CN101090633A - 树突细胞肿瘤注射（dcti）疗法 - Google Patents
树突细胞肿瘤注射（dcti）疗法 Download PDFInfo
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Abstract
本发明涉及在患者内治疗肿瘤细胞的方法，其中将从患者的单核细胞发育而来的树突细胞和佐剂导入至患者直接进入该患者的肿瘤细胞。所述树突细胞和佐剂与所述肿瘤细胞中的抗原结合形成癌疫苗，因而立即治疗所述患者的肿瘤细胞。本发明也提供预先的治疗步骤，即用放射疗法或化学疗法方案治疗患者。
Description
与相关申请案的交叉参考
本申请案要求于2004年9月17日申请的暂时申请案60/610,822的优先权。
发明领域
本发明涉及肿瘤治疗，所述的疗法包括将未成熟的树突细胞和佐剂直接注射进患者(人或动物)的肿瘤组织中，所述的肿瘤组织在注射时呈递抗原性为疫苗抗原。这些元件在肿瘤组织内的复合快速诱导并激活患者的免疫系统而显著减少和/或消除肿瘤细胞。大多数增加免疫应答的佐剂可与未成熟的树突细胞一起直接注射进肿瘤组织来获得肿瘤组织的减少或消除。
发明背景
免疫学佐剂与疫苗结合使用来增强对抗原的免疫应答。免疫学佐剂发挥功能的一种方式是吸引巨噬细胞至抗原，这样所述巨噬细胞可以将所述抗原呈递至局部淋巴结并起始有效的抗原反应。佐剂也可以本身作为抗原的载体，或可以通过其它机制(如储库效果、细胞因子诱导、补体激活、免疫学系统不同细胞群的募集、抗原递送至不同的抗原呈递细胞、I型或II型HLA分子表达的调控以及刺激产生不同的抗体亚型)来影响免疫应答。许多更新的疫苗仅是弱免疫原性的并因而需要佐剂的存在。
具有佐剂活性的材料是熟知的。明矾(Al(OH)3)和类似的铝凝胶是批准用于人使用的佐剂。明矾的佐剂活性首先在1962年由Glenny发现(Chemistry and Industry，Jun.15，1926；J.Path.Bacteriol，34，267)。氢氧化铝和磷酸铝(通常统称为明矾)常规上在人和兽用疫苗中用作佐剂。明矾在对抗白喉和破伤风毒素中增强抗体的效力得以很好的确立并且最近，已经将明矾用作HBsAg疫苗的佐剂。
开发佐剂的研究的一方面已经指向树突细胞的研究。树突细胞(DC)是专职性抗原呈递细胞(APC)，其具有起始体内和体外初级免疫应答的独特能力。它们源于骨髓(DC1)或淋巴(DC2)前体并且以它们的未成熟形式分布在整个通常遭遇环境病原体的组织体(皮肤、粘膜、肠上皮等)。然而，DC1和DC2只占小百分比的外周循环中的单核细胞总数，CD14+/CD11c+/HLA-DR+单核细胞形式的DC1前体相对丰富，构成了约10％-15％的单核血细胞。
未成熟的DC表达大量涉及抗原获取、DC活化/成熟和抗原递呈的表面结构。一旦DC遇到抗原，它们则进行成熟过程，所述的成熟过程的特征是I型和II型HLA分子以及共刺激分子的上调，并且与T和B淋巴细胞上的相关受体相互作用，导致抗原特异性细胞和体液免疫应答的产生。
DC被认为是免疫系统中的初级APC。分离这些细胞和/或它们的前体以及在体外研究它们的能力已经对它们在先天性和获得性免疫性中的作用的认识增加了相当的深度。体外产生人DC的典型的手段是从外周循环分离并富集CD 14+单核细胞并在GM-CSF和IL-4中将它们培养不同时间，随后用一系列细胞因子(包括IL-2、IL-6、IL-7、IL-13、IL-15、TNFα，IL-10)或用多种其它试剂包括脂多糖、PGE2、1型干扰素或双链RNA进行最后的成熟。
许多研究者已经表明这些体外产生的源于单核细胞的DC为有效的能起始初始和记忆性抗原-特异性CD4+和CD8+T细胞应答的抗原呈递细胞(APC)。最近的体外研究已经得到了更丰富的关于DC1的生物学信息并有助于说明体内产生抗原特异性免疫应答的过程。在外周组织中，未成熟的DC在危险信号的背景下获取抗原物质，起始了由DC与附近其它细胞类型产生的复杂的细胞因子/趋化因子环境。由DC产生的可溶性介体(mediator)可以以自分泌或旁分泌的方式起作用。与结合抗原的DC相互作用后，T细胞产生另外的细胞因子和趋化因子，由释放的所述细胞因子激活的其它免疫细胞也一样。这种相互作用的复杂网络依次产生促进DC细胞从它们的单核细胞前体产生的环境。
据认为，那些促进树突细胞成熟的佐剂，当与疫苗抗原结合施用时，将导致更多将所述疫苗抗原呈递至T淋巴细胞和B细胞的抗原呈递细胞，因而促进了对所述疫苗抗原的免疫应答。然而，因为APC的抗原性总是进行抗原性漂移和/或抗原性转变的演变，最有效的疫苗抗原的分离相当困难，因而许多较新的疫苗即使存在树突细胞和佐剂也仅是弱免疫原性的。在治疗过程中对抗活肿瘤细胞的最有效的疫苗抗原应该与树突细胞和佐剂一起使用来促进和诱导更强的免疫原性。
发明描述
本发明通过提供与树突细胞和佐剂一起的最有效的抗原疫苗抗原来增加对抗肿瘤细胞的免疫应答的量和质量而解决上述需要。
本发明提供使用完全的抗原元件通过将它们定位于人体(或备选地，动物体)中活肿瘤组织内来治疗肿瘤组织，所述的抗原元件包括未知和已知的抗原呈递细胞的抗原性。这与培养从肿瘤细胞系获得的抗原或任何加入抗原的方法的先前技术形成对照，作为用于患者肿瘤细胞的疫苗抗原时先前的技术具有有限的抗原性和过时的抗原数据或效力。特别是，本发明涉及治疗，所述的治疗包括将未成熟的树突细胞和佐剂直接注射进患者的肿瘤组织中，所述肿瘤组织在注射位点呈递抗原元件作为疫苗抗原。这些元件在肿瘤组织内的复合快速地诱导并激活患者的免疫系统而显著地减少和/或消除肿瘤细胞。大多数增加免疫应答的佐剂可与未成熟的树突细胞一起直接注射进肿瘤组织来获得肿瘤细胞的减少或消除。这种佐剂可以包括(但不限于)基于脂类的、基于蛋白质的和基于多糖的佐剂，例如：
Marignase
LCM
Agaricus
OK432
BCG
蘑菇多糖(香菇)
Reishi
Sarunokoshikake
TNF
Meshimakobu
Froint氏完全或不完全佐剂
LPS
脂肪酸
磷脂
细胞因子
病毒
本发明提供快速减少和/或消除肿瘤细胞，这可通过MRI和/或CT和/或回波扫描(Echo scan)在注射后两周内肉眼检测。根据本发明的优选的实施方案的治疗包括以下步骤：
步骤1：从患者收集外周血单核细胞(PBMC)
步骤2：用GM-CFS和IL-4培养这些PBMC得到未成熟的树突细胞。
步骤3：将培养的未成熟树突细胞和佐剂注射进肿瘤内。
步骤4：在两周内评估肿瘤。
在一个特别的实施方案中，这种治疗方法的功效(免疫应答)可以通过在上述步骤1-4前用已知的化学治疗和/或放射治疗技术预先治疗肿瘤细胞来增强，所述的预先治疗减弱了存在的免疫系统。而且，这种治疗方法的功效(免疫应答)也可以通过在上述步骤1-4前注射与抗T单核细胞抗体一起的肿瘤细胞(单独进行或加上上述的化学疗法和/或放射疗法)来增强。
Claims (33)
1.在患者的肿瘤组织中减少肿瘤细胞的方法，所述的方法包括以下步骤：从患者收集单核细胞，用一种或多种因子培养所述的单核细胞来从所述单核细胞形成未成熟的树突细胞，将所述未成熟的树突细胞引入患者的肿瘤组织，并将佐剂引入患者的肿瘤组织。
2.权利要求1中所述的方法，其中所述的患者是人。
3.权利要求1所述的方法，其中所述的一种或多种因子选自：IL-4和GM-CFS。
4.权利要求1所述的方法，其中所述的佐剂选自：marignase、LCM、agaricus、OK432、BCG、蘑菇多糖、Reishi、Sarunokoshikake、TNF、Meshimakobu、Froint氏完全或不完全佐剂、LPS、脂肪酸和磷脂。
5.权利要求1所述的方法，其中所述的佐剂是细胞因子。
6.权利要求5所述的方法，其中所述的细胞因子选自IL-2、IL-6、IL-7、IL-10、IL-13和IL-15。
7.权利要求1所述的方法，其中所述的佐剂是病毒。
8.权利要求1所述的方法，所述的方法进一步包括在将所述未成熟树突细胞和佐剂引入肿瘤组织前用化学疗法治疗患者的步骤。
9.权利要求1所述的方法，所述的方法进一步包括在将所述未成熟树突细胞和佐剂引入肿瘤组织前用放射疗法治疗患者的步骤。
10.权利要求1所述的方法，所述的方法进一步包括在将所述未成熟树突细胞和佐剂引入肿瘤组织前用抗T细胞单克隆抗体治疗患者的步骤。
11.权利要求1的方法，所述的方法包括从所述引入开始计算的14天后评估肿瘤组织以确定是否已经发生细胞减少。
12.在肿瘤组织中减少肿瘤细胞的方法，所述的方法包括以下步骤：用化疗方案治疗患者的肿瘤，从患者收集单核细胞，用一种或多种因子培养所述的单核细胞来从所述单核细胞形成未成熟的树突细胞，将所述未成熟树突细胞引入患者的肿瘤组织，并将佐剂引入该患者的肿瘤组织。
13.权利要求12中所述的方法，其中所述的患者是人。
14.权利要求12所述的方法，其中所述的一种或多种因子选自：IL-4和GM-CFS。
15.权利要求12所述的方法，其中所述的佐剂选自：marignase、LCM、agaricus、OK432、BCG、蘑菇多糖、Reishi、Sarunokoshikake、TNF、Meshimakobu、Froint氏完全或不完全佐剂、LPS、脂肪酸和磷脂。
16.权利要求12所述的方法，其中所述的佐剂是细胞因子。
17.权利要求16所述的方法，其中所述的细胞因子选自IL-2、IL-6、IL-7、IL-10、IL-13和IL-15。
18.权利要求12所述的方法，其中所述的佐剂是病毒。
19.权利要求12所述的方法，所述的方法进一步包括在将所述未成熟树突细胞和佐剂引入肿瘤组织前用放射疗法治疗患者的步骤。
20.在肿瘤组织中减少肿瘤细胞的方法，所述的方法包括以下步骤：用放射治疗方案治疗患者的肿瘤，从患者收集单核细胞，用一种或多种因子培养所述的单核细胞来从所述单核细胞形成未成熟的树突细胞，将所述未成熟树突细胞引入患者的肿瘤组织，并将佐剂引入该患者的肿瘤组织。
21.权利要求20中所述的方法，其中所述的患者是人。
22.权利要求20所述的方法，其中所述的一种或多种因子选自：IL-4和GM-CFS。
23.权利要求20所述的方法，其中所述的佐剂选自：marignase、LCM、agaricus、OK432、BCG、蘑菇多糖、Reishi、Sarunokoshikake、TNF、Meshimakobu、Froint氏完全或不完全佐剂、LPS、脂肪酸和磷脂。
24.权利要求20所述的方法，其中所述的佐剂是细胞因子。
25.权利要求24所述的方法，其中所述的细胞因子选自IL-2、IL-6、IL-7、IL-10、IL-13和IL-15。
26.权利要求20所述的方法，其中所述的佐剂是病毒。
27.权利要求20所述的方法，所述的方法进一步包括在将所述未成熟树突细胞和佐剂引入肿瘤组织前用化学疗法治疗患者的步骤。
28.癌疫苗前体，当引入肿瘤组织中时，所述的癌疫苗前体与抗原结合来减少患者中的肿瘤，所述的癌疫苗前体包括：源于从患者收集的单核细胞的未成熟树突细胞、佐剂和源于患者中的肿瘤的抗原。
29.权利要求28所述的疫苗，其中所述的患者是人。
30.权利要求28所述的疫苗，其中所述的一种或多种因子选自：IL-4和GM-CFS。
31.权利要求28所述的疫苗，其中所述的佐剂选自：marignase、LCM、agaricus、OK432、BCG、蘑菇多糖、Reishi、Sarunokoshikake、TNF、Meshimakobu、Froint氏完全或不完全佐剂、LPS、脂肪酸和磷脂。
32.权利要求28所述的疫苗，其中所述的佐剂是细胞因子。
33.权利要求32所述的疫苗，其中所述的细胞因子选自IL-2、IL-6、IL-7、IL-10、IL-13和IL-15。
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| CN102978233A (zh) * | 2012-11-16 | 2013-03-20 | 河南农业大学 | 一种黑根霉菌丝脂质体直接转化方法 |
| CN107007830A (zh) * | 2017-06-02 | 2017-08-04 | 中山大学 | 一种无毒株弓形体和中药多糖佐剂组合物的用途、疫苗及制备方法 |
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| JP2010508364A (ja) * | 2006-10-31 | 2010-03-18 | ハスミ インターナショナル リサーチ ファウンデイション | 樹状細胞腫瘍注射治療及び関連するワクチン |
| US20080294115A1 (en) * | 2007-05-22 | 2008-11-27 | Chen Raymond H | Microscopic Tumor Injection Treatment |
| US20090259160A1 (en) * | 2008-04-10 | 2009-10-15 | Therinject, Llc | System and composition for dendritic cell therapy using pharmacologically active microcarriers |
| GB201013443D0 (en) * | 2010-08-11 | 2010-09-22 | Cytovac As | Compositions and methods for producing dendritic cells |
| EP2543386A1 (en) * | 2011-07-05 | 2013-01-09 | Sotio a.s. | Means and methods for active cellular immunotherapy of cancer by using tumor cells killed by high hydrostatic pressure |
| CN104911148A (zh) * | 2015-07-14 | 2015-09-16 | 奥思达干细胞有限公司 | 一种人免疫活性细胞dc-cik细胞制剂及其有效制备方法 |
| WO2017218533A1 (en) | 2016-06-13 | 2017-12-21 | Torque Therapeutics, Inc. | Methods and compositions for promoting immune cell function |
| US11524033B2 (en) | 2017-09-05 | 2022-12-13 | Torque Therapeutics, Inc. | Therapeutic protein compositions and methods of making and using the same |
| WO2023200897A1 (en) * | 2022-04-13 | 2023-10-19 | The Regents Of The University Of California | Use of viral il-6 in cancer therapy |
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| WO1998046083A1 (en) * | 1997-04-17 | 1998-10-22 | The Regents Of The University Of California | Use of lentiviral vectors for antigen presentation in dendritic cells |
| US6482405B1 (en) * | 1998-09-15 | 2002-11-19 | University Of Pittsburgh Of The Commonwealth System Of Higher Education | In situ injection of antigen-presenting cells with genetically enhanced cytokine expression |
| TW454321B (en) * | 2000-09-13 | 2001-09-11 | Siliconware Precision Industries Co Ltd | Semiconductor package with heat dissipation structure |
| US20030202963A1 (en) * | 2000-10-12 | 2003-10-30 | Cornell Research Foundation, Inc. | Method of treating cancer |
| BRPI0317064B8 (pt) * | 2002-12-06 | 2021-05-25 | Northwest Biotherapeutics Inc | composições compreendendo células dendríticas parcialmente amadurecidas in vitro |
| US7785583B2 (en) * | 2002-12-10 | 2010-08-31 | Argos Therapeutics, Inc. | In situ maturation of dendritic cells |
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| CN102978233A (zh) * | 2012-11-16 | 2013-03-20 | 河南农业大学 | 一种黑根霉菌丝脂质体直接转化方法 |
| CN107007830A (zh) * | 2017-06-02 | 2017-08-04 | 中山大学 | 一种无毒株弓形体和中药多糖佐剂组合物的用途、疫苗及制备方法 |
| CN107007830B (zh) * | 2017-06-02 | 2020-07-14 | 中山大学 | 一种无毒株弓形体和中药多糖佐剂组合物的用途、疫苗及制备方法 |
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| EP1793678A1 (en) | 2007-06-13 |
| US20060216269A1 (en) | 2006-09-28 |
| KR20070061831A (ko) | 2007-06-14 |
| BRPI0515428A (pt) | 2008-07-22 |
| EP1793678A4 (en) | 2008-09-03 |
| MX2007003230A (es) | 2007-10-16 |
| JP2008513470A (ja) | 2008-05-01 |
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