CN108778312B - 使用基于细胞的疗法治疗癌症和传染病的方法 - Google Patents
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Abstract
本公开涉及通过中断血管活性肠肽(VIP)信号传导和/或抑制磷脂酰肌醇‑3‑激酶(PI3激酶)抑制剂信号传导来逆转T细胞衰老的组合物和方法,以及用于管理癌症和慢性病毒感染的用途。在某些实施例中,本公开构思通过在体外将T细胞与阻止VIP与VIP受体相互作用的试剂和/或PI3激酶抑制剂混合来逆转T细胞衰老的方法。在某些实施例中,本公开构思通过与PI3激酶抑制剂、阻断VIP和VIP受体信号传导的试剂、VIP降解酶及其组合混合来扩增衰老T细胞。
Description
相关申请的交叉引用
本申请要求于2016年4月8日提交的美国临时申请号62/319,957的权益。出于所有目的,本申请的全部内容通过引用结合于此。
关于联邦资助研究的声明
本发明是在国立卫生研究院授予的RO1HL116737-01A和RO1CA188523的政府支持下完成的。美国政府享有本发明的某些权利。
通过办公室电子申请系统(EFS-WEB)提交作为文本文件的材料的引用结合
与本申请相关的序列表以文本格式提供以代替纸质副本,并且通过引用结合到本说明书中。包含序列表的文本文件的名称是16094PCT_ST25.txt。该文本文件为11KB,于2017年4月5日创建,并通过EFS-Web以电子方式提交。
背景技术
细胞毒性T细胞直接杀死细胞,并且该应答是抗原特异性的。为了破坏肿瘤,细胞毒性细胞必须以足够的数量增殖以超过分裂的癌细胞。然而,如果T细胞具有响应抗原刺激的有限增殖潜力,则认为它们是衰老的。Filaci等人报道了效应T细胞的一个亚群CD8+CD28-T调节淋巴细胞抑制人癌症中的T细胞增殖和细胞毒性功能(J Immunol[免疫学杂志],2007,179:4323-4334)。Montes等人表明作为肿瘤免疫逃避的潜在形式,肿瘤诱导衰老T细胞(Cancer Res[癌症研究],2008,68:870-879)。衰老T细胞的特征在于CD27和CD28表达的丧失,增殖能力的缺乏以及衰老相关分子的表达增加。参见Ramello等人.Cell Deathand Disease[细胞死亡与疾病],2014.5,e1507。因此,需要鉴定通过逆转T细胞衰老来治疗癌症的改进方法。
已经报道了用抗CD3和抗CD28(抗CD3/CD28珠)包被的磁珠用于T细胞扩增,T细胞扩增已被实验地用于增强免疫抑制的癌症患者中的T细胞免疫。参见Porter等人,A phase1trial of donor lymphocyte infusions expanded and activated ex vivo via CD3/CD28costimulation[通过CD3/CD28共刺激扩增和离体活化供体淋巴细胞输注的1期试验].Blood[血液],2006,107:1325-1331。
Li等人报道通过拮抗血管活性肠肽信号来调节同种异体移植物中的移植物抗白血病(Cancer Res[癌症研究],2016,76(23):6802-681)。还参见Li等人PLoS One[公共科学图书馆期刊].2013,8(5):e63381;Li等人,Blood[血液].2013,121(12):2347-51,Li等人,JImmunol[免疫学杂志].2011,187(2):1057-65;美国专利9,458,217;以及美国公开申请号2013/0302351。
本文引用的参考文献不是对现有技术的承认。
发明内容
本公开涉及通过中断血管活性肠肽(VIP)信号传导和/或抑制磷脂酰肌醇-3-激酶(PI3激酶)抑制剂信号传导来逆转T细胞衰老的组合物和方法,以及用于管理癌症和慢性病毒感染的用途。在某些实施例中,本公开构思通过在体外将T细胞与阻止VIP与VIP受体相互作用的试剂混合和/或添加PI3激酶抑制剂来逆转T细胞衰老的方法。在某些实施例中,本公开构思通过与PI3激酶抑制剂、阻断VIP和VIP受体信号传导的试剂、VIP降解酶及其组合混合来扩增衰老T细胞。
在某些实施例中,本公开构思通过将T细胞体外暴露于跟PI3激酶抑制剂、艾代拉利司(idelalisib)(阻止VIP与VIP受体相互作用的试剂,例如阻止通过VIP受体的信号传导)、VIP降解酶及其组合相组合的结合CD3和/或CD28的抗体来刺激分离的T细胞或扩增衰老T细胞的方法。在某些实施例中,本公开构思使用任选与固体基质如磁珠连接的抗CD3和抗CD28抗体或结合剂。
在某些实施例中,本公开构思使用如本文公开的体外细胞培养物增殖CD28和/或CD27阴性的T细胞的方法,其提供与复制前水平相比具有增加的CD28和/或CD27表达的复制的T细胞。
在某些实施例中,本公开构思增殖T细胞的方法,其中在增殖T细胞之前、过程中或之后,将T细胞与具有编码嵌合抗原受体的核酸序列的载体在使得这些细胞在细胞表面表达嵌合抗原受体的条件下混合,其中该嵌合抗原受体包含癌靶向序列、跨膜结构域、T细胞共刺激分子结构域和T细胞抗原受体结构域的信号转导组分。
在某些实施例中,本公开涉及体外细胞培养组合物,其包含最小必需培养基和T细胞和VIP受体拮抗剂、PI3激酶抑制剂、VIP降解酶及其组合,并且任选地还包含任选地固定在固体基质如珠子上的抗CD3抗体和抗CD28抗体。在某些实施例中,从骨髓细胞或血细胞中纯化T细胞。
在某些实施例中,磷脂酰肌醇-3-激酶抑制剂选自艾代拉利司、渥曼青霉素、去甲氧基绿啶(demethoxyviridin)、哌立福辛、布帕尼西(buparlisib)、度维利塞(duvelisib)、库潘尼西(copanlisib)和阿培利司(alpelisib)。在某些实施例中,磷脂酰肌醇-3-激酶抑制剂选自培养物中的艾代拉利司,其浓度大于0.001nM、0.1nM、1nM、10nM、100nM或是10nM至10微摩尔或10nM至500nM、或10nM至1微摩尔。
在某些实施例中,培养物包含VIP受体拮抗剂,例如VIPhyb,其包含具有C端酰胺的(SEQ ID NO:1)KPRRPYTDNYTRLRKQMAVKKYLNSILN。在某些实施例中,培养物包含VIP受体拮抗剂,例如VIPhyb,其浓度至少为0.001微摩尔、0.01微摩尔、0.1微摩尔、0.5微摩尔、1.0微摩尔、2或3微摩尔。在某些实施例中,培养物包含VIP受体拮抗剂,例如VIPhyb,其浓度为0.5微摩尔至10微摩尔或1微摩尔至8微摩尔。
在某些实施例中,培养物包含水解VIP的酶。在某些实施例中,培养物包含VIP降解酶,例如肽酶、丝氨酸肽酶、类胰蛋白酶、糜酶、人糜酶1(CMA1)或缓激肽释放丝氨酸蛋白酶(chymotrypic serine proteinase)。在某些实施例中,培养物具有至少0.001微克/mL、0.01微克/mL、0.1微克/mL或1微克/mL的VIP降解酶,例如肥大细胞糜酶。在某些实施例中,本公开构思T细胞培养物,其包含最小必需培养基和表达CD3和/或CD4和/或CD8并且对CD27和/或CD28呈阴性的分离细胞和PI3激酶抑制剂、阻断VIP和VIP受体信号传导的试剂及其组合。可以使用与固体支持物(例如珠子、磁珠或荧光结合剂颗粒)连接的结合剂通过阴性或阳性选择分离细胞。
在某些实施例中,抗CD3抗体和抗CD28抗体固定在珠子、磁珠或固体表面上。在某些实施例中,培养物中的所有细胞中超过5.0%或10%或15%表达CD3和/或CD4和/或CD8。在某些实施例中,所有细胞中超过20%、25%或50%表达CD3和/或CD4和/或CD8。在某些实施例中,培养物中超过15%或20%或30%的T细胞对CD28和/或CD27是阴性的。在某些实施例中,超过20%、25%或50%的T细胞对CD28和/或CD27是阴性的。
在某些实施例中,纯化的T细胞获自在血浆和红细胞分离的条件下离心血液,从而在血浆和红细胞之间的白细胞混合物中提供纯化的T细胞。在某些实施例中,纯化的T细胞通过骨髓抽吸物或骨髓活组织检查获得。
在某些实施例中,通过将细胞与结合CD3的荧光标志物混合并通过荧光激活细胞分选纯化细胞来获得纯化的T细胞。在某些实施例中,通过将细胞与结合CD3的磁化标志物混合并通过磁性分选纯化细胞来获得纯化的T细胞。在某些实施例中,通过将细胞与结合CD3和/或CD4和/或CD8的荧光标志物混合并通过荧光激活细胞分选纯化细胞来获得纯化的T细胞。在某些实施例中,通过将细胞与结合CD3和/或CD4和/或CD8的磁化标志物混合并通过磁性分选纯化细胞来获得纯化的T细胞。
在某些实施例中,本公开构思具有抗CD3和抗CD28抗体并且具有偶联于表面的VIP降解酶的固体基质,例如珠子。在某些实施例中,构思珠子排列在培养基中,并且T细胞在培养基上扩增,使得珠子是在细胞下面的。
在某些实施例中,VIP降解酶包含人CMA1登录号GenBank:AAI03975.1:
MLLKLKEKASLTLAVGTLPFPSQFNFVPPGRMCRVAGWGRTGVLKPGSDTLQEVKLRLMDPQACSHFRDFDHNLQLCVGNPRKTKSAFKGDSGGPLLCAGVAQGIVSYGRSDAKPPAVFTRISHYRPWINQILQAN(SEQ IDNO:2)。在某些实施例中,VIP降解酶是人重组脑啡肽酶(中性内肽酶,EC3.4.24.11),具有(SEQ ID NO:3)DGICKSSDCIKSAARLIQNMDATTEPCTDFFKYACGGWLKRNVIPETSSRYGNFDILRDELEVVLKDVLQEPKTEDIVAVQKAKALYRSCINESAIDSRGGEPLLKLLPDIYGWPVATENWEQKYGASWTAEKAIAQLNSKYGKKVLINLFVGTDDKNSVNHVIHIDQPRLGLPSRDYYECTGIYKEACTAYVDFMISVARLIRQEERLPIDENQLALEMNKVMELEKEIANATAKPEDRNDPMLLYNKMTLAQIQNNFSLEINGKPFSWLNFTNEIMSTVNISITNEEDVVVYAPEYLTKLKPILTKYSARDLQNLMSWRFIMDLVSSLSRTYKESRNAFRKALYGTTSETATWRRCANYVNGNMENAVGRLYVEAAFAGESKHVVEDLIAQIREVFIQTLDDLTWMDAETKKRAEEKALAIKERIGYPDDIVSNDNKLNNEYLELNYKEDEYFENIIQNLKFSQSKQLKKLREKVDKDEWISGAAVVNAFYSSGRNQIVFPAGILQPPFFSAQQSNSLNYGGIGMVIGHEITHGFDDNGRNFNKDGDLVDWWTQQSASNFKEQSQCMVYQYGNFSWDLAGGQHLNGINTLGENIADNGGLGQAYRAYQNYIKKNGEEKLLPGLDLNHKQLFFLNFAQVWCGTYRPEYAVNSIKTDVESPGNFRIIGTLQNSAEFSEAFHCRKNSYMNPEKKCRVW。
在某些实施例中,本文所述的细胞培养物和方法还包括IL-12。在某些实施例中,构思IL-12增强VIP受体拮抗剂对体外用CD3和CD28抗体刺激的T细胞增殖的作用。
在某些实施例中,本公开涉及扩增T细胞,或扩增或逆转T细胞中的衰老,可发现天然存在的对癌症的反应性浸润入受试者的肿瘤中。可以收获肿瘤,并且可以使用本文公开的方法扩增这些肿瘤浸润淋巴细胞(TIL)。
附图说明
图1A显示了表明VIPhyb处理增强的、由同种异体抗原刺激的体外T细胞增殖的数据。用经照射的FVB脾细胞在MLR中培养3天荧光素酶B6脾T细胞的增殖,其中每天加入VIP和/或VIPhyb以实现所示浓度(0-10mmol/L)。
图1B显示了VIPhyb的变体浓度的数据。
图2显示了在样品的体外培养中产生的CD27+和CD28+细胞的相对数量的数据,其中患者具有衰老的T细胞。“Id”指的是艾代拉利司。“VA”指VIPhyb。“MC”指人肥大细胞糜酶(CMA1)。
图3A显示了在扩增第14天CD27和CD28在总CD3+群体上表达的数据。在存在30U/mLIL-2的情况下,使用或不使用所示化合物,将DLBCL患者T细胞用CD3/CD28珠扩增14天。
图3B显示了存在或不存在所示化合物情况下患者T细胞的扩增曲线。用艾代拉利司和VIPhyb在DLBCL患者T细胞扩增中CD27+CD28+区室的保留以及增加的总体产量。
图4显示了表明在添加VIPhyb、艾代拉利司或两者的组合的情况下在淋巴瘤患者T细胞中的Bcl-2表达增加的数据。在第7天和第14天制备来自患者T细胞扩增培养物的蛋白质裂解物。样品在SDS-PAGE凝胶上电泳,然后转移到硝酸纤维素膜上。然后探测膜的促存活Bcl-2蛋白,剥离,然后重新探测作为上样对照的肌动蛋白。
图5A显示肿瘤细胞注射后第18天肿瘤体积的数据。给小鼠皮下注射5x 105个E.G7-OVA细胞,使其生长7天直至形成可触诊肿瘤。在此期间,在IL-2和所示化合物存在下,用CD3/CD28珠扩增OT-I、OT-II和B6T细胞3天。在肿瘤生长的第7天,给小鼠静脉注射扩增的OT-I、OT-II和B6T细胞(2x 106OT-I细胞、1x 106OT-II细胞、和2x 106B6细胞)或作为对照的2x 106B6T细胞。然后监测小鼠的肿瘤生长,计算为(LxW2)/2。
图5B显示肿瘤生长曲线,该曲线显示组间随时间的生长速率。在艾代拉利司、VIPhyb或两者的组合存在下扩增小鼠T细胞增强了它们在表达OVA的淋巴瘤模型中的治疗功效。
具体实施方式
在更详细地描述本披露之前,应理解的是本披露不限于所描述的具体实施例,因此这些当然可以改变。还应理解的是,本文使用的术语仅是出于描述具体实施例的目的,并不旨在是限制性的,因为本披露的范围将仅由所附权利要求书限制。
除非另外定义,在此所用的全部技术术语和科学术语具有与本披露所属领域的普通技术人员通常所理解的相同意义。虽然与在此所述的那些方法和材料相似或等同的任意方法和材料也可以用于实施或测试本披露中,然而现在描述优选的方法和材料。
在本说明书中引用的所有公开物和专利通过引用结合于此,就好像每个单独的公开物或专利被确切地并单独地指示为通过引用结合,并且通过引用结合于此从而结合引用的公开物披露和描述这些方法和/或材料。任何公开物的引用内容是针对在提交日之前的披露,并且不能理解为承认因为先前披露而本披露不能获得比这些公开物更早的申请日。此外,所提供的公开日期可能与实际的公开日期不同,实际的公开日期可能需要单独地确认。
如将对于本领域技术人员清楚的是,在阅读本披露时,本文描述和展示的单独实施例的每一个具有离散的组成部分和特征,这些组成部分和特征可以在不偏离本披露的范围或精神的情况下易于与任何其他一些实施例的特征分离或组合。可以按照所叙述的事件的顺序或按照逻辑上可行的任何其他顺序来进行任何叙述的方法。
除非另外说明,本披露的实施例将采用免疫学、医学、有机化学、生物化学、分子生物学、药理学、生理学等的技术,这些技术是在本领域的技术之内。此类技术在文献中得到充分解释。
如本文所述,测量来自个体的生物样品中至少一种基于蛋白质的表面生物标志物的水平。可以使用能够特异性确定生物样品中生物标志物水平的任何可用测量技术来测量该一种或多种蛋白质的水平。测量可为定量或定性的,只要测量能够指示生物样品中的生物标志物的水平是高于还是低于参考值即可。
虽然一些测定格式将允许在没有事先处理样品的情况下测试生物样品,但也有可能在测试之前对外周血液生物流体样品进行处理。处理通常可采取消除血液样品中的细胞(成核和非成核)例如红细胞、白细胞以及血小板的形式,并且还可包括消除某些蛋白质,例如来自血液的某些凝固级联蛋白质。在一些实例中,将外周生物流体样品收集在包含EDTA的容器中。
比较测量值和参考值的过程可以以适合于所讨论的生物标志物的测量值和参考值的类型的任何方便的方式进行。如上所述,可以使用定量或定性测量技术来执行测量,并且比较测量值和参考值的模式可以根据所采用的测量技术而变化。例如,当使用定性比色测定来测量生物标志物水平时,可以通过目测比较有色反应产物的强度,或通过比较有色反应产物的光密度或光谱测量数据(例如,比较从测量设备导出的数字数据或图形数据,例如条形图)来比较水平。然而,预期在本公开的方法中使用的测量值最通常是定量值(例如,浓度的定量测量,例如每毫升样品的纳克生物标志物,或绝对量)。至于定性测量,可以通过检查数值数据,通过检查数据的表示(例如,检查诸如条形图或线图的图形表示)来进行比较。
必须指出,如在说明书和所附权利要求书中所使用,单数形式“一个/一种(a/an)”和“该(the)”包括复数指示物,除非上下文另外清楚地规定。在本说明书和以下权利要求书中,将参考应定义为具有下列含义的大量术语,除非明显是相反的意图。
如本文所用,术语“艾代拉利司”是指化合物(S)-2-(1-(9H-嘌呤-6-基氨基)丙基)-5-氟-3-苯基喹唑啉-4(3H)-酮或其替代性盐。
如本文所用,“CD28和/或CD27阴性的T细胞”是指与健康受试者中表达CD3表面抗原标志物的正常T细胞相比,CD28和/或CD27的相对浓度表达低或缺乏。
术语“荧光激活细胞分选”或“FACS”是指基于每个细胞的荧光特征,分别施加的电荷以及运动通过静电场的分离将细胞混合物分选进入两个或更多个区域的方法,通常一次一个细胞。通常,振动机构使细胞流分裂成单个液滴。在液滴形成之前,流体中的细胞通过用于测量细胞荧光的区域。充电机构配置在流分裂成液滴的位置。基于荧光强度测量,当液滴从流中分裂出来时,相应的电荷施加在该液滴上。带电的液滴然后移动通过静电偏转系统,该系统基于相对电荷将液滴转移到区域中。在一些系统中,电荷直接施加到流上,并且液滴分裂保留与流相同符号的电荷。然后在液滴分裂后将流返回中性。在其他系统中,在导管上提供电荷,从而在液滴上引起相反的电荷。通常通过将细胞与特异性结合标志物(该标志物通过与荧光分子缀合而产生荧光)的抗体混合来使细胞发荧光。然而,可以构思制备细胞荧光的其他方法,例如通过使用分子信标。
“最小必需培养基”是指含有钙、镁、钾、钠、磷酸盐和碳酸氢盐、维生素和必需氨基酸的盐的培养基。12种必需氨基酸是:L-精氨酸;L-胱氨酸;L-谷氨酰胺;L-组氨酸;L-异亮氨酸;L-亮氨酸;L-甲硫氨酸;L-苯丙氨酸;L-苏氨酸;L-色氨酸;L-酪氨酸;以及L-丙氨酸。MEM通常补充有例如碳酸氢盐或谷氨酰胺的组分。在某些实施方案中,本公开构思了补充有非必需氨基酸的最小必需培养基:L-ala;L-asn;L-asp;L-glu;L-gly;L-pro以及L-ser。在某些实施例中,本公开构思了补充有核苷(核糖核苷和/或脱氧核糖核苷)的最小必需培养基。
当就核酸分子而言时,术语“重组”是指包含通过分子生物学技术而连接在一起的核酸区段的核酸分子。当就蛋白质或多肽而言时,术语“重组”是指使用重组核酸分子表达的蛋白质分子。术语重组核酸区别于由同源染色体之间的交换产生的天然重组体。如本文所用的重组核酸是来自非同源来源(通常来自不同的生物)的核酸的非天然集合。
术语“载体”或“表达载体”是指包含所希望的编码序列和用于可操作地连接的编码序列在具体宿主有机体或表达系统中的表达所必须的适当核酸序列的重组核酸,例如细胞的或无细胞的。在原核生物中的表达所必须的核酸序列通常包括启动子、操纵子(任选的)、以及核糖体结合位点,经常连同其他序列。已知真核细胞利用启动子、增强子和终止以及聚腺苷酸化信号。
除非上下文另有说明,否则术语“血管活性肠肽”和“VIP”是指(SEQ ID NO:12)HSDAVFTDNYTRLRKQMAVKKYLNSILN。VIP是多功能内源多肽,其在免疫细胞分化和激活的多个水平上调节先天免疫和适应性免疫。
VIP通常由多种细胞分泌,例如神经元(在中枢神经系统和外周神经系统中)B细胞、T细胞和辅助细胞。VIP和密切相关的神经肽垂体腺苷酸环化酶激活多肽(PACAP)与三种已知受体VPAC1、VPAC2和PAC1结合。认为T细胞和树突细胞(DC)表达VPAC1和VPAC2,但不表达PAC1。PAC1主要在脑和垂体和肾上腺中的神经元和内分泌细胞上表达,并且在大多数形式中选择性地结合PACAP。
术语“VIP拮抗剂”或“VIP受体拮抗剂”是指抑制或减损VIP改变免疫应答的能力的任何分子。已知VIP受体拮抗剂包括VIP类似物、VIP片段、生长激素释放因子类似物和杂合肽。许多VIP受体拮抗剂公开于美国专利号5,565,424;7,094,755;6,828,304,并且均通过引用结合在此。VIP受体拮抗剂的一些实例包括[Ac-Tyr1,D-Phe2]GRF 1-29,酰胺,即(SEQID NO:4)YFDAIFTNSYRKVLGQLSARKLLQDIMSR(修饰:Tyr-1=N端Ac,Phe-2=D-Phe,Arg-29=C端酰胺);VIP(6-28),即(SEQ ID NO:5)FTDNYTRLRKQMAVKKYLNSILN(修饰:Asn-23=C端酰胺);[D-p-Cl-Phe6,Leu17]-VIP,即,(SEQ ID NO:6)HSDAVFTDNYTRLRKQLAVKKYLNSILN(修饰:Phe-6=p-Cl-D-Phe,Asn=C端酰胺);VIP-hyb,也称为VIPhybrid(SEQ ID NO:1)KPRRPYTDNYTRLRKQMAVKKYLNSILN,即神经降压素和VIP的杂合肽,由N端(SEQ ID NO:7)KPRRPY[也称为神经降压素(6-11)],随后C端的VIP的22个氨基酸,即(SEQ ID NO:8)TDNYTRLRKQMAVKKYLNSILN[也称为VIP(7-28)]组成;N端硬脂酰,正亮氨酸17VIPhyb,即(SEQID NO:9)KPRRPYTDNYTRLRKQXAVKKYLNSILN,其中X是正亮氨酸;Ac His1[D-Phe(2),Lys(15),Arg(16),Leu(27)]-VIP(l-7)/GRF(8-27),即(SEQ ID NO:10)HFDAVFTNSYRKVLKRLSARKLLQDIL,C端酰胺;和垂体腺苷酸环化酶激活多肽,PACAP(6-38)C端酰胺,即(SEQ ID NO:11)TDSYSRYRKQMAVKKYLAAVLGKRYKQRVKNK。构思这些分子中的任何一种可以用烃或聚乙二醇基团修饰,以提供改善的性质,例如溶解度、生物利用度和/或生物降解。
如本文所用的术语“治疗(treat)”和“治疗(treating)”并不限于受试者(如患者)被治愈并且疾病被根除的情况。相反,本披露的实施例还考虑了仅减轻症状和/或延缓疾病发展的治疗。
复发性淋巴瘤患者的免疫表型
在生理老化过程总和暴露于重复化疗或慢性炎症状态的个体中,T细胞发展衰老病症,其中它们是无反应性的或具有响应于抗原刺激的有限的增殖潜力。已经将衰老T细胞的表型描述为缺乏共刺激受体CD27和CD28或具有高水平的CD57标志的那些T细胞。此外,PD1(程序性死亡配体的受体)的表达与无反应状态有关。无反应性T细胞的存在是患者对疫苗应答或对慢性病毒感染或癌症产生保护性和持久性免疫应答的能力的关键辅助因子。需要新的逆转T细胞衰老和无反应性的方法来为患有慢性感染和癌症的患者提供有效的基于细胞的免疫疗法的前景。
复发性淋巴瘤患者的免疫表型特征为具有无反应性表型的T细胞过度呈现:CD3阳性,CD27阴性,CD28阴性。测试了通过血管活性肠多肽受体的信号传导是否有助于T细胞衰老和抗原特异性能量。向VIP受体添加称为VIPhyb的肽拮抗剂在体外增强T细胞增殖并减轻天然VIP肽对T细胞增殖的抑制作用。
测试了是否加入VIPhyb拮抗剂可以逆转长期复发的癌症患者的无反应性T细胞的增殖缺陷。评估患有复发性淋巴瘤的患者中T细胞的免疫表型。缺乏共刺激受体CD27和CD28的细胞相对过度呈现。此外,来自该情况的T细胞具有高水平的CD57表达、PD1和Tim-3。
使用高速细胞分选,T细胞亚群通过其来自患有复发性淋巴瘤和健康对照的患者的CD27和CD28表达水平来分离定义。将具有由CD27和CD28表达定义的四种表型中的每一种的CD3阳性T细胞分选并在抗CD3/抗CD28珠子存在下体外培养。虽然来自健康供体的总T细胞在培养4天后具有100%Ki67增殖标志物的表达,但来自具有淋巴瘤治疗后的无反应性T细胞的患者的相应总T细胞群仅具有90%T细胞表达Ki67标记。
在每天向这些培养物中加入3μM VIPhyb后,来自无反应性淋巴瘤患者的Ki67阳性T细胞的比例增加至100%。基于来自该患者的CD27和CD28表达分选的T细胞亚群显示CD27阳性、CD28阳性(双阳性)群体响应于抗CD3/CD28珠子正常增殖。相反,当与抗CD3/CD28珠子孵育时,缺乏CD27或CD28任一或这两种标志物表达的T细胞亚群具有受损的增殖应答。
拮抗剂VIPhyb的添加增强了缺乏CD27或CD28任一的亚群中的T细胞增殖。向这些培养物中加入IL 12对增加CD28阴性但不是CD27阴性的T细胞的增殖分数具有显著影响。用抗CD3/抗CD28珠子培养的T细胞的流式细胞术分析显示,与未添加VIP拮抗剂的对照培养物相比,添加3uMVIPhyb导致PD-1表达水平降低。该数据表明VIP在T细胞的抗原特异性激活过程中被诱导,并且阻断VIP信号传导的策略可以增强T细胞增殖并逆转来自具有慢性炎性病症的个体或已经暴露于多个化疗周期的那些的衰老T细胞的无反应性。
由于VIP肽在体内的半衰期非常短,不到两分钟,并被内肽酶切割,因此在通过T细胞受体激活的T细胞附近过表达VIP特异性肽酶被认为导致增强T细胞的激活和增殖并且可以逆转免疫衰老。
治疗使用的方法
在某些实施例中,本公开构思通过输注、植入或给予有效量的抗CD3抗体和抗肿瘤抗体以及重组肥大细胞糜酶来逆转T细胞衰老的体内方法。在某些实施例中,将重组肥大细胞糜酶以静脉内给予或输注给接受抗CD3抗体和肿瘤相关抗原抗体的受试者/患者。
在某些实施例中,本公开构思治疗癌症或慢性感染的方法,其包括:从受试者中纯化T细胞提供分离的T细胞;将这些分离的T细胞与跟PI3激酶抑制剂、VIP受体拮抗剂、VIP降解酶或其组合相组合的任选固定在珠子或固体表面上的抗CD3抗体和抗CD28抗体混合;在使这些T细胞复制的条件下,提供与复制前的水平相比CD28表达增加的复制的T细胞;并且将有效量的这些复制的T细胞给予有需要的受试者。
在某些实施例中,本公开构思治疗癌症的方法,其包括:从受试者中纯化T细胞提供分离的T细胞;将这些分离的T细胞与跟PI3激酶抑制剂、VIP受体拮抗剂、VIP降解酶或其组合相组合的任选固定在珠子或固体表面上的抗CD3抗体和抗CD28抗体混合;在使这些T细胞复制的条件下,提供与复制前的水平相比CD28表达增加的复制的T细胞;并且将有效量的这些复制的T细胞给予有需要的受试者。在某些实施例中,复制的T细胞在细胞表面上表达嵌合抗原受体。在某些实施例中,该方法还包括在给予复制的T细胞之前、过程中或之后给予PI3激酶抑制剂、VIP受体拮抗剂、VIP降解酶或其组合。
在某些实施例中,本公开构思治疗癌症的方法,其包括:从受试者中纯化T细胞提供分离的T细胞;通过将T细胞体外暴露于跟PI3激酶抑制剂、艾代拉利司(阻止VIP与VIP受体相互作用的试剂,例如阻止通过VIP受体的信号传导)、VIP降解酶及其组合相组合的结合CD3和/或CD28的抗体来培养分离的T细胞,从而提供具有增加的CD28表达的扩增的T细胞;并且将有效量的扩增的T细胞给予受试者。
在某些实施例中,本公开构思治疗癌症的方法,其包括将有效量的双特异性抗体以及VIP受体拮抗剂和/或磷脂酰肌醇-3-激酶抑制剂组合地给予需要其的受试者,其中该双特异性抗体包含癌症靶向结合序列和CD3结合序列。在某些实施例中,双特异性抗体是卡妥索单抗(catumaxomab)或博纳吐单抗(blinatumomab)。
在某些实施例中,本公开构思用双特异性抗体或抗癌抗体或肿瘤相关抗原抗体以及VIP受体拮抗剂例如VIPhyb的给药或肠胃外给药的组合来治疗癌症的方法。在某些实施例中,抗肿瘤特异性抗体针对CD19。在某些实施例中,抗癌抗体针对CD123。在某些实施例中,抗癌抗体针对HER2/neu。在某些实施例中,抗癌抗体针对骨髓瘤相关抗原BMCA。在某些实施例中,抗癌抗体针对EGFR。在某些实施例中,抗癌抗体针对PD-L1或PD1。
在某些实施例中,本公开构思治疗癌症的方法,其包括将有效量的具有嵌合抗原受体的细胞与VIP受体拮抗剂或磷脂酰肌醇-3-激酶抑制剂组合地给予有需要的受试者,其中嵌合抗原受体包括癌症靶向序列、跨膜结构域、T细胞共刺激分子结构域和T细胞抗原受体结构域的信号转导组分。
在某些实施例中,本公开构思了体内逆转T细胞衰老的方法,其包括遗传修饰T细胞以在其表面上表达VIP降解酶。在某些实施例中,VIP降解酶是重组人CMA1肥大细胞糜酶。在某些实施例中,遗传修饰的T细胞还表达将它们靶向癌细胞的嵌合抗原受体。在某些实施例中,将遗传修饰的T细胞给予或输注到患有癌症的受试者中。
在某些实施例中,本公开涉及治疗癌症的方法,其包括:从受试者纯化表达T细胞受体的T细胞,其中T细胞表达CD3和任选的CD4和/或CD8,提供分离的T细胞;将分离的T细胞与本文公开的细胞培养物在使细胞扩增的条件下混合,并将有效量的扩增的细胞植入或给予受试者中。
在某些实施例中,本公开构思治疗癌症的方法,其包括跟给予VIP受体拮抗剂例如VIPhyb、VIP降解酶、PI3抑制剂或其组合相组合地给予T细胞(这些T细胞包含配置成表达嵌合抗原受体的载体,例如,这些细胞已经被具有编码嵌合抗原受体的核酸的重组病毒感染)。
在某些实施例中,本公开构思治疗癌症的方法,其包括:从受试者纯化表达CD3和/或CD4和/或CD8的细胞,提供分离的T细胞;测量分离的T细胞上CD27和/或CD28的表达,提供CD27和/或CD28的测量值;将CD27和/或CD28的测量值与参考水平进行比较,如果测得的CD27水平低于正常值和/或测得的CD28水平低于正常值,则将有效量的VIP受体拮抗剂、VIP降解酶、PI3抑制剂或其组合给予受试者。
在某些实施例中,本公开构思治疗癌症的方法,其包括从受试者纯化表达CD3和/或CD4和/或CD8的细胞,提供分离的T细胞;测量分离的T细胞上CD27和/或CD28的表达,提供CD27和/或CD28的测量值;如果CD27的测量值低于正常值和/或CD28的测量值低于正常值,提供复制的T细胞,然后将分离的T细胞与VIP受体拮抗剂、VIP降解酶、PI3抑制剂或其组合在使得分离的T细胞复制的条件下混合;并且任选地跟给予VIP受体拮抗剂、VIP降解酶、PI3抑制剂或其组合相组合地将有效量的复制的T细胞植入或给予受试者中。
在某些实施例中,本公开涉及扩增CD3阳性和CD4与CD8阴性的T细胞,例如γδT细胞。γδT细胞表面具有独特的T细胞受体(TCR)。大多数T细胞是αβT细胞,其TCR由称为α和βTCR链的两个糖蛋白链组成。相反,γδT细胞具有由一条γ链和一条δ链组成的TCR。
在某些实施例中,本公开构思遗传修饰的T细胞,以在其表面上表达VIP降解酶。在某些实施例中,VIP降解酶是重组人CMA1肥大细胞糜酶。在某些实施例中,遗传修饰的T细胞还表达将它们靶向癌细胞的嵌合抗原受体。在某些实施例中,将遗传修饰的T细胞给予或输注到患有癌症的人受试者中。
在某些实施例中,本公开涉及治疗癌症的方法,其包括与VIP受体拮抗剂、PI3激酶抑制剂、VIP降解酶及其组合相组合地给予有效量的双特异性抗体。在某些实施例中,双特异性抗体是卡妥索单抗(catumaxomab)。在某些实施例中,受试者被诊断患有恶性腹水。在某些实施例中,双特异性抗体是博纳吐单抗(blinatumomab)。在某些实施例中,癌症是白血病。
在某些实施例中,本公开构思治疗癌症的方法,其包括:使用本文提供的方法纯化和扩增T细胞,提供分离的T细胞;在使双特异性抗体结合CD3-T细胞受体复合物的条件下,将分离的T细胞与双特异性抗体混合;并且与给予有需要的受试者VIP受体拮抗剂、PI3激酶抑制剂、VIP降解酶及其组合相组合地将有效量的结合T细胞的双特异性抗体给予受试者。
双特异性抗体含有两种靶向序列,第一种靶向肿瘤相关抗原,第二种靶向CD3T细胞受体复合物,使得T细胞可以与癌细胞结合。双特异性抗体将T细胞与癌细胞连接。参见Zhukovsky等人,Bispecific antibodies andCARs:generalized immunotherapeuticsharnessing T cell redirection[双特异性抗体和CAR:利用T细胞重定向的广义免疫治疗剂],Current Opinion inImmunology[免疫学前沿观点],2016,40:24-35。在某些实施例中,本公开构思双特异性抗体针对肿瘤相关抗原、CD19表位、CD123、HER2/neu或骨髓瘤相关抗原BMCA。
为了提高免疫细胞杀死癌细胞的能力,可以从患者的血液中分离T细胞并进行遗传改变以表达嵌合抗原受体,以特异性靶向在癌细胞表面上表达的蛋白质并刺激免疫应答。当放回患者体内时,这些细胞攻击癌细胞。在某些实施例中,本公开构思使用靶向CD22和/或CD19抗原的CAR T细胞。CD19是在癌性B细胞上表达的蛋白质。Brentjens等人报道T细胞改变以结合CD19可诱导化疗难治性急性淋巴细胞白血病患者的癌症缓解。Sci TranslMed[科学转化医学],2013,5(177):177ra38。
在典型的程序中,从血液或骨髓中纯化并分离T细胞。例如,通过单采术收集T细胞,单采术是从身体中抽取血液并去除一种或多种血液组分(例如血浆、血小板或其他白细胞)。然后剩余的血液返回到体内。将细胞暴露于重组载体,例如慢病毒载体,其以产生有待呈现在细胞膜中的CAR蛋白质的方式感染细胞。可将T细胞送至实验室或药物制造设施,在那里对它们进行遗传工程改造以在其表面上产生嵌合抗原受体(CAR)。在用重组载体感染分离的细胞之前和/或之后,可以使用本文公开的方法诱导细胞复制。可以通过在实验室中培养细胞来扩增经遗传修饰的T细胞,直到它们数量足够。任选地,冷冻这些CAR T细胞。然后将经修饰的细胞给予患者。在某些实施例中,本公开构思在接受CAR T细胞输注之前,任选地与一种或多种化疗剂组合地向受试者给予VIP受体拮抗剂、VIP降解酶和/或IP3激酶抑制剂。
在某些实施例中,本公开涉及通过本文公开的方法制备的细胞,其含有重组体载体,该重组体载体包含编码嵌合多肽的核酸,该嵌合多肽包含靶向序列、跨膜结构域、T细胞共刺激分子结构域和T细胞抗原受体结构域的信号转导组分。
在某些实施例中,嵌合抗原受体中的靶向序列是指能够选择性结合靶细胞(例如癌细胞)上的表面蛋白的任何种类的多肽序列。其他靶向序列可以是抗体、单链抗体和抗体模拟物的可变结合区。在某些实施例中,通过衍生自单克隆抗体的单链可变片段(scFv)实现靶向。靶向序列通常通过铰链/跨膜区(通常衍生自CD8或IgG4)与细胞内结构域连接。细胞内结构域可含有共刺激结构域,例如与CD3ζ的细胞质信号传导结构域连接的4-1BBζ和/或CD28ζ。
实例
VIP信号传导调节同种异体抗原诱导的T细胞增殖
为了探索VIP信号传导在同种异体免疫应答中的作用,进行含有VIP和/或拮抗性VIPhyb肽的单向混合淋巴细胞反应(MLR)。VIP的添加以剂量依赖性方式降低荧光素酶T细胞增殖,同时添加VIPhyb增加T细胞增殖。VIPhyb逆转了VIP在MLR中的抑制作用,使T细胞增殖恢复到比对照培养物更高的水平。
在用于CAR T制造的离体T细胞扩增过程中的药理学阻断增加了产量并保留了原初和中枢记忆区室
弥漫性大B细胞淋巴瘤(DLBCL)是一种侵袭性B细胞恶性肿瘤,主要影响老年患者群体。尽管有强有力的治疗方案,但DLBCL患者的一部分患者存在高度抵抗治疗的淋巴瘤。由于这些患者的疾病几乎对所有目前的治疗方案都是难治的,因此CAR T疗法作为有效的救治方案具有巨大前景,但是许多患者由于离体T细胞扩增失败而未能在临床试验中接受治疗。这种失败在很大程度上是由于多轮治疗所造成的损害以及患者的年龄。此外,数据表明患有NHL的患者的记忆与原初T细胞的比率偏差,这导致细胞免疫治疗受损。
指示患者成功T细胞扩增潜力的两种表面蛋白是CD27和CD28。表达CD27和CD28两者的T细胞具有最大的增殖潜力,而缺乏两者表达的T细胞在抗CD3/CD28激活和扩增过程中通常不扩增并且死亡。健康个体具有丰富的CD27+CD28+(双阳性)T细胞,而具有DLBCL的患者具有过量丰富的CD27-CD28-(双阴性)T细胞。淋巴瘤患者中这种双阴性群体的过度呈现有助于进一步解释T细胞在CAR T制造过程中不能充分扩增。除缺乏CD27和CD28表达外,DLBCL患者T细胞还表现出衰竭和衰老的迹象,这两者都会导致功能障碍和不能扩增。
为了解决在CAR T细胞制造过程中DLBCL患者T细胞扩增的问题,使用多种技术以增强特定期望T细胞群的扩增。在T细胞激活过程中单独地包含或与肥大细胞糜酶或血管活性肠肽拮抗剂(VIPhyb)组合地包含PI3Kδ抑制剂艾代拉利司增加了获得的活T细胞的数量并增加了原初和中枢记忆细胞的比例。原初和中枢记忆细胞是过继细胞免疫疗法的最有效子集。另外,包含艾代拉利司或VIPhyb任一增加CD27+CD28+细胞的频率,同时降低CD27-CD28-细胞的频率。使用鼠和人T细胞的进一步研究表明,尽管PI3Kδ的阻断对增殖具有抑制作用,但是预防终末分化和保留原初区室增强T细胞存活和产量。该数据表明,所使用的培养条件不仅增加患者T细胞的总数量,而且还保留过继性T细胞免疫疗法中最有效的区室。因此,在CAR T制造过程中使用我们的方法有潜力能够开发许多DLBCL患者以前不能得到的最后治疗手段。
用PI3激酶抑制剂并阻断VIP信号传导来扩增衰老T细胞
艾代拉利司是PI3激酶的抑制剂。PI3激酶是淋巴细胞激活和分化的重要信号传导途径,并调节AKT和mTOR1活性。艾代拉利司经FDA批准用于治疗慢性淋巴细胞白血病和惰性B细胞恶性肿瘤患者。已经注意到用艾代拉利司治疗的患者在药物治疗停止后的持续抗癌应答并且发展自身免疫样迹象和症状,包括结肠炎和皮疹,这导致假设艾代拉利司调节免疫系统并激活或保留Th1极化T细胞。
艾代拉利司治疗导致CLL患者的T细胞激活增加。激活的T细胞离体暴露于艾代拉利司加强其激活和体外扩增。通过向用抗CD3/CD28珠子体外培养的T细胞添加一系列艾代拉利司浓度,测量T细胞扩增和分化。
尝试使用淋巴瘤患者的T细胞样品,该患者具有在制造CAR T细胞时不能体外扩增的衰老T细胞。单核细胞从T细胞样品中耗尽,因为已知单核细胞在含有抗CD3/CD28珠子的培养物中抑制T细胞扩增。单独地或与以下各项组合地比较一系列艾代拉利司浓度对T细胞激活、分化和增殖的影响:3μM VIP肽拮抗剂(VIPhyb)或1ug/ml肥大细胞糜酶(该酶是降解内源性VIP的酶)。在体外培养10天过程中测量活T细胞的数量以及T细胞分化和激活谱,重点关注具有衰老表型的T细胞(其中共刺激受体CD27和CD28都不存在(CD27-CD28-))与激活表型(其中共刺激受体CD27,CD28任一或两者都存在(CD27+CD28+))的相对数量。
将冷冻患者单采术产物或来自聚蔗糖化(ficolled)的全血的PBMC的等分试样快速解冻并在补充有10%胎牛血清、100U/mL青霉素、100μg/mL链霉素和50μM 2-巯基乙醇的完全RPMI 1640(完全培养基)中静置过夜。第二天,通过聚蔗糖(ficoll)梯度从单采术产物中除去红细胞。然后根据制造商的说明使用EasySep人T细胞富集试剂盒富集白细胞的T细胞。将细胞铺板在96孔平底板的每个孔中的200μL完全培养基中。以指定浓度加入化合物,并针对所有孔将DMSO浓度归一化至0.1%。以1:1珠子:细胞比率添加抗CD3/CD28珠子。在刺激后第7天,将来自每个处理的细胞转移到新培养基中。然后加入新鲜化合物和珠子,并将细胞再培养3天。在初始刺激后第10天,除去珠子,并将细胞染色用于流式细胞术分析。
将细胞在PBS中洗涤两次。还使用可固定的活力染料染色细胞。然后通过添加针对CD3、CD4、CD8、CD27、CD28、CD45RA、CD45RO、PD-1和CCR7的荧光染料缀合的抗体对表面标志物进行染色。为了评估增殖,评估一半细胞的Ki67表达。使用FoxP3细胞内染色试剂盒进行Ki67染色。在运行样品之前,将Accucheck计数珠子添加到每个管中。在BD FACS Aria上获得样品,并使用FlowJo软件进行分析。在分析中使用活细胞。根据Accucheck计数珠的制造商提供的说明计算每个群的绝对细胞数。
与没有添加药物的对照培养物相比,向T细胞培养物中添加浓度为1μM或100nM的艾代拉利司显著增加了共表达CD27和CD28的T细胞的比例。值得注意的是,缺乏CD27和CD28共刺激受体两者的衰老T细胞的比例从没有添加药物的对照培养物中的55.2%降低至具有10nM艾代拉利司的培养物中的16.1%,具有3uM VIPhyb的培养物中的35.7%和具有1μg/ml肥大细胞糜酶的培养物中的37.4%。
当与VIPhyb或糜酶组合时,浓度为100nM的艾代拉利司在提高表达共刺激受体的T细胞的比例方面是协同的,CD27+CD28+细胞的比例在100nM艾代拉利司和VIPhyb组合情况下为21.5%,在100nM艾代拉利司和糜酶组合情况下为14.2%,而在没有添加药物的对照培养物中为3.5%。
10天培养物中效应记忆T细胞(Tem)的数量也通过暴露于艾代拉利司、VIPhyb以及艾代拉利司和糜酶与VIPhyb的组合而增加。与没有添加药物的对照培养物相比,用艾代拉利司和糜酶组合或艾代拉利司和VIPhyb组合显著增加培养物中存活T细胞的总数。值得注意的是,与不含添加药物的培养物相比,在含有100nM艾代拉利司、1uM艾代拉利司加1ug/ml糜酶或100nM艾代拉利司加3uM VIPhyb的培养物中,CD27+CD28+T细胞亚群的总数富集10倍以上,而与不添加药物的对照培养物相比,10天培养物中CD3+Tem的总数在含有1μM艾代拉利司加糜酶的培养物中增加10倍。CD3+中枢记忆T细胞(Tcm)在含有单独的艾代拉利司、单独的VIPhyb、单独的糜酶或艾代拉利司与VIPhyb或糜酶的组合的培养物中与不添加药物的对照培养物相比增加5-10倍。
该数据表明,在培养基中不能用抗CD3/CD28珠子扩增并且不能产生足够的制造CAR T细胞供临床使用的衰老T细胞可以通过作为单一试剂地添加或组合地添加艾代拉利司、VIPhyb或肥大细胞糜酶而在体外显著扩增,这些结果支持在CAR T制造过程中添加这些试剂并支持其在体外用于扩增衰老T细胞以增强癌症免疫疗法和抗病毒免疫力的用途。
序列表
<110> 爱默蕾大学
<120> 使用基于细胞的疗法治疗癌症和传染病的方法
<130> 16094 PCT
<150> US 62/319,957
<151> 2016-04-08
<160> 12
<170> PatentIn 版本 3.5
<210> 1
<211> 28
<212> PRT
<213> 人工
<220>
<223> 合成
<400> 1
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435 440 445
Tyr Lys Glu Asp Glu Tyr Phe Glu Asn Ile Ile Gln Asn Leu Lys Phe
450 455 460
Ser Gln Ser Lys Gln Leu Lys Lys Leu Arg Glu Lys Val Asp Lys Asp
465 470 475 480
Glu Trp Ile Ser Gly Ala Ala Val Val Asn Ala Phe Tyr Ser Ser Gly
485 490 495
Arg Asn Gln Ile Val Phe Pro Ala Gly Ile Leu Gln Pro Pro Phe Phe
500 505 510
Ser Ala Gln Gln Ser Asn Ser Leu Asn Tyr Gly Gly Ile Gly Met Val
515 520 525
Ile Gly His Glu Ile Thr His Gly Phe Asp Asp Asn Gly Arg Asn Phe
530 535 540
Asn Lys Asp Gly Asp Leu Val Asp Trp Trp Thr Gln Gln Ser Ala Ser
545 550 555 560
Asn Phe Lys Glu Gln Ser Gln Cys Met Val Tyr Gln Tyr Gly Asn Phe
565 570 575
Ser Trp Asp Leu Ala Gly Gly Gln His Leu Asn Gly Ile Asn Thr Leu
580 585 590
Gly Glu Asn Ile Ala Asp Asn Gly Gly Leu Gly Gln Ala Tyr Arg Ala
595 600 605
Tyr Gln Asn Tyr Ile Lys Lys Asn Gly Glu Glu Lys Leu Leu Pro Gly
610 615 620
Leu Asp Leu Asn His Lys Gln Leu Phe Phe Leu Asn Phe Ala Gln Val
625 630 635 640
Trp Cys Gly Thr Tyr Arg Pro Glu Tyr Ala Val Asn Ser Ile Lys Thr
645 650 655
Asp Val Glu Ser Pro Gly Asn Phe Arg Ile Ile Gly Thr Leu Gln Asn
660 665 670
Ser Ala Glu Phe Ser Glu Ala Phe His Cys Arg Lys Asn Ser Tyr Met
675 680 685
Asn Pro Glu Lys Lys Cys Arg Val Trp
690 695
<210> 4
<211> 29
<212> PRT
<213> 人工
<220>
<223> 合成
<400> 4
Tyr Phe Asp Ala Ile Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gln
1 5 10 15
Leu Ser Ala Arg Lys Leu Leu Gln Asp Ile Met Ser Arg
20 25
<210> 5
<211> 23
<212> PRT
<213> 人工
<220>
<223> 合成
<400> 5
Phe Thr Asp Asn Tyr Thr Arg Leu Arg Lys Gln Met Ala Val Lys Lys
1 5 10 15
Tyr Leu Asn Ser Ile Leu Asn
20
<210> 6
<211> 28
<212> PRT
<213> 人工
<220>
<223> 合成
<400> 6
His Ser Asp Ala Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg Lys Gln
1 5 10 15
Leu Ala Val Lys Lys Tyr Leu Asn Ser Ile Leu Asn
20 25
<210> 7
<211> 6
<212> PRT
<213> 人工
<220>
<223> 合成
<400> 7
Lys Pro Arg Arg Pro Tyr
1 5
<210> 8
<211> 22
<212> PRT
<213> 人工
<220>
<223> 合成
<400> 8
Thr Asp Asn Tyr Thr Arg Leu Arg Lys Gln Met Ala Val Lys Lys Tyr
1 5 10 15
Leu Asn Ser Ile Leu Asn
20
<210> 9
<211> 28
<212> PRT
<213> 人工
<220>
<223> 合成
<220>
<221> X
<222> (1)..(28)
<223> X是正亮氨酸
<400> 9
Lys Pro Arg Arg Pro Tyr Thr Asp Asn Tyr Thr Arg Leu Arg Lys Gln
1 5 10 15
Xaa Ala Val Lys Lys Tyr Leu Asn Ser Ile Leu Asn
20 25
<210> 10
<211> 27
<212> PRT
<213> 人工
<220>
<223> 合成
<400> 10
His Phe Asp Ala Val Phe Thr Asn Ser Tyr Arg Lys Val Leu Lys Arg
1 5 10 15
Leu Ser Ala Arg Lys Leu Leu Gln Asp Ile Leu
20 25
<210> 11
<211> 32
<212> PRT
<213> 人工
<220>
<223> 合成
<400> 11
Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Gln Met Ala Val Lys Lys Tyr
1 5 10 15
Leu Ala Ala Val Leu Gly Lys Arg Tyr Lys Gln Arg Val Lys Asn Lys
20 25 30
<210> 12
<211> 28
<212> PRT
<213> 人工
<220>
<223> 合成
<400> 12
His Ser Asp Ala Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg Lys Gln
1 5 10 15
Met Ala Val Lys Lys Tyr Leu Asn Ser Ile Leu Asn
20 25
Claims (9)
1.一种体外细胞培养组合物,其包含纯化的T细胞和VIP受体拮抗剂和固定在珠子或固体表面上的抗CD3抗体和抗CD28抗体。
2.如权利要求1所述的组合物,其中超过15%的T细胞是CD28阴性的。
3.如权利要求1所述的组合物,其中该VIP受体拮抗剂的序列由KPRRPYTDNYTRLRKQMAVKKYLNSILN(SEQ ID NO:1)组成。
4.一种使用权利要求1-3中提供的体外细胞培养组合物增殖CD28阴性的T细胞的方法,该方法提供复制的T细胞。
5.如权利要求4所述的方法,其中与复制前的水平相比,这些复制的T细胞具有增加的CD28表达。
6.如权利要求5所述的方法,其中在增殖这些T细胞之前、过程中或之后,将这些T细胞与具有编码嵌合抗原受体的核酸的载体在使这些细胞在其表面上表达该嵌合抗原受体的条件下混合,其中该嵌合抗原受体包含癌靶向序列、跨膜结构域、T细胞共刺激分子结构域和T细胞抗原受体结构域的信号转导组分。
7.CD28表达增加的复制的T细胞在制备用于治疗癌症或慢性感染的药物中的用途,其中所述CD28表达增加的复制的T细胞通过以下方法获得:从受试者中纯化T细胞提供分离的T细胞;将这些分离的T细胞与跟VIP受体拮抗剂相组合的固定在珠子或固体表面上的抗CD3抗体和抗CD28抗体混合;以及在使这些T细胞复制的条件下,提供与复制前的水平相比CD28表达增加的复制的T细胞,并且其中当使用所述药物时,有效量的这些复制的T细胞被给予有需要的受试者。
8.如权利要求7所述的用途,其中当使用所述药物时,这些复制的T细胞在细胞表面上表达嵌合抗原受体。
9.如权利要求7所述的用途,其中当使用所述药物时,还包括在给予这些复制的T细胞之前、过程中或之后给予PI3激酶抑制剂、VIP受体拮抗剂、VIP降解酶或其组合。
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CN113795269A (zh) * | 2018-11-15 | 2021-12-14 | 埃默里大学 | 血管活性肠肽(vip)拮抗剂的组合物和用途 |
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