CN107735096A - 树突状细胞免疫疗法 - Google Patents
树突状细胞免疫疗法 Download PDFInfo
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Abstract
提供了在受试者中提供靶向免疫应答的方法,其包括施用树突细胞群。在一些方面,树突细胞连同I型干扰素(INF)、TLR‑7激动剂、TLR‑9激动剂、AIMp1、TLR‑3激动剂、维甲酸诱导基因‑1(RIG‑1)样受体配体或细胞溶质DNA(CDS)受体配体一起施用和/或施用于接近患病组织的组织部位。同样提供了治疗性树突细胞组合物。
Description
本申请要求于2015年5月7日提交的美国临时专利申请第62/158,237号的权益,其全部内容以引用的方式并入本文。
本发明是受政府支持在美国国家卫生研究院授予的批准号AI036211、CA125123和RR024574下进行的。政府对本发明具有一定的权利。
序列表的并入
命名为“BACMP0004WO_ST25.txt”的文件中所含的,为4KB(正如在Microsoft中所测量的),且创建于2016年4月19日的序列表,通过电子投递随函提交并且以引用的方式并入本文。
发明背景
1.技术领域
本发明总体上涉及分子生物学、免疫学和医学领域。更具体地,涉及在受试者中提供免疫应答的方法。
2.相关技术说明
作为关键的TH1相关效应子,CD8+细胞毒性T细胞(CTL)是治疗性干预有吸引力的靶标,因为它们的效应子功能对于抗病毒和抗肿瘤免疫力是至关重要,并且因此对于宿主的存活至关重要(Dudda等人,2013)。T细胞活化需要与专职抗原呈递细胞(APC)的相互作用,其中树突细胞(DC)在抗原加工和呈递、淋巴细胞共刺激,以及细胞因子和调节终末T细胞分化的其它炎症介质的产生中大部分高度特化(Lotze等人,2001)。DC均具有促进T细胞极化以及自身变成极化TH1(例如DC1)的功能(Hokey等人,2005)。DC1-极化可通过炎性细胞因子(Hilkens等人,1997)、干扰素(Longhi等人,2009)和包括toll样受体(TLR)配体的模式识别受体(PRR)激动剂的各种组合来促进(Spranger等人,2010),但源自TLR-/-、MyD88-/-、I型干扰素(IFN)-/-和I型IFNR-/-系统的混淆数据提到了另外、未经鉴定的调节DC极化的机制(Ahmed等人,2009;Carvalho等人,2011;Lopez等人,2003;Lopez等人,2006A;Lopez等人,2006B;Tam和Wick,2009)。此外,尝试通过使用免疫原性、异源II类肽来增强T细胞的帮助和DC许可(Jones等人,1999;Rosa等人,2004)成功地增强了CD40信号传导,但自相矛盾的是也下调了某些模型中的抗原特异性CD8+CTL(Hung等人,2007;Kim等人,2008;Ressing等人,2000)。其它研究表明流感特异性TH1免疫力通常可以在缺乏CD4+ T-细胞的小鼠中产生(Allan等人,1990),但是在缺乏II类MHC的小鼠中有缺陷(Tripp等人,1995),表明在TH极化中对MHC的潜在作用。尽管对调节树突细胞抗原呈递和功能的因素进行了显著的机械研究,但到目前为止,还不清楚如何调节树突细胞抗原呈递以增强免疫刺激。
发明概述
在第一个实施方案中,本发明提供了一种在具有患病细胞群的受试者中提供免疫应答的方法,其包括获得致敏的树突细胞群,其中所述细胞已经用至少一种对患病细胞群有特异性的抗原致敏,并且向所述受试者施用有效量的致敏的树突细胞群。在一些方面,致敏的树突细胞群连同I型干扰素(INF)、TLR-7激动剂、TLR-9激动剂、AIMp1、TLR-3激动剂、维甲酸诱导基因-1(RIG-1)样受体配体或细胞溶质DNA(CDS)受体配体一起施用。在另外的方面,将致敏的树突细胞群施用于受试者中接近患病细胞群的淋巴组织部位。在另一方面,致敏的树突细胞群连同I型干扰素(INF)、TLR-7激动剂、TLR-9激动剂、AIMp1TLR-3激动剂、维甲酸诱导基因-1(RIG-1)样受体配体或细胞溶质DNA(CDS)受体配体一起施用且施用于受试者中接近患病细胞群的淋巴组织部位。
实施方案的一些方面涉及连同I型干扰素(INF)、TLR-7激动剂、TLR-9激动剂、AIMp1或其混合物一起施用致敏的树突细胞群。例如,在一些情况下,所述致敏的树突细胞群连同I型INF一起施用。在一些方面,I型INF可为INF-α、IFN-β、IFN-ε、IFN-κ或IFN-ω。在另外的方面,致敏的树突细胞群连同TLR-7激动剂一起施用。在一些方面,TLR-7激动剂可选自CL075、CL097、CL264、CL307、GS-9620、聚(dT)、咪喹莫特(imiquimod)、嘎德莫特(gardiquimod)、雷西莫特(resiquimod)(R848)、洛索立宾(loxoribine)和ssRNA寡核苷酸。在另外的方面,致敏的树突细胞群连同TLR-9激动剂一起施用。例如,在一些情况下,TLR-9激动剂可为CpG寡脱氧核苷酸(CpG ODN)。在另外的方面,致敏的树突细胞群连同AIMp1多肽一起施用(参见例如NCBI登录号NP_001135887.1和NP_001135888.1,各自以引用的方式并入本文)。在一些方面,致敏的树突细胞群连同TLR-3激动剂一起施用。在特定方面,TLR-3激动剂为聚肌苷-聚胞苷酸(聚(I:C))或RGC100。在某些方面,致敏的树突细胞群连同RIG-1样受体配体一起施用。在一些方面,RIG-1样受体配体被进一步限定为RIG-1、MDA5、LGP2或IPS-1配体。例如,RIG-1样受体配体选自MDA5配体、LGP2配体、ssRNA、dsRNA、5'ppp-dsRNA、聚(dA:dT)和聚(I:C)。在某些方面,致敏的树突细胞群连同CDS受体配体一起施用。在一些方面,CDS受体配体被进一步限定为cGAS-STING配体。例如,cGAS-STING配体为细菌环状二核苷酸(CDN)。
在某些方面,I型INF、TLR-7激动剂、TLR-9激动剂、AIMp1、TLR-3激动剂、维甲酸诱导基因-1(RIG-1)样受体配体或细胞溶质DNA(CDS)受体配体在致敏的树突细胞群之前、之后或基本上同时施用。在一些方面,全身施用I型INF、TLR-7激动剂、TLR-9激动剂或AIMp1,而局部施用树突细胞群。在另外的方面,I型INF、TLR-7激动剂、TLR-9激动剂或AIMp1和树突细胞群均局部施用,例如在受试者中接近患病细胞群的部位。在特定方面,I型INF、TLR-7激动剂、TLR-9激动剂或AIMp1在致敏的树突细胞群的约1周、1天、8小时、4小时、2小时或1小时内施用。在某些方面,施用了致敏的树突细胞群的受试者先前已经用I型INF、TLR-7激动剂、TLR-9激动剂或AIMp1治疗,或者目前正在治疗。在一些方面,所述方法还包括向所述受试者施用包含有效量的致敏的树突细胞群和I型INF、TLR-7激动剂、TLR-9激动剂或AIMp1的组合物。
在另外的方面,实施方案的方法还包括向受试者施用免疫检查点抑制剂(连同致敏树突细胞组合物一起)。例如,在一些方面,免疫检查点抑制剂为CTLA-4拮抗剂。在一些方面,CTLA-4拮抗剂是对CTLA-4有特异性的小分子抑制剂或抑制剂核酸。在某些方面,抑制性核酸为RNA。在另外的方面,所述RNA为小干扰RNA(siRNA)或短发夹RNA(shRNA)。在另外的方面,CTLA-4拮抗剂为CTLA-4结合抗体。在一些方面,抗体为单克隆抗体或多克隆抗体,在一些方面,CTLA-4结合抗体可为IgG(例如,IgG1、IgG2、IgG3或IgG4)、IgM、IgA、经遗传修饰的IgG同种型或其抗原结合片段。抗体可为Fab'、F(ab')2、F(ab')3、单价scFv、二价scFv、双特异性或单域抗体。抗体可为人、人源化或去免疫化抗体。在另外的方面,免疫检查点抑制剂为伊匹单抗、帕姆单抗或纳武单抗。
在实施方案的某些方面,将致敏的树突细胞群施用于受试者中接近患病细胞群的淋巴组织部位。在另外的方面,致敏的树突细胞群连同I型INF、TLR-7激动剂、TLR-9激动剂、AIMp1、TLR-3激动剂、维甲酸诱导基因-1(RIG-1)样受体配体或细胞溶质DNA(CDS)受体配体一起施用,并将致敏的树突细胞群施用于受试者中接近患病细胞群的淋巴组织部位。在具体方面,所述淋巴组织部位是为患病细胞群周围的组织引流的淋巴组织。例如,在一些方面,将致敏的树突细胞群施用于为患病细胞群周围的组织引流的淋巴结。在一些具体方面,将致敏的树突细胞群施用于亚段淋巴结、段淋巴结、叶淋巴结、叶间淋巴结、肺门淋巴结、纵隔淋巴结、滑车上淋巴结、三角胸肌淋巴结、外侧淋巴结、胸肌淋巴结、肩胛下淋巴结、中间淋巴结、锁骨下淋巴结、腹股沟浅淋巴结、腹股沟深淋巴结、腘淋巴结、面部颊淋巴结、面部鼻唇淋巴结、前列腺淋巴结、下颌淋巴结、颏下淋巴结、枕淋巴结、乳突/耳后淋巴结、腮腺淋巴结、腮腺前深淋巴结、腮腺下深淋巴结、腮腺内深淋巴结、颈深淋巴结、颈前深淋巴结、气管前淋巴结、气管旁淋巴结、喉前淋巴结、甲状腺淋巴结、颈外侧深淋巴结、颈上深淋巴结、颈下深淋巴结、咽后淋巴结、颈内静脉二腹肌淋巴结、颈前淋巴结、颈外侧淋巴结、锁骨上淋巴结、主动脉后淋巴结、主动脉外侧淋巴结、腹膜淋巴结、胃淋巴结、肝淋巴结、脾淋巴结、肠系膜上淋巴结、肠系膜淋巴结、回肠结肠淋巴结、结肠系膜淋巴结、肠系膜下淋巴结或直肠旁淋巴结。在一些方面,通过直接注射到淋巴结内施用树突细胞群。
在某些方面,根据实施方案治疗的受试者患有癌症、自身免疫性疾病或感染性疾病。自身免疫性疾病的实例包括但不限于乳糜泻、1型糖尿病(IDDM)、全身性红斑狼疮(SLE)、斯耶格伦综合征(syndrome)、多发性硬化(MS)、桥本氏甲状腺炎(Hashimoto's thyroiditis)、格雷夫斯病(Graves'disease)、特发性血小板减少性紫癜、类风湿关节炎(RA)、急性特发性血小板减少性紫癜、慢性特发性血小板减少性紫癜、皮肌炎、西登哈姆氏舞蹈病(Sydenham's chorea)、重症肌无力、全身性红斑狼疮、狼疮性肾炎、风湿热、多腺性综合征、大疱性类天疱疮、糖尿病、亨-舍二氏紫癜(Henoch-Schonleinpurpura)、链球菌感染后肾炎、结节性红斑、高安氏动脉炎(Takayasu's arteritis)、阿狄森病(Addison's disease)、类风湿性关节炎、多发性硬化、结节病、溃疡性结肠炎、多形性红斑、IgA肾病、结节性多动脉炎、强直性脊柱炎、古德帕斯彻综合征(Goodpasture'ssyndrome)、血栓闭塞性脉管炎、干燥综合征(Sjogren's syndrome)、原发性胆汁性肝硬化、桥本氏甲状腺炎、甲状腺毒症、硬皮病、慢性活动性肝炎、多肌炎/皮肌炎、多软骨炎、寻常型天疱疮、韦格纳肉芽肿(Wegener's granulomatosis)、膜性肾病、肌萎缩性侧索硬化、脊髓痨、巨细胞性动脉炎/多肌痛、恶性贫血、急进性肾小球肾炎、牛皮癣和纤维性肺泡炎。感染性疾病的实例包括但不限于炭疽病、水痘、白喉、甲型、乙型或丙型肝炎、HIB、HPV、HIV、莱姆病(Lyme disease)、季节性流感、脑炎、疟疾、麻疹、脑膜炎、腮腺炎、百日咳、脊髓灰质炎、狂犬病、风疹、带状疱疹、天花、破伤风、TB和黄热病(yeller fever)。
在实施方案的一些方面,通过实施方案的方法和组合物治疗的患病细胞群为癌细胞。可以根据实施方案治疗的癌细胞包括但不限于来自膀胱、血液、骨、骨髓、脑、乳腺、结肠、食道、胃肠、齿龈、头、肾、肝、肺、鼻咽、颈部、卵巢、前列腺、皮肤、胃、睾丸、舌头或子宫的细胞。在一些方面,所述癌症可为恶性肿瘤;癌;未分化癌;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;毛母质癌;移行细胞癌;乳头状移行细胞癌;腺癌;恶性胃泌素瘤;胆管癌;肝细胞癌;混合型肝细胞癌和胆管癌;小梁腺癌;腺样囊性癌;腺瘤性息肉内腺癌;家族性结肠息肉腺癌;实体癌;恶性类癌瘤;细支气管腺泡状腺癌;乳头状腺癌;嫌色细胞癌;嗜酸细胞癌;嗜酸性腺癌;嗜碱细胞癌;透明细胞腺癌;颗粒细胞癌;滤泡状腺癌;乳头状和滤泡状腺癌;非包围性硬化性癌;肾上腺皮质癌;内膜样癌;皮肤附属器癌;顶泌腺癌;皮脂腺癌;耵聍腺癌;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;乳腺佩吉特式病(paget's disease);腺泡细胞癌;腺鳞癌;腺癌伴鳞状化生;恶性胸腺瘤;恶性卵巢间质肿瘤;恶性泡膜细胞瘤;恶性粒膜细胞瘤;恶性男性细胞瘤;塞尔托利细胞癌(sertoli cell carcinoma);恶性莱迪希细胞瘤(leydig cell tumor);恶性脂质细胞瘤;恶性副神经节瘤;恶性乳房外副神经节瘤;嗜铬细胞瘤;血管球肉瘤;恶性黑素瘤;无黑色素性恶性黑素瘤;浅表扩散性黑素瘤;巨大色素痣内恶性黑色瘤;上皮样细胞黑素瘤;恶性蓝痣;肉瘤;纤维肉瘤;恶性纤维组织细胞瘤;粘液肉瘤;脂肪肉瘤;平滑肌肉瘤;横纹肌肉瘤;胚胎横纹肌肉瘤;泡状横纹肌肉瘤;间质肉瘤;恶性混合肿瘤;苗勒氏混合瘤(mullerianmixed tumor);肾母细胞瘤;肝母细胞瘤;癌肉瘤;恶性间质瘤;恶性布伦纳瘤(brennertumor);恶性叶状瘤;滑膜肉瘤;恶性间皮瘤;无性细胞瘤;胚性癌;恶性畸胎瘤;恶性卵巢甲状腺瘤;绒毛膜癌;恶性中肾瘤;血管肉瘤;恶性血管内皮瘤;卡波西肉瘤(kaposi'ssarcoma);恶性血管外皮细胞瘤;淋巴管肉瘤;骨肉瘤;皮质旁骨肉瘤;软骨肉瘤;恶性成软骨细胞瘤;间质软骨肉瘤;骨巨细胞瘤;尤因氏肉瘤(ewing's sarcoma);恶性牙源性肿瘤;成釉细胞牙肉瘤;恶性成釉细胞瘤;成釉细胞纤维肉瘤;恶性松果体瘤;脊索瘤;恶性胶质瘤;室管膜瘤;星形细胞瘤;原浆性星形细胞瘤;纤维性星形细胞瘤;成星形细胞瘤;成胶质细胞瘤;少突神经胶质瘤;成少突神经胶质细胞瘤;原始神经外胚层肿瘤;小脑肉瘤;成神经节细胞瘤;成神经细胞瘤;成视网膜细胞瘤;嗅神经源性肿瘤;恶性脑膜瘤;神经纤维肉瘤;恶性神经鞘瘤;恶性粒细胞瘤;恶性淋巴瘤;霍奇金氏病(hodgkin's disease);霍奇金氏病;类肉芽肿;小淋巴细胞性恶性淋巴瘤;大细胞弥漫性恶性淋巴瘤;滤泡性恶性淋巴瘤;蕈样霉菌病;其它指定的非霍奇金淋巴瘤;恶性组织细胞增多症;多发性骨髓瘤;肥大细胞肉瘤;免疫增生性小肠疾病;白血病;淋巴性白血病;浆细胞白血病;红白血病;淋巴肉瘤细胞白血病;骨髓性白血病;嗜碱细胞性白血病;嗜酸细胞性白血病;单核细胞性白血病;肥大细胞白血病;巨核母细胞白血病;髓样肉瘤;和毛细胞白血病。在另外的方面,所述癌症为脑癌(例如,胶质瘤)、前列腺癌、乳腺癌(例如,三阴性乳腺癌)、胰腺癌(例如,胰腺导管腺癌)、急性骨髓性白血病(AML)、黑素瘤、肾细胞癌或慢性淋巴细胞性白血病。
在特定方面,患病细胞群为肿瘤,例如实体瘤。在另外的方面,将致敏的树突细胞群施用于为肿瘤引流的淋巴结。在具体方面,肿瘤为转移性肿瘤并将致敏的树突细胞群施用于为原发性肿瘤部位引流的淋巴结。在另外的方面,癌症为脑肿瘤(例如,胶质瘤)、前列腺肿瘤、乳腺肿瘤(例如,三阴性乳腺癌)、胰腺肿瘤(例如,胰腺导管腺癌)或肾细胞肿瘤。
在另外的方面,实施方案的方法还可包括向受试者施用多于一次的本发明的组合物,例如1、2、3、4、5、6、7、8、9、10、15、20次或更多次。
在一些方面,根据实施方案治疗的受试者为哺乳动物受试者。例如,受试者可为灵长类,如人。在另外的方面,受试者为非人哺乳类动物,例如狗、猫、马、牛、山羊、猪或动物园动物。
在另一个实施方案中,提供了免疫原性组合物,其包含:(i)抗原致敏的树突细胞和(ii)I型干扰素(INF)、TLR-7激动剂、TLR-9激动剂、AIMp1、TLR-3激动剂、维甲酸诱导基因-1(RIG-1)样受体配体或细胞溶质DNA(CDS)受体配体。在一些方面,抗原致敏的树突细胞已经用与癌症、自身免疫性疾病或感染性疾病相关的抗原致敏。在某些方面,抗原致敏的树突细胞已经用至少一种肿瘤抗原致敏。
因此,在具体方面,实施方案的组合物包含致敏的树突细胞群和I型INF。在一些方面,I型INF可为INF-α、IFN-β、IFN-ε、IFN-κ或IFN-ω。在其它方面,组合物包含致敏的树突细胞群和TLR-7激动剂。在一些方面,TLR-7激动剂可选自CL075、CL097、CL264、CL307、GS-9620、聚(dT)、咪喹莫特、嘎德莫特、雷西莫特(R848)、洛索立宾和ssRNA寡核苷酸。在另外的方面,组合物包含致敏的树突细胞群和TLR-9激动剂。在一些情况下,TLR-9激动剂可为CpG寡脱氧核苷酸(CpG ODN)。在另一方面,实施方案的组合物包含致敏的树突细胞群和AIMp1。
另一个实施方案提供了一种免疫原性组合物,其包含:(i)抗原致敏的树突细胞和(ii)TLR-3激动剂、RIG-1样受体配体或CDS受体配体。在一些方面,抗原致敏的树突细胞已经用与癌症、自身免疫性疾病或感染性疾病相关的抗原致敏。在某些方面,抗原致敏的树突细胞已经用至少一种肿瘤抗原致敏。在一些方面,肿瘤为脑肿瘤、肾细胞癌、黑素瘤、前列腺癌、乳腺癌或慢性淋巴细胞性白血病。在一些方面,所述组合物包含TLR-3激动剂。在特定方面,TLR-3激动剂为聚(I:C)或RGC100。在一些方面,其包含RIG-1样受体配体。在一些方面,RIG-1样受体配体选自MDA5配体、LGP2配体、ssRNA、dsRNA、5'ppp-dsRNA、聚(dA:dT)和聚(I:C)。在某些方面,所述组合物包含CDS受体配体。例如,CDS受体配体为细菌CDN。
在本发明的另一个实施方案中,提供了一种培养抗原特异性T细胞的方法,其包括在抗原呈递细胞群的存在下培养T细胞或T细胞前体的群体,其中所述培养是在AIMp1的存在下进行。在一些方面,抗原呈递细胞群为致敏的树突细胞群。在其它方面,抗原呈递细胞群可为人工抗原呈递细胞,已经灭活(例如,通过照射)的这种细胞。在一些方面,该方法被进一步限定为离体扩增抗原特异性T细胞的方法。在某些方面,树突细胞群包含原代树突细胞。在另外的方面,所述培养是在免疫检查点抑制剂,例如CTLA-4拮抗剂的存在下进行。在具体方面,CTLA-4拮抗剂是对CTLA-4有特异性的抑制剂核酸。在某些方面,抑制性核酸为RNA。在另外的方面,所述RNA为小干扰RNA(siRNA)或短发夹RNA(shRNA)。在其它方面,CTLA-4拮抗剂为CTLA-4结合抗体。
在另一个实施方案中,提供了一种培养抗原特异性T细胞的方法,其包括在已经用至少第一抗原致敏的抗原呈递细胞群的存在下培养T细胞或T细胞前体的群体,其中所述培养是在聚(I:C)的存在下进行。在一些方面,该方法被进一步限定为离体扩增抗原特异性T细胞的方法。在一些方面,抗原呈递细胞包含树突细胞。在某些方面,树突细胞同源负载抗原。在一些方面,树突细胞群包含原代树突细胞。在一些方面,培养是在受试者的免疫检查点抑制剂的存在下进行。在一些方面,免疫检查点抑制剂为CTLA-4拮抗剂。在特定方面,免疫检查点抑制剂为伊匹单抗、帕姆单抗或纳武单抗。
如本文中所用,“基本上游离的”,就指定组分而言,在本文中用于意指指定组分尚未有目的地配制成组合物和/或仅作为污染物或微量存在。因此由组合物的任何意外污染而产生的指定成分的总量远低于0.05%。最优选的是其中不能用标准分析方法检测到指定组分的量的组合物。
如说明书和权利要求书中所用,“一个/种”可以意指一个/种或多个/种。如说明书和权利要求书中所用,当连同词“包含”一起使用时,词“一个/种”可以意指一个/种或多于一个/种。如本文中所用,在说明书和权利要求书中,“另一个”或“另一”可以意指至少第二个或更多个。
如本文在说明书和权利要求书中所用,术语“约”用于表示值包括用于测定该值的装置、方法的固有误差变化,或存在于研究对象之间的变化。
从以下详细描述中,本发明的其它目的、特征和优点将变得显而易见。然而,应当理解,详细描述和具体实例尽管指出了本发明的某些实施方案,但仅以说明的方式给出,因为对于本领域技术人员而言从这种详细描述中,本发明的精神和范围将变得显而易见。
附图简述
以下附图形成本说明书的一部分,并且被包括在内以进一步证明本发明的某些方面。通过参考这些附图中的一个或多个,结合本文提出的具体实施方案的详细描述可以更好地理解本发明。
图1A-F:抗原相关MHC I类和II类决定簇的同时负载促进小鼠DC的TH1-极化。(A)一起负载同源mRNA(电穿孔)和裂解物(孵育)的小鼠DC与脾细胞共培养时通过ELISA测定,分泌的IL-12p70比交替负载的DC显著更多。这种效应通过AIMp1的siRNA敲低所消除。抗原源自RAW264.7细胞系。异源II类抗原源自4T1乳腺癌细胞系。Y轴:来自无负载(UL)DC的IL-12p70分泌的倍数变化。(B)在共培养之前,通过48小时细胞培养物上清液的蛋白质印迹测定,同源负载DC分泌的AIMp1比负载异源决定簇或其它单负载的DC显著更多。上图:同源负载RAW264.7抗原决定簇后的AIMp1释放。源自4T1的异源裂解物。下图:同源负载原代SV抗原决定簇后的AIMp1释放。源自原代前列腺的异源裂解物。(C)同源负载DC也显示出sCTLA-4分泌的显著降低。显示:同源负载RAW264.7抗原决定簇后的sCTLA-4释放。源自4T1的异源裂解物。(D)同源负载DC中的AIMp1 siRNA敲低将sCTLA-4分泌恢复到同源负载B16黑素瘤决定簇(左图)和原代SV决定簇(右图)的DC的基线。所示数据表明典型AIMp1敲低>70%。(E)同源负载SV决定簇的DC与自体脾细胞体外共培养期间,与通过任何其它方式负载的DC相比,引起显著增加的CD3+、CD3+CD8+和CD3+CD8+CD25+T细胞增殖。通过用AIMp1siRNA处理同源负载DC消除了这种效应。异源裂解物为原代前列腺。Y轴:与无负载(UL)DC相比,总细胞计数的倍数变化。(F)同源负载SIINFEKL(SEQ ID NO:1)MHC I类H-2Kd结合表位和整个OVA蛋白的DC与以任何其它方式负载的DC相比,引起显著增加的CD3+、CD3+CD8+和CD3+CD8+CD25+T细胞体内增殖。这种效应通过用AIMp1 siRNA处理同源负载DC消除并且在H2-DM-/-DC未观察到。异源II类抗原为原代SV裂解物。Y轴:与无负载(UL)DC相比的倍数变化百分比。对于所有实验而言,siNT或NT=非靶向siRNA。siAIMp1=AIMp1 siRNA。
图2A-F:同源I类和II类抗原决定簇以独立于PRR激动作用的方式产生TH1极化DC。(A)用表达GFP的腺病毒转导、与rGFP蛋白一起孵育,两项都不进行或两项都进行后,人DC培养物上清液的sCTLA-4 ELISA。使用无关抗原,鼠IL-4也表示异源负载。(C)在两个不同的蛋白质浓度下用GFP-mRNA电穿孔、与rGFP蛋白一起孵育,两项都不进行或两项都进行后,人DC培养物上清液的AIMp1蛋白质印迹。示出了五个中的一个代表性实验。(C)用I类流感HA肽电穿孔并与重叠(同源)或非重叠(异源)II类流感HA肽一起孵育后,人DC培养物上清液的sCTLA-4蛋白质印迹。(D)在各种TLR激动刺激物的存在下负载同源或异源I类和II类肽对后,人DC培养物上清液的sCTLA-4和AIMp1蛋白质印迹。示出了三个中的代表性实验。(E)(d)中描绘的三个独立实验的数据的AIMp1/sCTLA-4比率的密度计量定量(F)RT-PCR分析表明DC负载同源流感HA肽对(B8-166(SEQ ID NO:3)/DR3-162(SEQ ID NO:2)和A2-443(SEQ IDNO:5)/DR3-440(SEQ ID NO:4))(Decker等人,2009)显著下调CTLA-4和sCTLA-4mRNA转录物。无负载、单负载和异源负载DC继续表达CTLA-4。GAPDH扩增显示为负载对照。(*)=负载异源肽对+/-I类肽电穿孔对CLTA-4表达无影响。
图3A-G:AIMp1/sCTLA-4调节依赖于同源I类和II类肽与MHC的结合。(A)单一、同源或异源负载SV mRNA和裂解物后,野生型(上图)和H2-DM-/-(下图)鼠DC培养物上清液的sCTLA-4(右图)和AIMp1(左图)蛋白质印迹。示出了代表性实验。(B)(a)中描绘的三个独立实验的数据的AIMp1/sCTLA-4比率的密度计量定量。上图:野生型DC。下图:H2-DM-/-DC。(C)H2-DM-/-DC负载与CLIP具有氨基酸序列同源性的I类H-2Db肽重现AIMp1和sCTLA-4(Ii CLIP=SEQ IDNO:6;H2-Db CLIP=SEQ ID NO:7)的适当调节。(D)响应于H2-DM-/-DC同源负载I类H-2Db CLIP的高AIMp1/sCTLA-4分泌率介导了体外TH1应答的下游增加,这通过负载H-2DbCLIP的H2-DM-/-DC与自体脾细胞共培养后,活化CD8+T细胞的发育增强所证明。(E)引入I类或II类结合肽的氨基酸取代(Gly取代为Met),从而限制与三个氨基酸有连续同源性的区域,足以消除响应于肽负载的高AIMp1/sCTLA-4分泌率。在同源肽上引入补偿性取代,从而重现延长的同源性,足以拯救高AIMp1/sCTLA-4分泌率。显示:16个中的代表性实验。(甘氨酸对:I类=SEQ ID NO:3,II类=SEQ ID NO:2;甲硫氨酸对:I类=SEQ ID NO:8,II类=SEQID NO:9)(F)(e)中呈现的数据的密度计量定量。16个独立实验的平均值。*p<0.05。(G)AIMp1coIP表明当DC负载同源肽时,AIMp1与MHC的相互作用被大幅消除,表明分泌的AIMp1可能源自MHC结合的AIMp1。(异源肽=SEQ ID NO:3和SEQ ID NO:10;同源肽=SEQ ID NO:3和SEQ ID NO:11;II类肽=SEQ ID NO:11和SEQ ID NO:10;I类肽=SEQ ID NO:3和SEQ IDNO:8)
图4A-E:通过同源抗原决定簇极化的DC克服了外周耐受性并消融精囊。(A)取自仅注射佐剂或注射SV-负载的同源DC疫苗加佐剂的雄性C57BL/6小鼠的精囊的整体(右图)和亚整体(左图)图像。(B)3D纵向MRI显示SV在六个月的时间进程中的消融。(C)接种后6个月的H&E染色SV显示,与仅接受佐剂的小鼠相比,剩余SV主要由接种小鼠中的纤维化组成。(D)在处理后一个月,用抗CD8进行的IHC染色表明与仅接受佐剂的小鼠相比,接种的小鼠中的CD8+ T细胞浸润显著。(E)将来自接种反应性SV接种的动物的外周血淋巴细胞(PBL)过继转移到初次接受者中,在转移六周内重现SV破坏。来自虚假接种或仅接种佐剂的动物的PBL过继转移未对正常SV组织病理学表现出影响(上图)。二次过继转移产生了相同的效果(下图)。总SV反应性=25/42(60%)。
图5A-J:通过同源抗原决定簇极化的DC以特异性和差异性方式消融前列腺和精囊。正常前列腺(上图)和来自接种了同源负载DC前列腺疫苗的动物的前列腺(下图)的MRI(A和D)和整体(B和E)图像。接种和仅佐剂处理的动物的H&E染色显示了(C)仅佐剂处理的动物中的正常前叶和(F)接种动物前叶的明显肥大和炎症。随着时间的推移,接种动物的前列腺叶倾向于收缩并消失,正如与仅佐剂处理的动物相比(G),接种动物(H)前叶缺少和发育不良的图像所示。虽然SV和前列腺非常接近,但接种具高度特异性,正如(I)前列腺的炎症病理连同前列腺接种的动物中的正常SV以及(J)SV的特征性炎症病理连同SV接种动物中的正常前列腺所证明。总前列腺反应性=8/17(47%)。
图6A-J:同源接种在生理模型系统中区分正常组织与肿瘤自身,并控制前列腺腺癌。源自Pro-Cat/JOCK1小鼠的前列腺腺癌决定簇(Carstens等人,2014)用于在腺癌阶段接种另外的Pro-Cat/JOCK1动物组群。数据表明(A)虽然负载腺癌的疫苗和佐剂与正常前列腺几乎没有明显的交叉反应性,但(B)诱导至疾病腺癌阶段的小鼠在接种时,表现出最令人联想到mPIN的病毒病理学发现,并且还表现出在未接种的或非癌变小鼠中未观察到的淋巴细胞浸润的腺泡(B.1插图)。仅接受佐剂的诱导小鼠(C)展示出Pro-Cat/JOCK1腺癌的典型病理特征。(D)病理评分(如实验程序中所定义)表明接种的诱导小鼠与仅用佐剂处理的诱导小鼠之间的病理表型具有统计学显著性差异。Y轴:组织病理学评分。接种也似乎赋予剂量反应效应,如在没有接受DC(E&F)、接受1x 105DC(G&H)和4x 105DC(I&J)诱导的(E,G,I)和未诱导的对照动物(F,H,J)中所观察到。基准尺=100μM。
图7A-H:同源接种在自发性CNS恶性肿瘤的大型动物模型中是可行的并具有潜在功效。在CNS恶性肿瘤诊断后,招募了两名大型(>25kg)犬类患者进行非随机I期兽医试验。脑部的临床MR成像显示了诊断时(A和E)、紧接保守性肿瘤切除之前(B和F)、紧接切除后(C和G)及接种方案开始后五周(D和H)两只动物的肿瘤。箭头指示肿瘤区域。在单次疫苗注射后,第一只动物(上面四张图)显示肿瘤体积减小50%(参见C和D),而在三次疫苗注射后,第二只动物(下面四张图)显示肿瘤体积减小79%(参见G和H)。
图8A-B:AIMp1在DC同源负载后的早期和成熟前释放,而sCTLA-4分泌物的消融发生在下游。(A)早在DC负载同源I和II类肽后3小时,观察到AIMp1开始分泌,而在这个早期时间点,sCTLA-4分泌仍然不受影响。直至成熟后的较晚期时间点才看到sCTLA-4分泌物的消融(例如如负载后48小时所示)。(B)负载后3小时和48小时来自负载了错配异源肽(浅灰色)或重叠同源肽(深灰色)的DC的AIMp1和sCTLA-4分泌物的定量。Y轴:AIMp1/sCTLA-4比率。
图9:AIMp1 coIP和互逆MHC I类coIP表明强烈的相互作用,特别是在成熟DC中,AIMp1和MHC之间。通过串联质谱法(未示出)确认结果。IP=用于免疫沉淀的抗体的特异性。IB=用于检测的抗体的特异性。示出了三个中的代表性实验。
图10:AIMp1与MHC的结合依赖于DC负载同源抗原决定簇(mRNA和裂解物)。以类似于负载同源I类和II类肽对的DC的方式,AIMp1 coIP表明当DC负载同源mRNA和裂解物制剂时,AIMp1与MHC II类和I类(未示出)的相互作用被基本上消除,表明分泌的AIMp1可能源自MHC结合的AIMp1。有趣的是,通过使用异源制剂在I类(mRNA)和II类(裂解物)决定簇之间引入增加的抗原异质性似乎会增强AIMp1与MHC的结合。示出了三个中的代表性实验。
图11A-B:通过β2-微球蛋白或HLA-DM的siRNA敲除消除MHC负载,除去了人DC响应于同源肽负载调节AIMp1/sCTLA-4分泌的能力。(A)在用非靶向(NT)siRNA处理时,负载两种不同的同源肽对(野生型流感HA和gly取代为met的HA)的DC增强了AIMp1分泌而减弱了sCTLA-4分泌;然而,用β2-微球蛋白或HLA-DM siRNA处理完全消除了调节AIMp1和sCTLA-4的能力,致使分泌的AIMp1/sCTLA-4比率与无负载、单负载或异源负载DC难以区别。示出了四个实验中的代表。(B)(a)中呈现的数据的密度计量定量。四个独立实验的平均值。*p<0.05。
图12:概述针对自身免疫性体内靶向的DC同源负载的方法的示意图。
图13:概述过继转移时间表和分析时间轴的示意图。
图14:部分HLA匹配的人DC的同源负载产生特异性裂解WPMY-1正常前列腺的能力增强的CTL。负载源自WPMY-1正常人前列腺细胞系的决定簇的人DC用于致敏和扩增自体淋巴细胞。三次刺激后,收获T细胞并通过51Cr裂解测定法测试裂解特异性,如前所述进行。50数据表明,负载WPMY-1mRNA和WPMY-1裂解物的DC比负载单独的WPMY-1裂解物或WPMY-1mRNA的DC产生大体上优良的特异性CTL活性。Y轴:特异性裂解百分比。X轴:E:T比。
图15A-D:通过同源抗原负载产生的疫苗以依赖于CD8+细胞的方式抑制已建立的4T1乳腺癌肿瘤的生长和转移扩散。(A)在表达荧光素酶的4T-1肿瘤异位建立后8天,用同源负载的树突细胞接种小鼠或用虚假接种和全身性佐剂进行处理。通过IVIS监测肿瘤的转移扩散。如图所示,虚假接种的小鼠发展出向肝、肺和脑部的远处转移,并在植入后一个月开始死亡。接种小鼠未发展出转移性疾病并且原发性肿瘤保持受良好控制。用于同源负载的抗原物质源自不表达荧光素酶4T1细胞系。示出了代表性小鼠。组群大小=6只/组。(B)(A)描绘的数据的Kaplan-Meier存活分析。第56天p<0.001。(C)为证明对CD8+细胞的依赖性,用同源疫苗接种非荷瘤小鼠组群两次。在单个组群的CD8耗尽之后,收获脾细胞并将其过继转移到荷瘤小鼠组群中。数据表明,虽然过继转移了同源接种的、同种型耗尽的脾细胞的小鼠维持肿瘤控制,并没有表现出转移扩散,但过继转移了同源接种的、CD8耗尽的脾细胞的小鼠最终死于疾病。过继转移了异源接种的、同种型耗尽的脾细胞的小鼠表现最差,表明可能存在通过同源接种产生的附加、CD8-效应子。示出了代表性小鼠。组群大小=5只/组。(D)(C)描绘的数据的Kaplan-Meier存活分析。在第43天,80%过继转移了源自同源接种宿主的同种型耗尽的脾细胞的小鼠仍然生存,而仅有20%过继转移了源自同源接种宿主的同种型耗尽的脾细胞的小鼠。到第32天,所有过继转移了源自同种型耗尽的、异源接种宿主的脾细胞的小鼠死于肿瘤。在第43天,p<0.001。
图16:重组AIMp1(p43)增强了TH1应答的产生。人DC负载指定的肽组合并用于在存在或不存在100ng/ml重组AIMp1(p43)的情况下使自体T细胞致敏。在所有测试条件下,在AIMp1的存在下,活化CD8+ T细胞的百分比增加50%至150%。对于所测试的每个配对条件,p<0.05。用同源负载抗原的DC观察到rAIMp1之间最稳健的增加。
说明性实施方案的描述
I.本发明的实施方案
树突细胞包含高度特化类别的抗原呈递细胞。先前的研究已经证明,树突细胞可以有效地致敏以刺激特异性靶向受试者中的细胞群例如癌细胞的T细胞应答(参见例如美国专利8,728,806,其以引用的方式并入本文)。然而,仍然需要增强树突细胞组合物的功效并因此而提供更稳健的免疫应答的方法。
本文提出的研究首次证明共刺激分子和树突细胞施加的位点都可以显著影响细胞组合物的功效。具体而言,发现树突细胞连同共刺激物如I型干扰素(例如,INFα)、TLR-7激动剂、TLR-9激动剂或AIMp1一起施用会显著增强由致敏树突细胞组合物提供的T细胞应答。同样,通过连同TLR-3激动剂、维甲酸诱导基因-1(RIG-1)样受体配体或细胞溶质DNA(CDS)受体配体一起施用的致敏树突细胞可以实现增强的T细胞应答。而且,发现树突细胞的施加位点会显著改变T细胞刺激的有效性。具体而言,不受作用机制的任何特定理论的限制,据信树突细胞应优选暴露于接近靶向疾病组织(例如,肿瘤)部位的T细胞。因此,在一些优选的方面,通过直接引入到为患病细胞群如肿瘤部位引流的淋巴组织中,向受试者施用树突细胞组合物。因此,通过联合使用共刺激分子和将致敏树突细胞施用于接近疾病组织的部位,可以诱导极其稳健的免疫应答。
II.实施方案的树突细胞群
分离培养和致敏树突细胞的方法是本领域公知的。例如,以引用的方式整体并入本文的美国专利8,728,806提供了提供可用于实施方案的组合物和方法中的抗原致敏树突细胞的详细方法。在某些方面,根据实施方案使用的树突细胞分离自要通过实施方案的方法治疗的受试者。在其它方面,树突细胞可以来自不同的受试者,例如HLA匹配的供体。在某些方面,树突细胞来自具有限定的HLA分型的树突细胞库。在优选的方面,根据实施方案使用的致敏树突细胞同源负载如本文和美国专利8,728,806中详述的抗原。
用于分离富集来自各种来源(包括血液和骨髓)的树突细胞前体和未成熟树突细胞的细胞群的方法是本领域已知的。例如,树突细胞前体和未成熟树突细胞可以通过收集肝素化血液,通过血浆分离置换法或白细胞除去法,通过制备血沉棕黄层、形成玫瑰花结、离心、密度梯度离心(例如,使用Ficoll(例如)、(涂有非透析性聚乙烯吡咯烷酮(PVP)、蔗糖等的胶体二氧化硅颗粒(直径15-30mm))、细胞差异性裂解、过滤等等来分离。在某些实施方案中,可以制备白细胞群,例如通过收集来自受试者的血液,去纤维蛋白化(defribrinating)以去除血小板并裂解红细胞。树突细胞前体和未成熟树突细胞可任选地通过例如通过梯度的离心来富集单核细胞性树突细胞前体。在其它方面,可以使用G-CSF动员的外周血的CD14选择来选择树突细胞前体。
树突细胞前体和未成熟树突细胞可以任选地在封闭的无菌系统中制备。如本文中所用,术语“封闭的无菌系统”或“封闭系统”是指最小化或消除对非灭菌、环境或循环空气或其它非无菌条件的暴露的系统。用于分离树突细胞前体和未成熟树突细胞的封闭系统通常不包括顶部开口管中的密度梯度离心,细胞的敞开式转移,组织培养板或未密封的烧瓶中的细胞培养等。在典型的实施方案中,封闭系统允许将树突细胞前体和未成熟树突细胞从初始收集容器无菌转移到可密封的组织培养容器中而不暴露于非无菌空气。
在某些实施方案中,通过粘附于单核细胞结合基底来分离单核细胞性树突细胞前体。例如,白细胞群(例如,通过白细胞除去法分离的)可以与单核细胞性树突细胞前体粘附基底接触。当白细胞群与基底接触时,白细胞群中的单核细胞性树突细胞前体优先粘附于基底。其它白细胞(包括其它潜在的树突细胞前体)对基底显示出降低的结合亲和力,从而使单核细胞性树突细胞前体优先富集在基底的表面上。
合适的基底包括例如具有大表面积与体积比的那些。此类基底可以是例如颗粒或纤维基底。合适的颗粒基底包括例如玻璃颗粒、塑料颗粒、玻璃包覆的塑料颗粒、玻璃包覆的聚苯乙烯颗粒和适于蛋白质吸附的其它珠粒。合适的纤维基底包括微毛细管和微绒毛膜。颗粒或纤维基底通常允许粘附的单核细胞性树突细胞前体被洗脱而基本上不降低粘附细胞的活力。颗粒或纤维基底可以基本上无孔,以利于单核细胞性树突细胞前体或树突细胞从基底上洗脱。“基本上无孔”的基底是其中基底上存在的至少大部分孔比细胞小以使基底中的截留细胞减到最少的基底。
单核细胞性树突细胞前体对基底的粘附可以任选地通过添加结合介质来增强。合适的结合介质包括单核细胞性树突细胞前体培养基(例如,RPMI 1640、DMEM、X-VIVO等),单独或以任何组合补充了例如细胞因子(例如,粒细胞/巨噬细胞集落刺激因子(GM-CSF)、白介素4(IL-4)或白介素13(IL-13))、血浆、血清(例如,人血清,如自体或同种异体血清)、纯化的蛋白质(如血清白蛋白)、二价阳离子(例如,钙和/或镁离子)和有助于单核细胞性树突细胞前体对基底的特异性粘附,或阻止非单核细胞性树突细胞前体对基底的粘附的其它分子。在某些实施方案中,血浆或血清可以加热灭活。热灭活的血浆可以是白细胞自体的或异源的。
在单核细胞性树突细胞前体粘附到基底之后,将非粘附白细胞与单核细胞性树突细胞前体/基底复合物分离。可以使用任何合适的方式将非粘附细胞与复合物分离。例如,可以使非粘附白细胞和复合物的混合物沉降,并且将非粘附的白细胞和培养基轻轻倒出或排出。可选地,可以将混合物离心,并将含有非粘附白细胞的上清液从团块化复合物中轻轻倒出或排出。
可以离体培养分离的树突细胞前体用于分化、成熟和/或扩增。(如本文所用,分离的未成熟树突细胞、树突细胞前体、T细胞和其它细胞是指通过人工存在于其天然环境之外并因此不是自然产物的细胞。分离的细胞可呈纯化形式、半纯化形式存在或存在于非天然环境中。)简单地说,离体分化通常涉及在一种或多种分化剂的存在下培养树突细胞前体或具有树突细胞前体的细胞群。合适的分化剂可以是例如细胞生长因子(例如,细胞因子如(GM-CSF)、白介素4(IL-4)、白介素13(IL-13)和/或其组合)。在某些实施方案中,单核细胞性树突细胞前体分化形成单核细胞来源的未成熟树突细胞。
树突细胞前体可以在合适的培养条件下培养和分化。合适的组织培养基包括RPMI 1640、DMEM、X-VIVO等。组织培养基可补充有血清、氨基酸、维生素、细胞因子(如GM-CSF和/或IL-4)、二价阳离子等,以促进细胞的分化。在某些实施方案中,树突细胞前体可以在无血清的培养基中培养。此类培养条件可任选地排除任何动物来源的产品。在典型的树突细胞培养基中,典型的细胞因子组合为各约500单位/ml的GM-CSF(50ng/ml)和IL-4(10ng/ml)。当分化形成未成熟树突细胞时,树突细胞前体在表型上与皮肤朗格汉斯细胞(Langerhans cell)相似。未成熟树突细胞通常是CD14-和CD11c+,表达低水平的CD86和CD83,并且能够通过特化内吞作用来捕获可溶性抗原。未成熟的DC表达非常高水平的CD86。同样,该群体在CD14和CD11C方面是混合的。虽然大多数是CD11c+,但有不同的亚群为CD11c-和CD14+。
使未成熟树突细胞成熟化形成成熟树突细胞。成熟DC失去摄取抗原的能力,并显示共刺激细胞表面分子和各种细胞因子的表达上调。具体来说,成熟DC表达比未成熟树突细胞更高水平的MHC I类和II类抗原,并且成熟树突细胞通常被鉴定为CD80+、CD83+、CD86+和CD14-。更强的MHC表达导致DC表面上的抗原密度增加,而共刺激分子CD80和CD86的上调通过共刺激分子的对应物(例如T细胞上的CD28)增强T细胞活化信号。
可以通过使未成熟树突细胞与有效量或浓度的核酸组合物和肿瘤抗原组合物接触来制备本发明的成熟树突细胞(即,成熟化)。核酸组合物的有效量通常范围为每个培养皿或每个细胞至多、至少或约0.01、0.1、1、5、10至10、15、20、50、100ng(或mg)核酸,包括其间的所有值和范围。肿瘤抗原组合物的有效量通常范围为每个培养皿或每个细胞至多、至少或约0.01、0.1、1、5、10至10、15、20、50、100ng(或mg)蛋白质。在某些方面,可以使用0.001ng肿瘤抗原/个细胞至1μg肿瘤抗原/百万个细胞)。肿瘤抗原组合物可在与树突细胞接触之前任选地经热灭活或处理(例如,暴露于蛋白酶)。用核酸组合物和肿瘤抗原组合物使未成熟树突细胞成熟化,使成熟树突细胞对1型(Th-1)应答致敏。
未成熟DC通常与有效量的核酸组合物和肿瘤抗原组合物接触至多、至少或约1、2、3、4、5、6、7、8、9、10、11、12至10、11、12、13、14、15、16、17、18、19、20、21、22、23或24分钟、小时或天。未成熟树突细胞可以在合适的成熟化培养条件下培养和成熟化。合适的组织培养基包括RPMI 1640、DMEM、X-VIVO等。组织培养基可以补充有氨基酸、维生素、细胞因子(如GM-CSF和/或IL-4)、二价阳离子等,以促进细胞的成熟化。
树突细胞的成熟化可以通过本领域已知的方法来监测。可以在本领域公知的测定法中检测细胞表面标志物,例如流式细胞术、免疫组织化学等。也可以监测细胞的细胞因子生成(例如,通过ELISA、FACS或其它免疫测定法)。树突细胞前体、未成熟树突细胞和成熟树突细胞(已用抗原致敏或未致敏)可以冷冻保存供以后使用。用于低温保存的方法是本领域公知的。例如,美国专利第5,788,963号,其以引用的方式整体并入本文。
A.经遗传修饰的树突细胞
实施方案的某些方面涉及已经遗传修饰的树突细胞。在一些方面,遗传修饰包括在细胞中引入外源转基因,例如抑制性核酸。在另外的方面,转基因可以是受诱导型启动子控制的自杀基因,例如编码胸苷激酶的基因。因此,在一些方面,在刺激免疫应答之后,可以通过诱导控制自杀基因表达的启动子来杀灭所施用的树突细胞。
在另外的方面,遗传修饰包括细胞群中的基因组缺失或插入。例如,可以破坏一个或多个HLA基因以使树突细胞作为待治疗受试者的有效HLA匹配。
实施方案的其它方面涉及已经遗传修饰,例如以降低CTLA-4表达的树突细胞。在一些方面,遗传修饰包括引入对CTLA-4有特异性的外源抑制性核酸。在某些方面,抑制性核酸为RNA,例如由树突细胞中的DNA载体表达的RNA。在另外的方面,抑制性核酸可以是引入到树突细胞中的siRNA、dsRNA、miRNA或shRNA。上面提供了此类RNA的详细公开。
在另外的方面,遗传修饰包括减少CTLA-4的细胞群中的基因组缺失或插入。在其它方面,树突细胞包含CTLA-4基因内的半合子或纯合子缺失。例如,在一些方面,树突细胞的CTLA-4基因的一个或两个拷贝可以完全或部分缺失,使得CTLA-4多肽的表达被抑制。在一些方面,使其不表达一个或多个CTLA-4基因的细胞修饰可以包括向细胞中引入特异性靶向CTLA-4基因座的人工核酸酶。在各个方面,人工核酸酶可以是锌指核酸酶、TALEN或CRISPR/Cas9。在各个方面,向细胞中引入人工核酸酶可以包括将编码人工核酸酶的mRNA引入细胞中。
III.组合疗法
为了提高实施方案的树突细胞疗法的有效性,可能需要将这些组合物与有效治疗目标疾病的其它药剂组合。
在一些方面,树突细胞疗法连同分子如TLR激动剂、I型干扰素(INF)、AIMp1、维甲酸诱导基因-1(RIG-1)样受体配体或细胞溶质DNA(CDS)受体配体一起施用。TLR激动剂可为TLR3、TLR7、TLR8或TLR9激动剂。I型INF可为INF-α、IFN-β、IFN-ε、IFN-κ或IFN-ω。例如,TLR-7激动剂可选自CL075、CL097、CL264、CL307、GS-9620、聚(dT)、咪喹莫特、嘎德莫特、雷西莫特(R848)、洛索立宾和ssRNA寡核苷酸。示例性TLR-9激动剂包括CpG寡脱氧核苷酸(CpGODN)。其它TLR激动剂例如在美国专利公开第2014/0005255号中有描述;其以引用的方式并入本文。
本领域已知的RIG-I样受体(RLR)配体是指RIG-I、Mda5以及LGP2信号传导的活化剂。这些配体包括但不限于单链RNA、双链RNA和5'-三磷酸RNA。RIG-I样受体配体也指在RNA分子中引入的可引起RIG-I、Mda5和LGP2的结合和活化,从而产生RLR样生物活性的任何修饰。在一些方面,RLR配体可以是常见衔接蛋白的调节剂,例如IPS-1,也称为MAVS、VISA或CARDIF。例如,RIG-1样受体配体选自MDA5配体、LGP2配体、ssRNA、dsRNA、5'ppp-dsRNA、聚(dA:dT)和聚(I:C)。
在某些方面,致敏的树突细胞群连同CDS受体配体一起施用。在一些方面,CDS受体配体被进一步限定为cGAS-STING配体。例如,cGAS-STING配体为细菌环状二核苷酸(CDN)。例如在国际专利公开第WO2015/077354号中描述了其它cGAS-STING激动剂,例如核酸、蛋白质、肽或小分子。
作为非限制性实例,可以用本实施方案的致敏树突细胞组合物连同其它抗癌剂一起来实施癌症的治疗。“抗癌”剂能够对受试者的癌症产生负面影响,例如通过杀伤癌细胞,诱导癌细胞凋亡,降低癌细胞的生长速率,减少转移的发生率或数量,减小肿瘤大小,抑制肿瘤生长,减少肿瘤或癌细胞的血液供应,促进针对癌细胞或肿瘤的免疫应答,预防或抑制癌症进展,或增加患有癌症的受试者的寿命。更一般地说,这些其它组合物将以有效杀伤或抑制细胞增殖的组合量提供。该方法可以涉及使细胞同时与抗癌肽或纳米颗粒复合物和药剂或多种因子接触。这可以通过使细胞与包括两种药剂的单一组合物或药物制剂接触,或者通过使细胞同时与两种不同的组合物或制剂接触来实现,其中一种组合物包括树突细胞组合物而另一种包括第二药剂。
用树突细胞组合物治疗可以在其它药剂治疗之前或之后,间隔范围为几分钟到几周。在向受试者单独施加其它药剂和树突细胞组合物的实施方案中,通常将确保在每次递送时间间隔,有相当长的时间段不会到期,使得该药剂和树突细胞组合物仍然能够对细胞发挥有利的组合效应。在这种情况下,预期可以使细胞与两种用药程式彼此在约12-24小时内,且更优选彼此在约6-12小时内接触。在一些情况下,可能需要显著延长治疗时间,其中各次施用间隔几天(例如,2、3、4、5、6或7天)至几周(例如,1、2、3、4、5、6、7或8周)。
可以采用各种组合,其中树突细胞疗法为“A”且第二药剂,例如放射疗法、化学疗法或抗炎剂为“B”:
A/B/A B/A/B B/B/A A/A/B A/B/B B/A/A A/B/B/B B/A/B/B
B/B/B/A B/B/A/B A/A/B/B A/B/A/B A/B/B/A B/B/A/A
B/A/B/A B/A/A/B A/A/A/B B/A/A/A A/B/A/A A/A/B/A
在某些实施方案中,向患者施用本实施方案的树突细胞疗法施将遵循施用化学治疗剂的一般方案,同时考虑载体的毒性(如果有的话)。预计在必要时将重复治疗周期。还预期可以与所述过度增殖细胞疗法组合应用各种标准疗法以及手术干预。
A.化学疗法
癌症疗法还包括各种组合疗法。在一些方面,实施方案的树突细胞组合物与化学治疗剂一起施用(或配制)。例如,在一些方面,化学治疗剂是蛋白激酶抑制剂,例如EGFR、VEGFR、AKT、Erb1、Erb2、ErbB、Syk、Bcr-Abl、JAK、Src、GSK-3、PI3K、Ras、Raf、MAPK、MAPKK、mTOR、c-Kit、eph受体或BRAF抑制剂。蛋白激酶抑制剂的非限制性实例包括阿法替尼(Afatinib)、阿西替尼(Axitinib)、贝伐单抗(Bevacizumab)、博苏替尼(Bosutinib)、西妥昔单抗(Cetuximab)、克唑替尼(Crizotinib)、达沙替尼(Dasatinib)、厄洛替尼(Erlotinib)、福斯马替尼(Fostamatinib)、吉非替尼(Gefitinib)、伊马替尼(Imatinib)、拉帕替尼(Lapatinib)、乐伐替尼(Lenvatinib)、木利替尼(Mubritinib)、尼洛替尼(Nilotinib)、帕尼单抗(Panitumumab)、帕唑帕尼(Pazopanib)、哌加他尼(Pegaptanib)、雷珠单抗(Ranibizumab)、鲁索替尼(Ruxolitinib)、塞卡替尼(Saracatinib)、索拉非尼(Sorafenib)、舒尼替尼(Sunitinib)、曲妥珠单抗(Trastuzumab)、凡德他尼(Vandetanib)、AP23451、威罗非尼(Vemurafenib)、MK-2206、GSK690693、A-443654、VQD-002、米替福新(Miltefosine)、哌立福辛(Perifosine)、CAL101、PX-866、LY294002、雷帕霉素(rapamycin)、替西罗莫司(temsirolimus)、依维莫司(everolimus)、地磷莫司(ridaforolimus)、阿伏西地(Alvocidib)、染料木黄酮(Genistein)、司美替尼(Selumetinib)、AZD-6244、瓦他拉尼碱(Vatalanib)、P1446A-05、AG-024322、ZD1839、P276-00、GW572016或其混合物。
另外的组合化学疗法包括,例如,烷化剂如噻替派(thiotepa)和环磷酰胺;烷基磺酸盐,如白消安(busulfan)、英丙舒凡(improsulfan)和哌泊舒凡(piposulfan);氮丙啶(aziridine)如苯佐替派(benzodopa)、卡波醌(carboquone)、美妥替派(meturedopa)和乌瑞替派(uredopa);乙烯亚胺类和甲基三聚氰胺类包括六甲蜜胺、三亚乙基蜜胺、三亚乙基磷酰胺、三亚乙基硫代磷酰胺和三羟甲基蜜胺;己酸配质(acetogenin)(特别是布拉它辛(bullatacin)和布拉它辛酮(bullatacinone));喜树碱(包括合成类似物拓扑替康(topotecan));苔藓抑素(bryostatin);海绵多聚乙酰(callystatin);CC-1065(包括其阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin)合成类似物);念珠藻素(cryptophycin)(特别是念珠藻素1和念珠藻素8);多拉司他汀(dolastatin);倍癌霉素(duocarmycin)(包括合成类似物,KW-2189和CB1-TM1);艾榴塞洛素(eleutherobin);水鬼蕉碱(pancratistatin);匍枝珊瑚醇(sarcodictyin);海绵抑制素(spongistatin);氮芥例如苯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、氯磷酰胺(cholophosphamide)、雌莫司汀(estramustine)、异环磷酰胺(ifosfamide)、氮芥、盐酸甲氧氮芥、美法仑(melphalan)、新恩比兴(novembichin)、苯芥胆甾醇(phenesterine)、泼尼莫司汀(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥;亚硝基脲类例如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)和雷莫司汀(ranimnustine);抗生素类例如烯二炔抗生素(例如加利车霉素(calicheamicin),特别是加利车霉素γ1I和加利车霉素ωI1;烯二炔蒽环类抗生素(dynemicin),包括烯二炔蒽环类抗生素A;二膦酸盐类,例如氯膦酸盐;埃斯波霉素(esperamicin);以及新制癌菌素(neocarzinostatin)生色团和相关色素蛋白烯二炔类抗生素生色团)、阿克拉霉素(aclacinomysin)、放线菌素(actinomycin)、安曲霉素(authramycin)、重氮丝氨酸(azaserine)、博来霉素(bleomycins)、放线菌素C(cactinomycin)、卡拉比星(carabicin)、洋红霉素(carminomycin)、嗜癌霉素(carzinophilin)、色霉素(chromomycinis)、放线菌素D(dactinomycin)、柔红霉素(daunorubicin)、地托比星(detorubicin)、6-重氮-5-氧代-L-正亮氨酸、多柔比星(doxorubicin)(包括吗啉代多柔比星、氰基吗啉代多柔比星、2-吡咯啉-多柔比星和脱氧多柔比星)、表柔比星(epirubicin)、依索比星(esorubicin)、伊达比星(idarubicin)、麻西罗霉素(marcellomycin)、丝裂霉素类(mitomycins)如丝裂霉素C、麦考酚酸(mycophenolicacid)、诺拉霉素(nogalamycin)、橄榄霉素(olivomycins)、培洛霉素(peplomycin)、紫菜霉素(potfiromycin)、嘌呤霉素(puromycin)、三铁阿霉素(quelamycin)、罗多比星(rodorubicin)、链黑霉素(streptonigrin)、链佐星(streptozocin)、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他丁(zinostatin)、佐柔比星(zorubicin);抗代谢物类,例如甲氨蝶呤(methotrexate)和5-氟尿嘧啶(5-FU);叶酸类似物例如二甲叶酸(denopterin)、蝶罗呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤类似物例如氟达拉滨(fludarabine)、6-巯嘌呤、硫咪嘌呤(thiamiprine)、硫鸟嘌呤(thioguanine);嘧啶类似物例如安西他滨(ancitabine)、阿扎胞苷(azacitidine)、6-氮杂尿苷(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、双脱氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、依诺他滨(enocitabine)、氟尿苷(floxuridine);雄激素类,例如卡鲁睾酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、环硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾内酯(testolactone);抗肾上腺类(anti-adrenals),例如米托坦(mitotane)、曲洛司坦(trilostane);叶酸补偿剂,例如亚叶酸(frolinic acid);醋葡醛内酯(aceglatone)、醒磷酰胺糖苷(aldophosphamideglycoside)、氨基酮戊酸(aminolevulinic acid);恩尿嘧啶(eniluracil);安吖啶(amsacrine);倍曲布西(bestrabucil);比生群(bisantrene);依达曲沙(edatraxate);地磷酰胺(defofamine);秋水仙胺(demecolcine);地吖醌(diaziquone);依氟鸟氨酸(elfornithine);依利醋铵(elliptinium acetate);埃博霉素(epothilone);依托格鲁(etoglucid);硝酸嫁(gallium nitrate);羟基脲(hydroxyurea);香菇多糖(lentinan);氯尼达明(lonidainine);美坦生类(maytansinoids),例如美坦生(maytansine)和安丝菌素(ansamitocins);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌达醇(mopidanmol);尼曲吖啶(nitraerine);喷司他丁(pentostatin);苯来美特(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);鬼臼酸(podophyllinic acid);2-乙基酰肼(2-ethylhydrazide);丙卡巴肼(procarbazine);PSK多糖复合物;雷佐生(razoxane);利索新(rhizoxin);西佐喃(sizofiran);锗螺胺(spirogermanium);细交链孢菌酮酸(tenuazonic acid);三亚胺醌(triaziquone);2,2',2”-三氯三乙胺;单端孢霉烯类(特别是T-2毒素、韦拉库林A(verracurin A)、杆孢菌素A(roridin A)和蛇形菌素(anguidine));乌拉坦(urethan);长春地辛(vindesine);达卡巴嗪(dacarbazine);甘露莫司汀(mannomustine);二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);哌泊溴烷(pipobroman);加西托新(gacytosine);阿糖胞苷(arabinoside)("Ara-C");环磷酰胺(cyclophosphamide);紫杉烷类(taxoids),例如紫杉醇(paclitaxel)和多西他赛吉西他滨(docetaxel gemcitabine);6-硫鸟嘌呤;巯嘌呤;铂配位化合物如顺铂(cisplatin)、奥沙利铂(oxaliplatin)和卡铂(carboplatin);长春碱(vinblastine);铂;依托泊苷(etoposide)(VP-16);异环磷酰胺(ifosfamide);米托蒽醌(mitoxantrone);长春新碱(vincristine);长春瑞滨(vinorelbine);诺安托(novantrone);替尼泊苷(teniposide);依达曲沙(edatrexate);道诺霉素(daunomycin);氨蝶呤(aminopterin);希罗达(xeloda);伊班膦酸盐(ibandronate);伊立替康(irinotecan)(例如,CPT-11);拓扑异构酶抑制剂RFS2000;二氟甲基鸟氨酸(DMFO);类维生素A例如维甲酸;卡培他滨(capecitabine);卡铂、甲基苄肼(procarbazine)、普卡霉素(plicomycin)、吉西他滨(gemcitabien)、长春瑞滨(navelbine)、法呢基-蛋白转移酶抑制剂、反式铂(transplatinum)及任何上述物质的药学上可接受的盐、酸或衍生物。在某些实施方案中,本文提供的组合物可以与吉非替尼组合使用。在其它实施方案中,本实施方案可以与Gleevac组合实践(例如,可向患者施用约400至约800mg/天的Gleevac)。在某些实施方案中,一种或多种化学治疗剂可与本文提供的组合物组合使用。
B.放射疗法
引起DNA损伤并已广泛使用的其它因子包括通常所称的γ-射线、X-射线和/或放射性同位素向肿瘤细胞的定向递送。还考虑了其它形式的DNA损伤因子,例如微波和UV照射。所有这些因子最有可能对DNA、DNA前体、DNA复制和修复以及染色体组装和维持造成广泛的损伤。X-射线剂量范围为长时间(3至4周)50至200伦琴的日剂量,到2000至6000伦琴的单剂量。放射性同位素的剂量范围变化很大,且取决于同位素的半衰期、发射的辐射强度和类型及肿瘤细胞的摄取。
术语“接触”和“暴露”当应用于细胞时,在本文中用于描述将治疗性组合物和化学治疗剂或放射治疗剂递送至靶细胞或与靶细胞直接并列放置的方法。为了实现细胞杀伤或停滞,两种药剂以有效杀伤细胞或防止细胞分裂的组合量递送至细胞。
C.基因疗法
在另一个实施方案中,二级治疗是其中治疗性多核苷酸在治疗性组合物之前、之后或同时施用的基因疗法。用于表达基因产物的病毒载体是本领域公知的,并且包括诸如腺病毒、腺相关病毒、逆转录病毒、疱疹病毒、慢病毒、痘病毒(包括痘苗病毒)和乳头瘤病毒(包括SV40)的真核表达系统。可选地,表达构建体的施用可以用基于脂质的载体例如脂质体或DOTAP:胆固醇囊泡来完成。所有这些方法是本领域公知的(参见,例如Sambrook等人,1989;Ausubel等人,1998;Ausubel,1996)。
D.手术
大约60%的癌症患者将接受某种类型的手术,包括预防性、诊断性或分期、治愈性和姑息性手术。治愈性手术是可以连同其它疗法一起使用的癌症治疗,例如本文提供的治疗,化学疗法、放射疗法、激素疗法、基因疗法、免疫疗法和/或替代疗法。
治愈性手术包括其中物理去除、切除和/或破坏全部或部分癌组织的切除术。肿瘤切除术是指至少部分肿瘤的物理去除。除肿瘤切除术外,手术治疗包括激光手术、冷冻手术、电外科手术和显微镜控制的手术(Mohs手术)。进一步预期,本实施方案可以连同去除浅表癌、前期癌或偶然量的正常组织一起使用。在一些方面,在肿瘤切除术之后,将实施方案的树突细胞组合物施用于为肿瘤先前部位引流的淋巴组织。
IV.实施例
包括以下实施例以说明本发明的优选实施方案。本领域技术人员应当理解,下面的实施例中公开的技术表示发明人发现在本发明的实践中作用良好的技术,因此可以被认为构成其实践的优选模式。然而,根据本公开,本领域技术人员应当认识到,在不脱离本发明的精神和范围的前提下,可以在公开的具体实施方案中进行许多改变,并且仍然获得相同或相似的结果。
实施例1-材料和方法
如下述实施例中所用,从Harlan Laboratories(Indianapolis,IN)或从JacksonLaboratory(Barr Harbor,ME)获得8-12周龄的C57BL/6、Balb/c和FVB小鼠。C57BL/6背景下的H2-DM敲除小鼠是来自University of North Carolina,Chapel Hill的Jenny Ting博士的友好礼物。FVB背景下的Pro-Cat/JOCK1转基因小鼠是如所述(Carstens等人,2014),在Baylor College of Medicine,Houston TX的David Spencer博士的实验室中建立的。所有小鼠均按照Baylor College of Medicine的具体IACUC要求进行维护。
疫苗材料的制备、DC的负载和体外共培养-从10周龄的雄性小鼠收获精囊(SV)和前列腺并立即在-80℃冷冻。从美国模式培养物保藏中心(ATCC,Manassas,VA)获得RAW264.7、B16-F10、4T1和WPMY-1细胞系,在37℃、5%CO2下于T225烧瓶(CorningLifesciences,Tewksbury,MA)中生长至汇合,收获,并同样立即在-80℃冷冻。肽按10mg/ml在80:20dH2O:DMSO溶液中复水并储存于-80℃下。为了产生MHC I类(mRNA)或II类(裂解物)决定簇,首先使用Polytron PT1200E组织匀浆器(Kinematica,Inc,Bohemia,NY)破坏组织部分。为了产生细胞裂解物,将匀化组织悬浮液在PBS(Life Technologies,Carlsbad,CA)中稀释至50mg/ml,进行重复冻融循环,并储存在-20℃下。为了产生mRNA,使用Trizol试剂(Life Technologies,Carlsbad,CA)根据生产商的说明从匀化组织中分离总RNA,并且还根据生产商的说明使用Oligotex mRNA Maxi试剂盒(Qiagen,Valencia,CA)从总RNA中分离mRNA。用Nanodrop分光光度计(Thermo Scientific)定量mRNA,并通过凝胶电泳验证其完整性。人(Decker等人,2006;Decker等人,2009)和野生型小鼠(Konduri等人,2013)树突细胞如所述进行制备、负载和成熟化。根据生产商的说明(Thermo Scientific-Dharmacon)进行siRNA的使用。H2-DM-/-DC的成熟化混合物另外补充有1μg/mlCpG-ODN(InvivoGen)。如前所述进行体外共培养(Decker等人,2006;Decker等人,2009;Konduri等人,2013)。
接种-治疗性接种的所有小鼠均腹膜内施用5x 104-5x 105个DC并且还腹膜内施用0.5mg悬浮但未溶解于20%DMSO/80%AIM-V中的咪喹莫特(LC Labs,Woburn,MA)。如图12所示小鼠接种1至4次。不同的疫苗处理包括负载mRNA的DC、负载裂解物的DC、同时负载同源或异源mRNA和裂解物的DC、负载同源mRNA和裂解物及AIMp1 siRNA的DC和无负载DC。间隔10天给予多次接种。接种了负载SIINFEKL(SEQ ID NO:1)/Ova的DC的小鼠在足垫中接种而未接受咪喹莫特。
组织学和总体分析-使用Olympus CX41显微镜(Olympus corporation,CenterValley,PA)与Olympus DP70数码相机(Olympus Corporation)通过光学显微术用苏木精和伊红为石蜡切片染色进行总体组织学分析。前列腺癌的盲选病理学评分由基于在两个不同深度的切片中所观察到的所有前侧、腹侧和背外侧视野中存在的主要疾病阶段的四点量表组成:0=正常,1=增生,2=PIN,3=腺癌,4=移行。如果不能辨别出主要阶段,则容许半分。
MRI分析-使用具有35mm体积共振器(Bruker BioSpin,Billerica,MA)的9.4T、21cm孔水平扫描仪进行前列腺和精囊的MRI。用于获得三维(3D)Turbo弛豫增强的快速采集(RARE)的图像参数如下:TR=3000ms;有效TE=30ms;FOV=30mm3;矩阵=128x 128x 128;RARE因子=8;平均数=1。使用Paravision软件版本5(Bruker BioSpin)获得图像。在成像期间,用与氧气混合的0.25%异氟烷(Abbott,Abbott Park,IL)麻醉小鼠并将核心温度保持在37℃。使用Amira 3.1软件(Visage Imaging,San Diego,CA)分析MRI图像。
CTLA-4/sCTLA-4 RT-PCR测定-使负载、成熟DC按<1x 107个细胞/份样品重新悬浮于1mL Trizol(Life Technologies)中并根据生产商的说明提取总RNA。用1μg/μl DNA酶I(Invitrogen)处理RNA。使用SuperScriptTM III第一链合成试剂盒(Life Technologies)由DNA酶处理过的RNA样品合成cDNA,并在55℃的退火温度下用CTLA-4正向引物:ATGGCTTGCCTTGGATTTCAGCGGC(SEQ ID NO:12)和CTLA-4反向引物:TCAATTGATGGGAATAAAATAAGGCTG(SEQ ID NO:13)通过PCR进行35次循环扩增。引物设计用于扩增对应于可溶性和膜结合CTLA-4同种型的转录物。
蛋白质印迹图像的定量-使用运行Image Lab软件2.0.1版本(Bio-RadLaboratories,Hercules,CA)的ChemiDoc XRS数字成像系统检测蛋白质印迹化学发光信号。所有蛋白质印迹均通过Ponceau S(Sigma-Aldrich)染色的膜的密度测定来定量。上清液受来自细胞死亡的残留细胞裂解物或碎片的污染通过用抗β-肌动蛋白(Santa Cruz)的免疫染色和另外的密度测定法来控制。使用ImageJ软件(NIH;Bethesda,MD)进行密度测定。为了检测单层膜上的sCTLA-4和AIMp1,通常首先用抗CTLA-4探测该膜,之后根据生产商的说明将其在Western Blot Restore缓冲液(Pierce,Rockford,IL)中剥离并用抗AIMp1再次探测。
Pro-Cat/JOCK1前列腺癌治疗模型-按照批准的IACUC方案将Pro-Cat/JOCK1小鼠置于无病原体的设施中。产生双转基因小鼠并如所述(Carstens等人,2014)进行基因分型。从六周龄开始按照在药物稀释剂中为2mg/kg(16.7%丙二醇、22.5%PEG400、1.25%吐温80),通过腹膜注射100μl AP20187(Ariad Pharmaceuticals)来处理小鼠,每周两次。在AP20187处理24周后将小鼠在下部尿生殖区内经腹膜内接种100μl 20%DMSO中的5x 104–4x 105个负载DC+0.5mg颗粒咪喹莫特(LC LABS)或仅注射0.5mg咪喹莫特。小鼠接受四次疫苗+咪喹莫特注射,间隔10天。AP20187注射保持两周一次,直到处死。
自发犬类少突神经胶质瘤治疗模型-通过临床MR成像诊断CNS恶性肿瘤后,经所有者知情同意后,根据通过翻译基因组学研究所(Translational Genomics ResearchInstitute)建立的IACUC方案,使大型(>25kg)犬类患者参加非随机I期试验。犬类患者进行开颅术和保守性肿瘤切除,之后将切除的肿瘤在液氮中快速冷冻。为了制备疫苗抗原,将解冻的肿瘤样本细分成可溶性裂解物和mRNA组分,并如上所述制备抗原部分。随后,用G-CSF(Neupogen,Amgen,Thousand Oaks,CA)动员患者,并收获外周血单核细胞(PBMC)。在补充有10%犬类血清(Equitech Bio)、1%抗-抗(Life Technologies)、30ng/ml rcGM-CSF和10ng/ml rcIL-4(两者均来自于R&D Systems)的AIM-V培养基中培养6天时由粘附的单核细胞部分产生犬类DC。负载如上所述的肿瘤抗原后,使用与所述相同但另外补充有10ng/mlrcIL-1β、15ng/mlrcIL-6、10ng/ml rcTNF-α(全部来自R&D Systems)和1μg/ml PGE2(Sigma-Aldrich)的培养基使负载DC成熟。然后收获DC并重新悬浮于2x 500μl等分PBS中通过超声波超声检查术,向颈深淋巴结附近双侧注射。如果施用多次剂量,注射间隔两周。在治疗过程中,动物佐以12周的人IFN-α,每周三次皮下施用,每个剂量两至八百万个单位。通过以下公式由数字MRI测量确定肿瘤体积:体积=4/3π(最小半径)2x(最大半径/最小半径)。
统计分析-统计学显著性定义为p<0.05(*=p<0.05,**=p<0.01),并且视统计学情况而定,通过单尾或双尾的学生非配对或配对t检验测定。多组之间的统计学差异通过单因素或双因素ANOVA验证。用Macintosh版本12.0的Microsoft Excel 2008进行统计检验。除非另有说明,否则所有归一化定量图均来自三个独立实验,且误差棒=+/-SD。
试剂-抗体:α人CTLA-4(ELISA)(eBioscience,San Diego,CA);α人/小鼠CTLA-4(WB)(Abcam;Cambridge,MA);α人/小鼠AIMP1(Lifespan Biosciences Inc,Seattle,WA);α小鼠IL-12p70(ELISA)(BD Biosciences,San Jose,CA);α人CD8(ICH)(Biorbyt;SanFrancisco,CA)、αMouseCD8(流式细胞术),α小鼠CD25、αMouseCD3和α小鼠CD4(BDBiosciences);α小鼠CD8(体内耗竭)和同种型对照(BioXCell,West Lebanon,NH))。α人/小鼠β-肌动蛋白购自Santa Cruz Biotechnologies(Santa Cruz,CA)。αHLA-A、B、C购自BioLegend,San Diego,CA。HLA分型抗体:αHLA-A2-FITC(BD Biosciences)、αHLA-B8-生物素(Abcam)和非偶联αHLA-DR3/DR6(Lifespan Biosciences)。TLR激动剂:从InvivoGen(SanDiego,CA)获得TLR-3激动剂聚(I:C)-若丹明、TLR-9激动剂CpG ODN-FITC和TLR-5激动剂鞭毛蛋白。TLR-4激动剂LPS获自Sigma-Aldrich(St.Louis,MO)。通过荧光显微镜术和使用LSRII流式细胞仪(BD Biosciences)的流式细胞术确认并定量聚(I:C)-若丹明和CpG-FITC的DC摄取,并用MacIntosh的FlowJo 10.0.00003版本(Tree Star Inc,Ashland,OR)的进行分析。所有TLR激动剂均在1μg/ml的浓度下使用。肽:流感A新喀里多尼亚血凝素肽WLTGKNGL(SEQ ID NO:3)、RNLLWLTGKNGLYPN(SEQ ID NO:2)、VLLENERTL(SEQ ID NO:5)和ELLVLLENERTLDFH(SEQ ID NO:4)(先前在Decker等人,2009中有描述)以及甲硫氨酸取代甘氨酸衍生物WLTMKNML(SEQ ID NO:8)和RNLLWLTMKNMLYPN(SEQ ID NO:9)由UnitedBioSystems(Herndon,VA)合成。卵白蛋白H-2Kb免疫显性肽SIINFEKL(SEQ ID NO:1)由Anaspec(Freemont,CA)合成。H-2DbCLIP-重叠MRMATPLLM(SEQ ID NO:6)由UnitedBiosystems合成。重组卵白蛋白购自InvivoGen。重组eGFP蛋白购自Biovision(Moutainview,CA)。其它:AIMp1(SCYE1、小鼠和人)、β2-微球蛋白(小鼠和人)和HLA-DM(人)siGenome SMART库和非靶向siRNA库购自Thermo Scientific(Wilmington DE)。纯化GFPmRNA购自Stemgent(Cambridge,MA)。
共免疫沉淀测定-DC按照指示负载并成熟2天,然后用1%NP-40缓冲液+蛋白酶混合抑制剂(均来自Sigma-Aldrich)裂解。碎片在台式微量离心机中在4℃下以14,000rpm团块化20分钟,随后用蛋白G加琼脂糖珠粒悬浮液IP04(EMD Millipore;Darmstadt,Germany)在4℃下预清洗细胞裂解物1小时。然后使裂解物在4℃下与蛋白G加涂有抗AIMp1(LifespanBiosciences)或抗HLA-A、B、C(BioLegend)的珠粒一起旋转过夜。然后将珠粒在1%NP-40缓冲液中洗涤3次,在PBS中洗涤2次,并且在PAGE分析之前通过在2%SDS(Sigma-Aldrich)变性缓冲液中煮沸收集免疫沉淀物。
51Cr裂解测定-51Cr裂解测定如前所述进行(Decker等人,2006)。
4T1-luc2肿瘤模型-通过将PCR扩增的luc2盒从pGL4.10克隆到pCDH-CMV-MCS-EF1-Hygro表达载体中制备4T1-luc2肿瘤细胞。将线性载体电穿孔到4T1亲本细胞中,并将100μg/ml潮霉素选择应用2周。为了产生肿瘤,为Balb/c小鼠皮内接种2.5x 105个4T1-luc2细胞。每隔一天通过卡尺测量和IVIS监测肿瘤生长。腹膜内注射0.5mg于100μl稀释剂中d-荧光素(Regis Technologies,Morton Grove,IL)后获得IVIs图像。
实施例2-AIMp1释放的表征和小鼠DC的TH1-极化
先前的工作意味着通过负载抗原同源性MHC I类和II类决定簇引发的DC TH1极化的TLR-和IFN-非依赖性机制的存在(Decker等人,2009)。为了确定AIMp1在该过程中是否发挥作用,发明人使DC负载同源I类和II类抗原决定簇,并测定TH1极化和AIMp1释放。小鼠DC在同源负载细胞系或原代组织决定簇(mRNA和裂解物)时,与单一或异源负载的DC相比,分泌10倍以上IL-12p70(图1A)以及显著更多的AIMp1(图1B)。除了AIMp1释放增加外,当I类和II类决定簇同源时,TH1DC分泌显著更少的sCTLA-4(图1C)。与指示AIMp1在TH1极化中的作用的研究一致,AIMp1 siRNA敲低明显减少了响应于同源负载的IL-12分泌(图1A)且恢复了sCTLA-4分泌(图1D)。因此,同源负载DC在体外产生比异源负载DC或用AIMp1siRNA电穿孔的同源负载DC显著更多的活化CD8+T细胞(图1E)。发明人接下来使用H-2Kb I类卵白蛋白(Ova)表位SIINFEKL和全Ova蛋白作为同源II类抗原的来源,以探索体内的这种相同现象。如同体外实验一样,仅在用SIINFEKL肽电穿孔并同时负载了Ova的DC中观察到CD3+、CD3+CD8+,且尤其是CD3+CD8+CD25+群体的扩增。相比之下,单负载DC、异源负载DC或经AIMp1 siRNA处理的同源负载DC在相关T细胞群中没有表现出差异(图1F)。总的来说,数据表明DC MHC I类和II类负载抗原相关决定簇促进TH1偏移,其包括分泌的AIMp1/sCTLA-4比率增加、IL-12的下游释放和活化CD8+T细胞的产生增多。
实施例3-人体系统DC AIMp1/sCTLA-4释放
当人DC同源负载模型GFP抗原(GFP mRNA和重组GFP蛋白)时,观察到AIMp1/sCTLA-4比率的显著增加(图2A-B)。发明人然后从多表位系统转变为先前表征的MHC结合肽(Decker等人,2009)。当I类和II类肽在氨基酸序列上重叠时,从负载DC常规地观察到sCTLA-4分泌的减少和AIMp1分泌的增加(图2C-E)。成熟前未观察到sCTLA-4分泌的差异,但从负载重叠肽的DC的AIMp1释放几乎立即开始或在成熟之前开始(图8),表明AIMp1释放的早期上游作用。因为所有肽均相同地制备,当单独或以异源方式添加时,对AIMp1和sCTLA-4分泌没有影响,并且没有已知的PRR配体,所以认为AIMp1分泌/sCTLA-4消融的机制实际上通过同源MHC同时负载触发而不是通过PRR激动作用触发。尽管如此,在各种TLR激动剂的存在下重复这些实验。在没有抗原负载的情况下,聚(I:C)、LPS、鞭毛蛋白和CpG-ODN都不改变从小鼠(未示出)或人DC分泌sCTLA-4或AIMp1(图2D-E)。另外,当同时添加到DC时,使用各种同源I类和II类结合肽消融了CTLA-4及其相应的mRNA,尽管添加单个或异源I类和II类结合肽没有这种作用(图2F)。AIMp1在mRNA水平上未显示出差异,与抗原负载无关。
为验证MHC结合对这种独特TH极化暗示功能的重要性,发明人利用了H2-DM-/-DC。H2-DM分子伴侣负责从MHC II类结合口袋中去除不变链的CLIP肽。在没有H2-DM的情况下,CLIP与I-Ab单倍体型中的II类结合口袋几乎不可逆地结合,从而消除负载外源性抗原的能力(Martin等人,1996;Miyazaki等人,1996)。无法负载外源性抗原是H2-DM-/-DC的主要分子缺陷。H2-DM-/-DC在TLR、NLR或其它PRR中没有已知缺陷,并且先前已经证实会对TLR激动作用适当响应(Strong等人,1997)。非常有趣的是,也有报道显示H2-DM-/-DC展示出物理依赖于结合CLIP肽的存在的TH2极化表型(Rohn等人,2004)。当负载同源mRNA和裂解物时,H2-DM-/-DC未显示出AIMp1或sCTLA-4的差异性分泌,当负载SIINFEKL(SEQ ID NO:1)和Ova也未刺激体内活化CD8+ T细胞的产生增强(图3A-B和图1F)。相反,H2-DM-/-DC组成性且不变地分泌低水平的AIMp1和高水平的sCTLA-4(图3A-B)。DC AIMp1/sCTLA-4释放和下游TH1应答受MHC结合肽的序列同源性调节。
因为H2-DM-/-DC将CLIP永久性保持在MHC II类结合槽内,所以通过本文描述的线索刺激H2-DM-/-DC中的TH1极化的唯一理论方式将是通过负载与CLIP具有显著同源性,即具有与MHC II类结合的CLIP序列LPKSAKPVSQMRMATPLLMRPMSM(SEQ ID NO:14)重叠的氨基酸序列的I类结合肽(Ghosh等人,1995)。为了检验这个假设,发明人设计了预测结合H-2Db并且与CLIP(MRMATPLLM,SEQ ID NO:6)具有完全序列重叠的I类肽。然后发明人使H2-DM-/-DC负载这种CLIP特异性H-2Db I类肽或作为对照的已建立的H-2b I类SIINFEKL(SEQ ID NO:1)肽。仅从负载H-2Db CLIP的细胞以剂量依赖方式观察到大量的AIMp1释放(图3C)。类似地,仅从负载H-2Db CLIP的H2-DM-/-DC,同样以剂量依赖方式观察到sCTLA-4分泌的减少。负载H2-DM-/-的DC与野生型、同系脾细胞的后续共培养导致,只有当H2-DM-/-DC负载H-2Db CLIP时,CD8+CD25+T细胞增加(图3D)。这些数据验证了先前的结果并表明了固有DC机械论方法的高水平特异性,该方法比较同时与MHC I类和II类结合的肽的氨基酸序列。
为了确定干扰AIMp1和sCTLA-4分泌所需的I类和II类序列同源性的程度,发明人利用了两对不同的同源结合肽,除了两个非锚定甘氨酸残基被甲硫氨酸取代之外,所述同源结合肽是相同的(图3E)。人DC负载这些肽对表明,一个或另一个HLA I类或II类结合肽的取代足以防止CTLA-4分泌的消除和AIMp1分泌的增加,而在互逆肽上的补偿性取代足以恢复先前所见的同源表型(图3E-F)。通过coIP和蛋白质印迹验证的串联质谱(未示出)表明AIMp1与MHC I类和II类分子显著相互作用,特别是在成熟DC内(图9)。使用同源和异源肽对,发明人然后通过AIMp1 coIP证明,只有当负载同源I类和II类肽时,AIMp1/MHC相互作用才显著降低(图3G),这是与细胞中AIMp1分泌增加密切相关的观察结果。当负载多个I类、II类或异源I类和II类肽时,未观察到类似发现。使用mRNA和裂解物的实验产生相同结果:在单负载或负载异源mRNA和裂解物的DC中AIMp1保持与MHC结合,而在负载同源mRNA和裂解物的DC中,很少AIMp1保持与MHC结合(图10)。
为了进一步确定人体系统中由于I类和II类表位之间的序列重叠而引起的TH1极化是否可以独立于传统的MHC结合而发生,发明人利用了针对β2-微球蛋白或HLA-DM的siRNA,其分别显著影响MHCI类或II类MHC负载肽抗原的能力。当负载I类或II类的能力受阻时,DC失去调节响应于同源I类和II类肽负载的AIMp1和CTLA-4分泌的能力(图11A-B),这一发现与从小鼠获得的先前数据一致(图1F和3)。总之,数据完全支持该假设,即DC具有TLR非依赖性、抗原序列依赖性机制,通过该机制调节重要信号分子的释放,其干扰对下游TH极化和CD8+ T细胞发育发挥高度显著的影响(Decker等人,2006;Decker等人,2009)。
实施例4-序列依赖性机制的生理相关性
为了确定这种新表征机制的生理相关性,发明人表征了同源抗原负载破坏对正常免疫本身的耐受性的能力。发明人针对包括精囊(SV)和前列腺在内的野生型组织生成了多种同源负载的DC疫苗,通过MRI容易地可视化相互缠绕但抗原性不同的泌尿生殖器官。给予野生型小鼠1-4次腹膜内(ip)注射(图12)0.5-2.0x 105个负载SV mRNA和裂解物的DC,连同原位咪喹莫特(imq),咪喹莫特是通过刺激类浆细胞DC(pDC)模拟病毒感染环境的佐剂。在治疗一个月内,注射SV负载的DC的小鼠展示出特征性病理变化,包括纤维化和坏死、平滑肌和上皮增生、腔内扩张和结块,以及混合谱系炎症性浸润(图4A)。可以通过MRI纵向监测SV根除,在治疗一个月后观察到MR可成像组织的分隔损失(图4B)。接种六个月后,接受SV负载的DC的小鼠仅保留主要由纤维组织组成的残余结构(图4C)。CD8+浸润通过免疫组织化学证实(图4D)。为了证明疫苗特异性和记忆,在接种两个月后从对照或SV接种的小鼠收获脾细胞并将其过继转移到未经实验的小鼠中,无需额外辅助。(图13)。在六周内,过继转移小鼠中的SV显示与接受初次接种的那些相同的特征性免疫病理(图4E)。
前列腺位于SV附近,沿其前叶和侧叶共享边界。施用同源负载野生型前列腺mRNA和裂解物的DC(图12),并通过MRI监测小鼠。与维持正常病理学的对照小鼠相比(图5A-C),经疫苗处理的小鼠显示较弱的前列腺MRI信号(图5D),其对应于组织的损失(图5E),并展示出类似于接种SV的免疫病理学(图5F)。由于前列腺接种,未观察到纤维化,相反前列腺组织倾向于完全消失(图5G-H)。发明人另外说明通过HLA部分匹配的人DC同源负载WPMY-1抗原决定簇,对人正常前列腺细胞系WPMY-1产生增强的CD8+应答(图14),表明对人疗法的潜在适用性。
针对两个抗原和空间相关的自我组织系统的疫苗特异性的产生允许辨别免疫特异性。如图所示,当用前列腺负载DC治疗小鼠时,病理学仅为前列腺特异性的(图5I)。相反,当用SV负载的DC治疗小鼠时,病理学仅为SV特异性的(图5J)。实际上,在一定范围的不同剂量下69只小鼠针对免疫自身接种不能产生可观察到的脱靶效应(未示出)。总的来说,在59%接种同源负载的DC的小鼠(37/63)中观察到适当的疫苗反应性,而不是在0%接种组织裂解物负载的DC的小鼠中(n=35,p<0.001)和0%接种组织mRNA负载的DC的小鼠中(n=12,p<0.001)。
实施例5-生理性瘤形成研究
为了确定这种策略解决生理性瘤形成的能力,发明人利用了各种不同的模型系统。在4T1型乳腺癌模型中,对具有第8天建立的表达4T1luc2的肿瘤的小鼠组群给予单剂量的同源疫苗(源自亲本、luc2-4T1细胞)或仅给予佐剂。虽然6只佐剂处理的小鼠中有5只发生转移并死亡,但是接种的小鼠在实验结束时维持相对较小的肿瘤并且没有显示明显的发病率(图15A-B)。为证明这种模型中肿瘤控制对CD8+细胞的依赖性(并因此证明TH1免疫性),给予未实验动物两个剂量的同源疫苗,然后耗尽CD8+细胞。然后收获脾细胞,并将其过继转移到预先接种了2.5x 105个4T1-luc2肿瘤细胞的同系动物中。如图所示(图15C-D),过继转移了同种型耗尽的脾细胞的小鼠表现出高于过继转移了CD8耗尽的脾细胞的小鼠的非常显著的存活优势,表明CD8+细胞在原发性肿瘤控制和转移扩散中的关键作用。有趣的是,过继转移了源自异源接种(4T1mRNA/B16.F10裂解物)动物的同种型耗尽的脾细胞的小鼠表现最差。
为了确定同源接种在高生理相关性模型中的作用,发明人利用了转基因Pro-Cat/JOCK1模型,其中在前列腺上皮中诱导FGFR1和β-连环蛋白(catenin)信号传导后发展出生理性原生胰腺癌(Carstens等人,2014)。在该模型中,小鼠从前列腺增生(8周)进展到前列腺上皮内瘤变(mPIN,12周)、腺癌(24周)和移行性肉瘤样(60周)阶段。诱导前列腺腺癌24周后,处死小鼠并切除癌变前列腺以产生腺癌期抗原制剂。然后诱导后续小鼠组群24周并治疗性接种同源负载疫苗。另外4个月后处死接种的小鼠,通过H&E染色的前列腺的盲选病理评分来确定癌症进展。接受负载腺癌期抗原的DC的小鼠进展为增生,但很大程度上停滞于mPIN,显示相对较少的组织病理学腺癌(图6B和6D)。另外,接种小鼠显示出淋巴细胞浸润的腺泡(例如图6B.1插图),这在未接种、对照接种或仅佐剂的组中未观察到。仅接受佐剂的诱导小鼠显示出典型的腺癌(图6C)。接受完整疫苗方案的未诱导对照小鼠未显示出与正常前列腺的交叉反应(图6A)。而且,接种似乎表现出剂量反应效应(图6E-J)。
最后,发明人对大型动物系统中的自发性脑肿瘤测试了这种方法,以证明这种方法在临床兽医环境中的可行性和安全性。简而言之,通过MRI诊断CNS恶性肿瘤后,经所有者知情同意后招募了两名大型(>25kg)犬类兽医患者。犬不是接受姑息性类固醇的护理标准,而是进行开颅术和保守性肿瘤切除术。将肿瘤样本细分为可溶性裂解物和mRNA组分。随后,用G-CSF(Neupogen)动员患者,并收获外周血单核细胞(PBMC)。粘附单核细胞分化为同时负载肿瘤裂解物和mRNA亚组分的DC并成熟化。然后收获DC,并重新悬浮于PBS中用于通过超声波超声检查术,向颈深淋巴结附近注射。连同接种一起,动物佐以12周的人IFN-α,每周三次皮下施用,每个剂量两至八百万个单位。除了证明这种方法的安全性和可行性外,每只动物在接种开始时也显示出快速且显著的肿瘤缩小。第一只动物接受单次剂量的5x 105个疫苗细胞,并在一个月的随访中显示出50%的肿瘤消退(图7A-D)。第二只动物在三次施用过程中接受5x 106个疫苗细胞并在一个月的随访中显示出近80%的肿瘤消退(图7E-H)。近200天的中位存活期比同等历史对照的中位存活期(69天)高三倍(Rossmeisl等人,2013)。
在这些实例中,发明人已经鉴定了先前未识别的和有些意想不到的DC调节检查点的机械基础,对其全面阐释可能对于在疫苗免疫疗法领域中实现临床目标至关重要。先前和当前的工作表明,DC同时负载同源I类和II类抗原诱导DC TH1极化及体外和体内下游CD8+T细胞应答的增强(Decker等人,2006;Decker等人,2009)。这里发明人证明,这种现象与AIMp1的分泌上调在机械论上相关,AIMp1是已知TH1极化功能的重要细胞因子,其释放上调IL-12分泌,同时附随下调CTLA-4及其相应mRNA转录物的分泌。AIMp1似乎在sCTLA-4和IL-12的上游起作用,如AIMp1 siRNA敲低和动力学研究所证明的那样。重要的是,发明人证明,响应于同源抗原负载的AIMp1的释放以不依赖TLR的方式进行。以异源方式添加时,TLR激动作用不能增加AIMp1释放或减少CTLA-4分泌,同样制备的肽决定簇也不能够刺激这种应答。siRNA敲低β2-微球蛋白或HLA-DM消除了DC对同源I类和II类结合肽应答的能力。此外,缺乏H2-DM且因此不能负载外源性抗原的鼠DC也不能被极化或增强下游CD8+应答,尽管MHC完好且模式识别受体保持功能性(Strong等人,2011)。然而,H2-DM-/-DC负载与Ii CLIP的氨基酸序列重叠的合成I类结合肽,理论上是以同源方式负载这些细胞的I和II类的唯一可能方式,以剂量反应方式释放野生型比率的AIMp1/sCTLA-4并产生CD8+CD25+T细胞。这些结果坚定地表明在这种TH1极化方法中MHC的肽结合的作用,这是先前未描述的独特过程。为进一步证明TH1极化取决于抗原同源性而不是先天性PRR,发明人在先前表征的(Decker等人,2009)II类结合肽中添加了两个非锚定氨基酸取代,使得超过三个氨基酸的连续I和II类序列同源性被中断。这种较小的同源性破坏足以消除极化AIMp1/sCTLA-4比率。向I类肽施加互补氨基酸取代,从而恢复完整的序列同源性,足以恢复高的AIMp1/CTLA-4比率。总的来说,数据表明DC中的独特TH1极化检查点取决于MHC I类和II类结合肽之间的高度序列同源性。除了鉴定该机制所依赖的重要效应分子外,发明人还通过产生破坏免疫耐受性并根除野生型小鼠中的正常免疫自身的组织特异性疫苗来证明生理学相关性,这是先前未报道的现象。进一步的实验还证明了在三种不同模型系统中对肿瘤自身的显著活性,包括表明在自发、远交犬类模型中对少突神经胶质瘤的活性的实验。
总的来说,发明人已经使用了29种不同的模型系统(表1),包括全细胞系统、单抗原系统和多对重叠的I类和II类MHC结合表位,以证明同源负载DC表现出多种TH1相关特征,包括差异性细胞因子分泌、表面标志物表达、全局转录改变以及增强CD8+ CTL产生的能力(表2)。在这29种不同系统中的每一种中,显示出TH1极化的组之间的唯一共性是DC负载的I类和II类抗原之间的高度抗原性或氨基酸序列同源性。
表1.所用抗原系统、测试的物种和向DC递送抗原的方法的汇总*=先前公开的系统。
表2.选择同源DC负载的标志物和表现。
***
根据本公开,本文公开和要求保护的所有方法可以在没有过度实验的情况下进行和执行。虽然已经根据优选实施方案描述了本发明的组合物和方法,但是对于本领域技术人员显而易见的是,在不脱离本发明的概念、精神和范围的前提下,可以对所述方法和在本文所述方法的步骤或步骤顺序上施加变化。更具体地,将显而易见的是,化学和生理相关的某些试剂可以代替本文所述的试剂,同时获得相同或相似的结果。对于本领域技术人员显而易见的所有此类相似取代和修改被视为在由所附权利要求书所限定的本发明的精神、范围以及概念之内。
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Claims (84)
1.一种在具有患病细胞群的受试者中提供免疫应答的方法,其包括:
(a)获得致敏的树突细胞群,其中所述细胞已经用至少一种对所述患病细胞群有特异性的抗原致敏;以及
(b)向所述受试者施用有效量的所述致敏的树突细胞群,其中按以下方式施用所述致敏的树突细胞群:
(i)连同I型干扰素(INF)、TLR-7激动剂、TLR-9激动剂或AIMp1一起施用;并且
(ii)施用到所述受试者中接近所述患病细胞群的淋巴组织部位。
2.根据权利要求1所述的方法,其中所述致敏的树突细胞群连同I型干扰素(INF)、TLR-7激动剂、TLR-9激动剂或AIMp1一起施用。
3.根据权利要求2所述的方法,其中所述致敏的树突细胞群连同I型INF一起施用。
4.根据权利要求3所述的方法,其中所述I型INF为INF-α。
5.根据权利要求2所述的方法,其中所述致敏的树突细胞群连同TLR-7激动剂一起施用。
6.根据权利要求5所述的方法,其中所述TLR-7激动剂选自CL075、CL097、CL264、CL307、GS-9620、聚(dT)、咪喹莫特、嘎德莫特、雷西莫特(R848)、洛索立宾和ssRNA寡核苷酸。
7.根据权利要求2所述的方法,其中所述致敏的树突细胞群连同TLR-9激动剂一起施用。
8.根据权利要求7所述的方法,其中所述TLR-9激动剂是CpG寡脱氧核苷酸(CpG ODN)。
9.根据权利要求2所述的方法,其中所述致敏的树突细胞群连同AIMp1一起施用。
10.根据权利要求2所述的方法,其中所述I型INF、TLR-7激动剂、TLR-9激动剂或AIMp1在所述致敏的树突细胞群之前或基本上同时施用。
11.根据权利要求2所述的方法,其中所述I型INF、TLR-7激动剂、TLR-9激动剂或AIMp1在所述致敏的树突细胞群之后施用。
12.根据权利要求10-11中任一项所述的方法,其中所述I型INF、TLR-7激动剂、TLR-9激动剂或AIMp1在所述致敏的树突细胞群的约1周、1天、8小时、4小时、2小时或1小时内施用。
13.根据权利要求2所述的方法,其还包括向所述受试者施用包含有效量的所述致敏的树突细胞群和I型INF、TLR-7激动剂、TLR-9激动剂或AIMp1的组合物。
14.根据权利要求1所述的方法,其还包括向所述受试者施用免疫检查点抑制剂。
15.根据权利要求14所述的方法,其中所述免疫检查点抑制剂为CTLA-4拮抗剂。
16.根据权利要求14所述的方法,其中所述免疫检查点抑制剂为伊匹单抗、帕姆单抗或纳武单抗。
17.根据权利要求1所述的方法,其中将所述致敏的树突细胞群施用于所述受试者中接近所述患病细胞群的淋巴组织部位。
18.根据权利要求17所述的方法,其中所述致敏的树突细胞群连同I型INF、TLR-7激动剂、TLR-9激动剂或AIMp1一起施用,并且其中所述致敏的树突细胞群施用于所述受试者中接近所述患病细胞群的淋巴组织部位。
19.根据权利要求17所述的方法,其中所述淋巴组织部位是为所述患病细胞群周围的组织引流的淋巴组织。
20.根据权利要求1所述的方法,其中所述受试者患有癌症,以及自身免疫性疾病或感染性疾病。
21.根据权利要求20所述的方法,其中所述患病细胞群为肿瘤。
22.根据权利要求21所述的方法,其中所述肿瘤为脑肿瘤、肾细胞癌、黑素瘤、前列腺癌、乳腺癌或慢性淋巴细胞性白血病。
23.一种免疫原性组合物,其包含:(i)抗原致敏的树突细胞和(ii)I型干扰素(INF)、TLR-7激动剂、TLR-9激动剂或AIMp1。
24.根据权利要求23所述的组合物,其中所述抗原致敏的树突细胞已经用与癌症、自身免疫性疾病或感染性疾病相关的抗原致敏。
25.根据权利要求24所述的组合物,其中所述抗原致敏的树突细胞已经用至少一种肿瘤抗原致敏。
26.根据权利要求25所述的组合物,其中所述肿瘤为脑肿瘤、肾细胞癌、黑素瘤、前列腺癌、乳腺癌或慢性淋巴细胞性白血病。
27.根据权利要求23所述的组合物,其包含I型INF。
28.根据权利要求27所述的组合物,其中所述I型INF为INF-α。
29.根据权利要求23所述的组合物,其包含TLR-7激动剂。
30.根据权利要求29所述的组合物,其中所述TLR-7激动剂选自CL075、CL097、CL264、CL307、GS-9620、聚(dT)、咪喹莫特、嘎德莫特、雷西莫特(R848)、洛索立宾和ssRNA寡核苷酸。
31.根据权利要求23所述的组合物,其包含TLR-9激动剂。
32.根据权利要求31所述的组合物,其中所述TLR-9激动剂是CpG寡脱氧核苷酸(CpGODN)。
33.根据权利要求23所述的组合物,其包含AIMp1。
34.根据权利要求23所述的组合物,其还包含免疫检查点抑制剂。
35.根据权利要求34所述的方法,其中所述免疫检查点抑制剂为CTLA-4拮抗剂。
36.根据权利要求34所述的方法,其中所述免疫检查点抑制剂为伊匹单抗、帕姆单抗或纳武单抗。
37.一种培养抗原特异性T细胞的方法,其包括在已经用至少第一抗原致敏的抗原呈递细胞群的存在下培养T细胞或T细胞前体的群体,其中所述培养是在AIMp1的存在下进行。
38.根据权利要求37所述的方法,其进一步限定为离体扩增抗原特异性T细胞的方法。
39.根据权利要求37所述的方法,其中所述抗原呈递细胞包含树突细胞。
40.根据权利要求19所述的方法,其中所述树突细胞同源负载抗原。
41.根据权利要求39所述的方法,其中所述树突细胞群包含原代树突细胞。
42.根据权利要求37所述的方法,其中所述培养是在所述受试者的免疫检查点抑制剂的存在下进行。
43.根据权利要求42所述的方法,其中所述免疫检查点抑制剂为CTLA-4拮抗剂。
44.根据权利要求42所述的方法,其中所述免疫检查点抑制剂为伊匹单抗、帕姆单抗或纳武单抗。
45.一种在具有患病细胞群的受试者中提供免疫应答的方法,其包括:
(a)获得致敏的树突细胞群,其中所述细胞已经用至少一种对所述患病细胞群有特异性的抗原致敏;以及
(b)向所述受试者施用有效量的所述致敏的树突细胞群,其中按以下方式施用所述致敏的树突细胞群:
(i)连同TLR-3激动剂、维甲酸诱导基因-1(RIG-1)样受体配体或细胞溶质DNA(CDS)受体配体一起施用;并且
(ii)施用到所述受试者中接近所述患病细胞群的淋巴组织部位。
46.根据权利要求45所述的方法,其中所述致敏的树突细胞群连同TLR-3激动剂一起施用。
47.根据权利要求46所述的方法,其中TLR激动剂为聚肌苷-聚胞苷酸(聚(I:C))或RGC100。
48.根据权利要求45所述的方法,其中所述致敏的树突细胞群连同RIG-1样受体配体一起施用。
49.根据权利要求48所述的方法,其中所述RIG-1样受体配体被进一步限定为RIG-1、MDA5、LGP2或IPS-1配体。
50.根据权利要求48所述的方法,其中所述RIG-1样受体配体选自MDA5配体、LGP2配体、ssRNA、dsRNA、5'ppp-dsRNA、聚(dA:dT)和聚(I:C)。
51.根据权利要求45所述的方法,其中所述致敏的树突细胞群连同CDS受体配体一起施用。
52.根据权利要求51所述的方法,其中所述CDS受体配体被进一步限定为cGAS-STING配体。
53.根据权利要求52所述的方法,其中所述cGAS-STING配体为细菌环状二核苷酸(CDN)。
54.根据权利要求45所述的方法,其中所述TLR-3激动剂、RIG-1样受体配体或CDS受体配体在所述致敏的树突细胞群之前或基本上同时施用。
55.根据权利要求45所述的方法,其中所述TLR-3激动剂、RIG-1样受体配体或CDS受体配体在所述致敏的树突细胞群之后施用。
56.根据权利要求45-55中任一项所述的方法,其中所述TLR-3激动剂、RIG-1样受体配体或CDS受体配体在所述致敏的树突细胞群的约1周、1天、8小时、4小时、2小时或1小时内施用。
57.根据权利要求45所述的方法,其还包括向所述受试者施用免疫检查点抑制剂。
58.根据权利要求57所述的方法,其中所述免疫检查点抑制剂为CTLA-4拮抗剂。
59.根据权利要求57所述的方法,其中所述免疫检查点抑制剂为伊匹单抗、帕姆单抗或纳武单抗。
60.根据权利要求45所述的方法,其中所述淋巴组织部位是为所述患病细胞群周围的组织引流的淋巴组织。
61.根据权利要求45所述的方法,其中所述受试者患有癌症,以及自身免疫性疾病或感染性疾病。
62.根据权利要求60所述的方法,其中所述患病细胞群为肿瘤。
63.根据权利要求62所述的方法,其中所述肿瘤为脑肿瘤、肾细胞癌、黑素瘤、前列腺癌、乳腺癌或慢性淋巴细胞性白血病。
64.一种免疫原性组合物,其包含:(i)抗原致敏的树突细胞和(ii)TLR-3激动剂、RIG-1样受体配体或CDS受体配体。
65.根据权利要求64所述的组合物,其中所述抗原致敏的树突细胞已经用与癌症、自身免疫性疾病或感染性疾病相关的抗原致敏。
66.根据权利要求65所述的组合物,其中所述抗原致敏的树突细胞已经用至少一种肿瘤抗原致敏。
67.根据权利要求66所述的组合物,其中所述肿瘤为脑肿瘤、肾细胞癌、黑素瘤、前列腺癌、乳腺癌或慢性淋巴细胞性白血病。
68.根据权利要求64所述的组合物,其包含TLR-3激动剂。
69.根据权利要求68所述的组合物,其中所述TLR-3为聚(I:C)或RGC100。
70.根据权利要求64所述的组合物,其包含RIG-1样受体配体。
71.根据权利要求70所述的组合物,其中所述RIG-1样受体配体选自MDA5配体、LGP2配体、ssRNA、dsRNA、5'ppp-dsRNA、聚(dA:dT)和聚(I:C)。
72.根据权利要求64所述的组合物,其包含CDS受体配体。
73.根据权利要求72所述的组合物,其中所述CDS受体配体为细菌CDN。
74.根据权利要求64所述的组合物,其还包含免疫检查点抑制剂。
75.根据权利要求74所述的组合物,其中所述免疫检查点抑制剂为CTLA-4拮抗剂。
76.根据权利要求74所述的组合物,其中所述免疫检查点抑制剂为伊匹单抗、帕姆单抗或纳武单抗。
77.一种培养抗原特异性T细胞的方法,其包括在已经用至少第一抗原致敏的抗原呈递细胞群的存在下培养T细胞或T细胞前体的群体,其中所述培养是在聚(I:C)的存在下进行。
78.根据权利要求77所述的方法,其进一步限定为离体扩增抗原特异性T细胞的方法。
79.根据权利要求77所述的方法,其中所述抗原呈递细胞包含树突细胞。
80.根据权利要求61所述的方法,其中所述树突细胞同源负载抗原。
81.根据权利要求79所述的方法,其中所述树突细胞群包含原代树突细胞。
82.根据权利要求77所述的方法,其中所述培养是在所述受试者的免疫检查点抑制剂的存在下进行。
83.根据权利要求82所述的方法,其中所述免疫检查点抑制剂为CTLA-4拮抗剂。
84.根据权利要求82所述的方法,其中所述免疫检查点抑制剂为伊匹单抗、帕姆单抗或纳武单抗。
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