水性无菌注射溶液、其可含有抗氧化剂、缓冲剂、抑菌剂和使制剂与预期接受者的血液等渗的溶质;和水性和非水性无菌混悬剂,其可以包括悬浮剂和增稠剂。制剂可以存在于单位剂量或多剂量容器中,例如密封的安瓿和小瓶中,并且,在使用前可以储存在仅需要无菌液体载体的条件的冷冻干燥(冻干)条件下,例如注射用水。即用型注射溶液和悬浮液可以由无菌粉末、颗粒、片剂等制备。应当理解,除了上述特别提及的成分之外,本文公开的组合物可以包括本领域中常规的其它试剂,考虑到所讨论的制剂的类型。
本文公开的化合物和包含它们的组合物可以通过与细胞直接接触或通过载体手段递送至细胞。用于将化合物和组合物递送到细胞的载体装置是本领域已知的,包括,例如将组合物包封在脂质体部分中。用于将本文公开的化合物和组合物递送至细胞的另一种手段包括将化合物连接至靶向递送至靶细胞的蛋白质或核酸。美国专利6,960,648和美国专利申请公开号20030032594和20020120100公开了可以偶联到另一种组合物并且允许组合物通过生物膜移位的氨基酸序列。美国申请公开号20020035243还描述了用于将生物部分转移穿过细胞膜进行细胞内递送的组合物。化合物也可以整合入聚合物中,其实例包括用于颅内肿瘤的聚(D-L丙交酯-共-乙交酯)聚合物;聚[双(对羧基苯氧基)丙烷:癸二酸](摩尔比为20:80)(如GLIADEL中所用);软骨素;几丁质和壳聚糖。
为了治疗肿瘤疾病,本文公开的化合物可以联合其它抗肿瘤或抗癌物质和/或放射和/或光动力治疗和/或手术治疗施用给需要治疗的患者以除去肿瘤。这些其它物质或治疗可以与本文公开的化合物相同或不同时给予。例如,使用时本文公开的化合物可以联合有丝分裂抑制剂如紫杉醇或长春碱,烷化剂如环磷酰胺或异环磷酰胺,抗代谢物如5-氟尿嘧啶或羟基脲,DNA嵌入剂如阿霉素或博来霉素,拓扑异构酶抑制剂如依托泊苷或喜树碱,抗血管生成剂例如血管抑制素,抗雌激素例如他莫昔芬和/或其他抗癌药物或抗体,例如分别为GLEEVEC(诺华药物公司)和赫塞汀(Genentech公司),或免疫治疗剂如依匹单抗(ipilimumab)和硼替佐米。
在某些实施例中,本文公开的化合物和组合物可以在一个或多个解剖部位局部给药,例如不想要细胞生长的部位(例如肿瘤部位或良性皮肤生长,例如注射或局部应用于肿瘤或皮肤生长),任选与药学上可接受的载体例如惰性稀释剂组合。本文公开的化合物和组合物可以全身施用,例如静脉内或口服,任选与药学上可接受的载体例如惰性稀释剂,或可吸收的可食用载体组合用于口服递送。它们可以包在硬或软壳明胶胶囊中,可以压制成片剂,或者可以直接与患者的饮食的食物结合。对于口服治疗性给药,活性化合物可与一种或多种赋形剂组合并以其形式使用,如可摄入片剂、口含片剂、锭剂、胶囊、酏剂、混悬剂、糖浆剂、囊剂(wafers)、气溶胶喷雾剂等。
片剂、锭剂、丸剂、胶囊等还可以含有以下物质:粘合剂如黄蓍胶、阿拉伯胶、玉米淀粉或明胶;赋形剂如磷酸二钙、崩解剂如玉米淀粉、马铃薯淀粉、海藻酸等;润滑剂如硬脂酸镁;并且可以加入甜味剂如蔗糖、果糖、乳糖或阿斯巴甜或调味剂如薄荷油、冬青油或樱桃调味剂。当单位剂型是胶囊时,除了上述类型的材料之外,其可以包含液体载体,例如植物油或聚乙二醇。各种其它材料可以作为包衣存在或以其它方式改变固体单位剂型的物理形式。例如,片剂、丸剂、或胶囊可以用明胶、蜡、虫胶或糖等包衣。糖浆或酏剂可以含有活性化合物,蔗糖或果糖作为甜味剂,对羟基苯甲酸甲酯和对羟基苯甲酸丙酯作为防腐剂,染料和调味剂如樱桃或橙味。当然,用于制备任何单位剂型的任何材料应当是药学上可接受的,并且在所使用的量下基本上无毒。此外,活性化合物可以掺入缓释制剂和装置中。
本文公开的化合物和组合物,包括其药学上可接受的盐或其水合物,可以静脉内、肌内或腹膜内输注或注射。活性剂或其盐的溶液可以在水中制备,任选与无毒表面活性剂混合。分散体也可以在甘油、液体聚乙二醇、三醋精及其混合物中和在油中制备。在普通储存和使用条件下,这些制剂可以含有防腐剂以防止微生物的生长。
适于注射或输注的药物剂型可包括含有活性成分的无菌水溶液或分散体或无菌粉末,其适于制备即用型无菌可注射或可输注的溶液或分散体,任选地包囊于脂质体中。最终剂型应在制造和储存条件下是无菌的、流动的和稳定的。液体载体或载体可以是溶剂或液体分散介质,其包含例如水、乙醇、多元醇(例如甘油、丙二醇、液体聚乙二醇等)、植物油、无毒甘油酯和其合适的混合物。可以例如通过形成脂质体,通过在分散体的情况下维持所需的粒度或通过使用表面活性剂来保持适当的流动性。
任选地,可以通过各种其它抗细菌和抗真菌剂防止微生物的活性,例如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸、硫柳汞等。在许多情况下,优选包括等渗剂,例如糖、缓冲剂或氯化钠。可注射组合物的延长吸收可以通过包含延迟吸收的试剂(例如单硬脂酸铝和明胶)来实现。
通过将所需量的本文公开的化合物和/或试剂与上述列举的各种其它成分在合适的溶剂中根据需要混合,随后过滤灭菌来制备无菌可注射溶液。在用于制备无菌注射溶液的无菌粉末的情况下,优选的制备方法是真空干燥和冷冻干燥技术,从而获得活性成分加上先前无菌过滤溶液中存在的任何额外所需成分的粉末。
对于局部给药,本文公开的化合物和试剂可以作为液体或固体施用。然而,通常期望将其作为组合物与皮肤病学可接受的载体(其可以是固体或液体)组合地局部施用于皮肤。本文公开的化合物和试剂和组合物可以局部施用于受试者的皮肤以减小恶性或良性生长的尺寸(并且可以包括完全去除)或治疗感染部位。本文公开的化合物和试剂可以直接施用于生长或感染部位。优选地,将化合物和试剂以制剂如软膏、乳膏、洗剂、溶液、酊剂等施用于生长或感染部位。
有用的固体载体包括细碎的固体,例如滑石、粘土、微晶纤维素、二氧化硅、氧化铝等。可用的液体载体包括水、醇或二醇或水-醇/二醇混合物,其中化合物可以任选地在无毒表面活性剂的帮助下以有效水平溶解或分散。可以加入佐剂如香料和额外的抗微生物剂以优化给定用途的性质。所得液体组合物可以从吸收垫施用,用于浸渍绷带和其它敷料,或者使用例如泵型或气溶胶喷雾器喷涂到受影响的区域上。
增稠剂如合成聚合物、脂肪酸、脂肪酸盐和酯、脂肪醇、改性纤维素或改性矿物材料也可以与液体载体一起使用以形成可涂抹的糊剂、凝胶、软膏、肥皂等,以直接施用于使用者的皮肤。
本文公开的化合物和试剂和药物组合物的起效剂量可以通过比较它们的体外活性和动物模型中的体内活性来确定。将小鼠和其它动物中的有效剂量外推至人的方法是本领域已知的。
在一个实施方案中,所公开的组合物以与肠胃外施用相当的剂量施用,每kg体重约0.1ng至约100g,每kg体重约10ng至约50g,约100ng至约1g每kg体重,约1μg至约100mg每kg体重,约1μg至约50mg每kg体重,约1mg至约500mg每kg体重;和约1mg至约50mg每kg体重。或者,施用组合物的量以实现约0.1ng、1ng、10ng、100ng、1μg、10μg、100μg、1mg、2mg、3mg、4mg、5mg、6mg、7mg、8mg、9mg、10mg、11mg、12mg、13mg、14mg、15mg、16mg、17mg、18mg、19mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、90mg、100mg、500mg每kg体重或更大的治疗有效量。
尽管组合物可以一天施用一次或几次,并且治疗的持续时间可以是每天一次持续约1、2、3、4、5、6、7天或更长的时间,但是更优选地以单个剂量单位或几个较小剂量单位的形式施用单一剂量或以一定间隔多次施用细分剂量。例如,可以从约0小时至约1小时,约1小时至约24小时,约1至约72小时,约1至约120小时,或约24小时至至少约120小时施用一剂量单位。或者,剂量单位可以在约0.5、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、30、40、48、72、96、120小时施用。随后的剂量单位可以在初始施用后的任何时间施用,使得实现治疗效果。使用所公开的组合物的治疗可以替代地包括多水平给药方案,其中组合物在两个或更多个时间段内施用,优选具有约12小时至约7天的组合持续时间,包括1、2、3、4、或5天或约15、15、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100、105、110、115、120、125、130、135、140、或144小时,或者约1至24小时,约12至36小时,约24至48小时,约36至60小时,约48至72小时,约60至96小时,约72至108小时,约96至120小时,或约108至136小时。在一个实施方案中,两水平给药方案具有约1天至约5天的组合持续时间;在其它实施方案中,两水平给药方案具有约1天至约3天的组合持续时间。
还公开了药物组合物,其包含本文公开的化合物联合药学上可接受的载体。适于口服、局部或肠胃外给药的药物组合物包含一定量的化合物构成优选方面。给予患者,特别是人的剂量应足以在合理的时间范围内在患者中实现治疗反应,而没有致死毒性,并且优选引起不超过可接受水平的副作用或发病率。本领域技术人员将认识到,剂量将取决于多种因素,包括施用对象的状况(健康)、施用对象的体重、同时治疗的种类(如果有的话)、治疗频率、治疗比、以及作为病理状态的严重性和阶段。
定义
术语“施用对象”是指作为给药或治疗的目标的任何个体。施用对象可以是脊椎动物,例如哺乳动物。因此,施用对象可以是人类或兽用患者。术语“患者”是指在临床医生(例如内科医生)治疗下的施用对象。
术语“治疗有效”是指所使用的组合物的量具有足以改善疾病或病症的一种或多种原因或症状的量。这种改善仅需要减少或改变,而不一定是消除。
术语“治疗”是指旨在治愈、改善、稳定或预防疾病、病理状况或病症的患者的医疗管理。该术语包括主动治疗,即特异性针对疾病、病理状况或病症的改善的治疗,并且还包括病因治疗,即针对去除相关疾病、病理状况或病症的原因的治疗。此外,该术语包括姑息治疗,即设计用于缓解症状而不是治愈疾病、病理状况或病症的治疗;预防性治疗,即最小化或部分或完全抑制相关疾病、病理状况或病症的发展的治疗;和支持性治疗,即用于补充针对改善相关疾病、病理状况或病症的另一种特定治疗的治疗。
术语“抑制”是指活性、反应、病症、疾病或其它生物学参数的降低。这可以包括但不限于活性、反应、病症或疾病的完全消除。这还可以包括例如与天然或对照水平相比活性、反应、病症或疾病减少10%。因此,与天然或对照水平相比,减少可以是10%、20%、30%、40%、50%、60%、70%、80%、90%、100%或任何量之间的减少。
术语“增生细胞”或“增生”是指经历生理(正常)细胞增殖(“增生”)的细胞。
术语“新生细胞”或“新生物”是指经历异常细胞增殖(“新生物形成性”)的细胞。新生细胞的生长超过并且不与其周围的正常组织的生长协调。生长通常以相同的过度方式持续,即使在刺激停止后,并且通常导致肿瘤的形成。新生物可以是良性的、恶变前的或恶性的。
术语“癌症”或“恶性新生物”是指显示不受控制的生长、侵入相邻组织并且经常转移到身体的其它位置的细胞。
术语“肿瘤”是指含有新生细胞的异常大量的组织。
术语“转移”是指恶性肿瘤细胞从一个器官或部分扩散到另一个不相邻的器官或部分。癌细胞可以从原发性肿瘤“脱离”、“泄漏”或“溢出”,进入淋巴和血管,通过血流循环,并沉降下来在体内其他地方的正常组织内生长。当肿瘤细胞转移时,新肿瘤称为继发性或转移性癌症或肿瘤。
术语“抗体”是指选择性结合于靶抗原的天然或合成抗体。该术语包括多克隆和单克隆抗体。除完整的免疫球蛋白分子外,术语“抗体”中还包括那些免疫球蛋白分子的片段或聚合物,以及选择性结合靶抗原的人或人源化形式的免疫球蛋白分子。
术语“肽”、“蛋白质”和“多肽”可互换使用,是指包含通过一个氨基酸的羧基与另一个氨基酸的α氨基连接的两个或更多个氨基酸的天然或合成分子。
如本文所用,“模拟肽”是指肽的模拟物,其包括正常肽化学的一些改变。模拟肽通常增强原始肽的一些性质,例如增加稳定性、增加功效、增强递送、增加半衰期等。模拟肽的使用可涉及在给定位置并入非氨基酸残基与非酰胺键。本发明的一个实施方案是模拟肽,其中所述化合物具有键、肽主链或用合适的模拟物替代的氨基酸组分。可以是合适的氨基酸模拟物的非天然氨基酸的一些非限制性实例包括β-丙氨酸、L-a-氨基丁酸、L-γ-氨基丁酸、L-a-氨基异丁酸、L-ε-氨基己酸、7-氨基庚酸、L-天冬氨酸、L-谷氨酸、N-ε-Boc-Na-CBZ-L-赖氨酸、N-ε-Boc-N-a-Fmoc-L-赖氨酸、L-甲硫氨酸砜、L-正亮氨酸、L-正缬氨酸,N-α-Boc-N-δCBZ-L-鸟氨酸、N-δ-Boc-N-α-CBZ-L-鸟氨酸、Boc-对硝基-L-苯丙氨酸、Boc-羟脯氨酸和Boc-L-硫代脯氨酸。
术语“肿瘤浸润淋巴细胞”或“TIL”是指已经离开血流并迁移到肿瘤中的白细胞。
术语“回归”不一定意味着100%或完全回归。相反,存在本领域普通技术人员认为具有潜在益处或治疗效果的不同程度的回归。该术语还包括延迟疾病或其症状或病症的发作。
已经描述了本发明的多个实施方式。
然而,应当理解,在不脱离本发明的精神和范围的情况下可以进行各种修改。因此,其他实施例在所附权利要求的范围内。
除非另有定义,本文使用的所有技术和科学术语具有与所公开的发明所属领域的技术人员通常理解的相同的含义。本文引用的出版物和其引用的材料通过引用特别地并入。
本领域技术人员将认识到或仅使用常规实验就能够确定本文所述的本发明的具体实施方案的许多等同物。这些等同物旨在被所附权利要求所涵盖。
实施例
实施例1:纳武单抗(Nivolumab)与GM.CD40L疫苗联合用于肺腺癌的随机I/II期临床研究。
以下是II期临床试验的描述,以建立结合抗PD-1治疗与GM.CD40L肿瘤疫苗的功效。
Claims (8)
1.一种治疗一施用对象体内癌症的方法,包括向所述施用对象施用一组合物,所述组合物包括治疗有效量的免疫检查点抑制剂和治疗有效量的肿瘤疫苗。
2.如权利要求1所述的方法,其中所述检查点抑制剂包括抗PD-1抗体、抗PD-L1抗体、抗CTLA-4抗体、或其组合。
3.如权利要求2所述的方法,其中抗PD-1抗体包括纳武单抗(Nivolumab)。
4.如上述任一权利要求所述的方法,其中所述癌症包括非小细胞肺癌。
5.如上述任一权利要求所述的方法,其中所述肿瘤疫苗包括经辐射的自体肿瘤细胞和工程化的表达GM-CSF和CD40配体的细胞系。
6.如权利要求5所述的方法,其中所述细胞被进一步工程化表达一个或多个选自下组的因子:IL-1、IL-2、IL-3、IL-4、IL-5、IL-IL-6、IL-7、IL-8、IL-9、IL-10、IL-11、IL-15、促红细胞生成素、GCSF、M-CSF、血小板衍生生长因子(PDGF)、MSF、FLT-3配体、EGF、成纤维细胞生长因子(FGF)、bFGF(FGF-2)、FGF-3、FGF-4、FGF-5、FGF-6或FGF-7、胰岛素样生长因子I(IGF-1)、胰岛素样生长因子2(IGF-2)、血管内皮生长因子(VEGF)、IFN-γ、IFN-α、IFN-β、白血病抑制因子(LIF)、睫状神经营养因子(CNTF)、制瘤素M;干细胞因子(SCF)、TGF-α、和TGF-βI。
7.如权利要求5或6所述的方法,其中所述细胞是MHC阴性的。
8.如权利要求5至7任一所述的方法,其中所示细胞是肿瘤细胞。
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PCT/US2016/035922 WO2016197067A1 (en) | 2015-06-05 | 2016-06-03 | Gm-csf/cd40l vaccine and checkpoint inhibitor combination therapy |
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