CN116391030A - 诱导异质免疫细胞趋化的转化免疫细胞 - Google Patents
诱导异质免疫细胞趋化的转化免疫细胞 Download PDFInfo
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Abstract
本发明涉及表达IL‑7、CCL19或其组合的免疫细胞,以及包含其作为活性成分的用于预防或治疗癌症或传染病的组合物。由于患者内源性T细胞和注射的自然杀伤细胞的互补免疫反应,本发明通过施用治疗有效量的单类型免疫细胞(特别是自然杀伤细胞),可以实现多方面和协同的治疗效果。T细胞和除T细胞以外的免疫细胞(特别是自然杀伤细胞)的共同施用也使这些异质细胞群以病变集中的方式作用,从而显著改善治疗效果。
Description
技术领域
本发明涉及免疫细胞,特别是T细胞以外的免疫细胞,更特别地是自然杀伤细胞,其表达用于使T细胞迁移到病变部位的特定趋化因子。
背景技术
癌症基本上是与组织生长调节异常有关的疾病,癌细胞较正常细胞过度生长增殖,具有侵袭邻近组织或向远处组织转移的特点。抗癌治疗抑制癌细胞生存所需基因的表达,例如癌基因、端粒酶、生长因子受体或信号分子,或通过物理去除癌组织、照射或施用抗癌药物诱导细胞死亡。然而,由于在此治疗过程中正常细胞也可能和癌细胞一同受到损伤,因此特异性除去肿瘤组织的免疫细胞疗法正在引起人们的关注。特别是,在过去的几十年中,已经积极研究了通过使用诸如树突细胞、自然杀伤细胞和T细胞等免疫细胞激活患者身体的免疫反应来去除肿瘤组织的抗癌疗法。
自然杀伤细胞(NK细胞)是淋巴样细胞,约占外周血淋巴细胞的15%,在先天免疫反应中发挥重要作用。具体而言,它们激活树突状细胞和诱导细胞毒性T淋巴细胞(CTL)对肿瘤产生特异性反应,从而去除肿瘤细胞。自然杀伤细胞直接杀伤包括肉瘤、骨髓瘤、淋巴瘤、白血病的恶性肿瘤,并且,通过在骨髓移植后向血癌(如白血病)患者施用体外活化的NK细胞证实了其治疗效果(血细胞分子&疾病,33:p261-266,2004)。然而,由于大多数自然杀伤细胞在正常人体内以非活性状态存在,因此研究已聚焦于在体外激活从血液中分离的NK细胞以提高治疗效率。
另一方面,构成免疫细胞另一轴的T细胞是在骨髓中产生并在胸腺中成熟的淋巴细胞。它们在免疫系统中具有记忆能力,并向B细胞提供信息以诱导抗体产生。T细胞在胸腺内经过免疫耐受试验后,分化为四种类型:细胞毒性T细胞、辅助T细胞、调节性T细胞和记忆T细胞。细胞毒性T细胞是CD8+,与I型MHC结合以识别癌细胞或感染细胞,主要针对病变细胞,类似于自然杀伤细胞。
虽然联合施用自然杀伤细胞和细胞毒性T细胞可以使治疗效果最大化,但仍需要开发新的细胞疗法,以克服注射分别满足治疗有效量的两种细胞的低效率问题。
在本申请中引用了许多出版物和专利文件,并在括号中标明了它们的引文。将所引用的出版物和专利文献的内容全部通过引用并入本文,以完整描述本发明所属技术领域的水平和本发明的内容。
发明内容
技术问题
本发明人进行了深入研究,以开发一种出色的细胞疗法,该疗法可以通过异质免疫细胞的组合产生的复杂免疫反应有效地去除患病细胞或组织。结果,本发明人发现当将表达IL-7、CCL19或其组合的免疫细胞(特别是除T细胞以外的免疫细胞,更特别是自然杀伤细胞)注射到受试者体内时,由IL-7和CCL19增殖和归巢的内源性T细胞与注射的自然杀伤细胞同时作用于病变部位,从而诱导多方面和协同的免疫反应。
因此,本发明的一个目的是提供一种表达IL-7、CCL19或其组合的免疫细胞,以及包含该免疫细胞作为活性成分的用于预防或治疗癌症或传染病的组合物。
本发明的另一个目的是提供一种用于诱导异质免疫细胞增殖或归巢的组合物,其包含编码IL-7、CCL19或其组合的核酸分子作为活性成分。
本发明的其他目的和优点将从以下对本发明的详细描述和所附权利要求和附图中变得更加明显。
技术方案
在本发明的一个方面,提供了一种免疫细胞,其表达编码IL-7(白细胞介素-7)或其功能部分的核酸分子、编码CCL19(C-C基序趋化因子配体19)或其功能部分的核酸分子、或其组合。
本发明人已经深入研究以开发能够通过异质免疫细胞的组合的复杂免疫反应有效地去除患病细胞或组织的优良细胞疗法。结果,本发明人发现,当将表达IL-7、CCL19或其组合的免疫细胞(特别是除T细胞以外的免疫细胞,最特别是自然杀伤细胞)注射到受试者体内时,由IL-7和CCL19增殖和归巢的内源性T细胞与注射的自然杀伤细胞的同时作用于病变部位,从而诱导多方面和协同的免疫反应。
如本文所用,术语“免疫细胞”是指参与免疫反应的启动或促进的任何细胞,更具体地,是指免疫效应细胞。免疫细胞包括但不限于例如T细胞、B细胞、自然杀伤(NK)细胞、自然杀伤T(NKT)细胞、肥大细胞和树突细胞。更具体地,免疫细胞是除T细胞之外的免疫细胞,并且最具体地,是自然杀伤细胞。
如本文所用,术语“T细胞”是与本领域所理解的相同范围的细胞群,并且包括直接裂解靶细胞或提供引起靶细胞死亡的效应子功能或辅助功能的CD8+或CD4+T细胞,但不限于此,并且可包括本发明所属领域中分类为“T细胞”的任何细胞。
本文所用术语“功能部分”是指全长蛋白质中缺失某些氨基酸残基的等效片段,其保留了全长蛋白原有生物学活性和功能。
如本文所用,术语“核酸分子”具有包括DNA(gDNA和cDNA)和RNA分子的广泛含义,核苷酸是核酸分子中的基本结构单元,包括天然存在的核苷酸和具有修饰的糖或碱基的核苷酸类似物(Scheit,核苷酸类似物,John Wiley,纽约(1980);Uhlman和Peyman,化学综述,90:543-584(1990))。
对本领域技术人员来说显而易见的是,本发明所用的核苷酸序列不限于所附序列表中的核苷酸序列。
对核苷酸而言,变异可能是纯基因的,即那些不会导致蛋白产物变化的。这包括包含功能等效密码子、或编码相同氨基酸的密码子(例如精氨酸或丝氨酸的六个密码子)、或编码生物学上等效氨基酸的密码子的核酸。考虑到具有生物学等效活性的上述突变,本发明的核酸分子可以包括具有与其基本同一性的序列。通过使用本领域熟知的序列对比算法之一进行测定,具有基本同一性的序列显示出与本发明的核酸分子至少80%、较具体地至少85%、更具体地至少90%、最具体地至少95%的相似性。
如本文所用,术语“表达”包括使用本发明的免疫细胞通过基因载体人工表达非天然表达的外源基因、通过内源表达系统自然表达内源基因、和通过基因载体增加内源基因的表达从而过表达内源基因。因此,本发明的免疫细胞包括内源表达IL-7和CCL19的细胞、内源表达IL-7并人工表达CCL19的细胞、内源表达CCL19并人工表达IL-7的细胞、以及人工表达IL-7和CCL19的细胞。
如本文所用,术语“表达”是指作为染色体外因子在靶细胞中人工复制或通过使用基因递送载体完成染色体整合而使靶细胞表达外源基因或过表达内源基因。变得因此,术语“表达”中的“表达”与“转化”、“转染”或“转导”同义。
如本文所用,术语“以表达(to express)”是指作为染色体外因子或通过基因递送系统染色体整合到靶细胞中而被人工地复制,以使靶细胞以表达外源基因或过表达内源性基因。因此,术语“以表达”中的“表达”与“转化(transformation)”、“转染(transfection)”或“转导(transduction)”可以互换使用。
如本文所用,术语“基因递送系统”是指将基因递送到细胞中的任何方式。基因递送与基因的细胞内转导具有相同的含义。在组织层面,术语“基因递送”一词与基因的传播具有相同的含义。因此,本发明的基因递送系统可以描述为基因渗透系统和基因传播系统。
IL-7和CCL19基因的核苷酸序列可应用于所有用于常规基因转移的基因递送系统,如质粒、腺病毒、腺相关病毒、逆转录病毒、慢病毒、单纯疱疹病毒、牛痘病毒、脂质体或囊泡(Niosome)。
当本发明的基因递送系统是裸重组DNA分子或质粒时,可以通过显微注射法(Capecchi,M.R.,细胞,22:479(1980))、磷酸钙沉淀法(Graham,F.L.等,病毒学,52:456(1973))、电穿孔(Tur-Kaspa等,分子细胞生物学,6:716-718(1986))、脂质体介导的转染(生物化学和生物物理学学报,721:185-190(1982)))、DEAE-葡聚糖处理(Gopal,分子细胞生物学,5:1188-1190(1985))和基因轰击(Yang等,美国国家科学院院刊,87:9568-9572(1990)),将基因导入细胞,具体地可以采用电穿孔法。
根据一个具体实施方式,IL-7包含与SEQ ID NO:1的氨基酸序列具有至少85%序列相似性、更具体地至少90%序列相似性、最具体地至少95%序列相似性的氨基酸序列。
根据本发明的一个具体实施方式,CCL19包含与SEQ ID NO:2的氨基酸序列具有至少85%或更高的序列相似性、更具体地至少90%或更高的序列相似性、最具体地95%或更高的序列相似性的氨基酸序列。
根据一个具体实施方式,编码IL-7或其功能部分的核酸分子包含SEQ ID NO:3的核苷酸序列。
根据本发明的一个具体实施方式,编码CCL19或其功能部分的核酸分子包括SEQID NO:4的核苷酸序列。
根据本发明,SEQ ID NO:3和SEQ ID NO:4分别为经过密码子优化的IL-7和CCL19核苷酸序列,用于在自然杀伤细胞中高效表达。
在本发明的另一个方面,提供了一种用于预防或治疗癌症或传染病的组合物,其包含上述的本发明的免疫细胞作为活性成分。
当本发明的免疫细胞作为细胞疗法应用时,可以应用于各种肿瘤和感染性疾病的治疗。本发明的免疫细胞(特别是自然杀伤细胞)可以应用于所有类型的肿瘤,包括实体癌和血癌。这些癌症包括但不限于例如胃癌、肝癌、肺癌、结直肠癌、乳腺癌、前列腺癌、卵巢癌、胰腺癌、宫颈癌、甲状腺癌、喉癌、急性骨髓性白血病、脑瘤、神经母细胞瘤、视网膜母细胞瘤、头颈癌、唾液腺癌和淋巴瘤。可以使用本发明的免疫细胞(特别是自然杀伤细胞)来预防或治疗的传染病可以是由病毒或病原体感染引起的疾病,其包括可以通过呼吸、血液或皮肤接触等传染的所有疾病。此类传染病包括但不限于乙型和丙型肝炎、人乳头瘤病毒(HPV)感染、巨细胞病毒感染、病毒性呼吸道疾病和流感。
如本文所用,术语“预防”是指在尚未被诊断患有疾病或病症但可能患所述疾病或病症的对象中抑制所述疾病或病症的发生。
如本文所用,术语“治疗”是指(a)抑制病症、疾病或症状的发展;(b)病症、疾病或症状的缓解;(c)消除病症、疾病或症状。当将本发明的免疫细胞施用于受试者时,通过自然杀伤细胞和被自然杀伤细胞募集到病变部位的内源性T细胞或外源性注射的自体或同种异体T细胞产生复杂的免疫反应,从而诱导杀死癌细胞、受感染的细胞、或病原体,从而抑制、消除或缓解因肿瘤或传染病引起的症状的发展。因此,本发明的组合物本身可以是疾病的细胞治疗组合物,或可以通过与治疗性T细胞或其他已知的抗癌剂一起给药,作为疾病的治疗佐剂应用。因此,本说明书中的术语“治疗”或“治疗剂”包括“治疗助剂”或“治疗佐剂”的含义。
如本文所用,术语“给药”或“施用”是指将治疗有效量的本发明的组合物直接给药至对象,使得在对象体内形成相同的量。
如本文所用,术语“治疗有效量”指的是本发明组合物足以对本发明的组合物所要给药的受试者提供治疗或预防效果的量,因此包括“预防有效量”的含义。
如本文所用,术语“对象”包括但不限于人、小鼠、大鼠、豚鼠、狗、猫、马、牛、猪、猴、黑猩猩、狒狒或恒河猴。具体地,本发明的对象是人。
在本发明的另一个方面,提供了一种用于诱导异质免疫细胞增殖或归巢的组合物,其包含编码IL-7(白细胞介素-7)或其功能部分的核酸分子、编码CCL19(C-C基序趋化因子配体19)或其功能部分的核酸分子、或其组合,作为活性成分。
由于本发明中使用的核酸分子已经在上面进行了详细描述,因此省略它们的描述以避免过多的冗余。
如本文所用,术语“异质免疫细胞(heterogeneous immune cell)”是指与引入本发明的核酸分子的靶细胞不同类型的免疫细胞。具体地,所述异质免疫细胞为T细胞或树突状细胞。根据本发明,通过将同时表达IL-7和CCL19的免疫细胞(具体地为除T细胞以外的免疫细胞,最具体地为自然杀伤细胞)注射到受试者体内以诱导T细胞增殖和趋化性,可以使大量内源性T细胞迁移至病灶。术语“趋化性”是指由化学刺激诱导的细胞的正向(趋向刺激)或负向(远离刺激)迁移,并且具体地指正向迁移。根据本发明,T细胞被IL-7增殖和分化并被相应的趋化因子CCL19激活,然后向表达IL-7和CCL19的自然杀伤细胞移动。这导致在病变部位周围形成由两种类型的互补免疫细胞(即T细胞和自然杀伤细胞)组成的异质细胞群。因此,本发明的组合物可作为治疗佐剂,其仅通过治疗有效量的单一细胞类型提供不同细胞群的共同施用的效果。
根据本一个具体实施方案,核酸分子可以通过一起插入单一基因递送系统或分别插入两个不同的基因递送系统而包含在组合物中。
根据本发明的另一个方面,本发明提供了一种预防或治疗癌症或传染病的方法,包括将上述的本发明免疫细胞给予受试者。由于本发明中使用的免疫细胞和可以通过它们预防或治疗的癌症和传染病已经在上文中详细描述,因此省略其描述以避免过多冗余。
根据本发明的另一个方面,本发明提供了一种诱导异质免疫细胞增殖或归巢的方法,其包括将编码IL-7(白细胞介素7)或其功能部分的核酸分子、编码CCL19(C-C基序趋化因子配体19)或其功能部分的核酸分子、或其组合引入免疫细胞中。由于本发明所使用的核酸分子和异质免疫细胞已在上文进行了详细描述,因此省略其描述以避免过多冗余。
本发明的效果
本发明的特点和优点概括如下:
(a)本发明提供表达IL-7、CCL19或其组合的免疫细胞,以及包含其作为活性成分的用于预防或治疗癌症或传染病的组合物。
(b)由于患者内源性T细胞和注射的自然杀伤细胞的互补免疫反应,本发明通过施用治疗有效量的单一类型免疫细胞(特别是自然杀伤细胞),可以实现多方面和协同的治疗效果。
(c)根据本发明,同时给予T细胞和T细胞以外的免疫细胞,特别是自然杀伤细胞,通过使这些异质细胞群以向病变集中的方式作用,也能够显著提高治疗效果。
附图简述
图1为作为阴性对照载体的pEF1-IRES空载体的结构示意图。
图2是插入了IL-7和CCL19基因的pEF1-IRES载体的结构示意图。
图3是显示插入了CCL19和IL-7基因的pEF1-IRES载体结构的示意图。
在下文中,将通过实施例更详细地描述本发明。对于本领域技术人员来说显而易见的是,这些实施例旨在更详细地说明,并且如所附权利要求所示的本发明的范围不受这些实施例限制。
实施例
实施例1:IL-7和CCL19表达载体的构建
构建了表达载体以产生表达IL-7和CCL19的人NK细胞。使用在人延伸因子1α(EF1α)启动子控制下的pEF1a-IRES双顺反子哺乳动物表达载体(宝生物(Takara),CAT#631970),作为表达载体。
要插入载体的IL-7和/或CCL19基因的ORF序列经过密码子优化(分别为SEQ IDNO:3和SEQ ID NO:4)并合成。将IL-7或CCL19克隆到pEF1α-IRES载体的多克隆位点A(MCSA),将CCL19或IL-7克隆到MCS B中。此时,在pEF1a-IRES中,一个内部核糖体进入位点(IRES)位于两个MCS之间,使得两个基因可以共表达。分别地,空载体即阴性对照载体的结构如图1所示,IL-7/CCL19表达载体的结构如图2所示,CCL19/IL-7表达载体的结构如图3所示。
实施例2:IL-7和CCL19表达的鉴定
NK92细胞系购自ATCC(CAT#CRL-2407),培养在含有12.5%马血清(西格玛(Sigma),CAT#H1270)、12.5%胎牛血清(FBS,Gibco,CAT#10099141)和白细胞介素-2(IL-2;派普泰克(Peprotech),CAT#200-02)的α-MEM(Alpha最低必需培养基)中。为了制备表达IL-7和CCL19的NK92细胞系(以下称“转化的NK92细胞系”),以1×106NK92细胞/0.1mL的密度进行电穿孔。.
电穿孔法使用NeonTM转染系统(NeonTM Transfection System)(赛默飞世尔(ThermoFisher),CAT#MPK5000),在以下条件下进行:1800-1850v电压,10ms脉冲长度,1次,10-20μg DNA(实施例1制备的阴性对照载体、IL-7/CCL19表达载体或CCL19/IL-7表达载体)。在2mL含有10%FBS的RPMI1640培养基(Gibco#11875168)中培养1天后,测量IL-7或CCL19的表达水平或进行侵袭(transwell)测定。
为了测量转化的NK92细胞系中IL-7和CCL19的表达水平,将培养基收集在6孔板中。800xg离心5分钟后分离上清液。取上清液0.1mL/孔适当稀释,用于IL-7或CCL19酶联免疫吸附试验(ELISA;IL-7,Komabiotech,CAT#k0331215;CCL19,艾博抗(Abcam),CAT#ab100601)测量IL-7或CCL19的表达水平。
IL-7和CCL19 ELISA按照各厂家标准测试方法进行,最终值在450nm波长下测定,见表1。
[表1]
转化细胞中IL-7和CCL19的分泌量
*N.D:未检出
表1的结果显示IL-7/CCL19 NK92细胞系和CCL19/IL-7NK92细胞系分泌IL-7和CCL19,而在注射了空载体的阴性对照细胞中,IL-7和CCL19未检出或检测到的水平不显著。
实施例3:表达IL-7和CCL19的NK细胞诱导的T细胞趋化性和增殖测定
为确定NK细胞分泌的IL-7和CCL19对T细胞的趋化的效果,使用12孔transwell(康宁(Corning),CAT#CLS3421)。使用5μm聚碳酸酯作为腔室过滤器。
使用HuT78 T细胞系进行的IL-7/CCL19 NK92细胞与阴性对照组的比较
1x107个HuT78细胞(ATCC,CAT#TIB-161)(T细胞),在含1% PS且不含FBS的IMDM(Gibco,CAT#12440053)培养基中培养24小时。此后,使用与上述相同的培养基将100μlHuT78细胞以5x106个细胞/mL的密度分配到上层室中,将实施例2制备的IL-7/CCL19 NK92细胞系中培养2-3天的培养液分装于下层室。
在37℃和5%CO2条件下在细胞培养箱中培养1天后,移除上层室并进一步培养3天。为了测量下层室中的细胞数量,将每孔400μl的培养基以800xg离心5分钟以去除上清液以获得浓缩样品。将10μL台盼蓝与10μL浓缩样品按1:1比例混合,用CountessTMII(英杰(Invitrogen),CAT#AMQAX1000)测定。结果换算成400μL内活细胞总数,显示在表2中。
[表2]
转化NK细胞引起的HuT78 T细胞系的趋化作用
使用PBMC来源的T细胞比较IL-7/CCL19
NK92细胞、CCL19/IL-7NK92细胞和阴性对
照
为评估来源于外周血单核细胞(PBMC)的T细胞的趋化性,使用EasySepTM人T细胞分离试剂盒(干细胞公司(STEMCELL)#17951)从PBMC中分离出T细胞。使用含2%FBS的RPMI1640培养基将T细胞稀释至2x106个细胞/mL浓度,分装100μl至上层室。在下层室分装实施例2中制备的IL-7/CCL19和CCL19/IL-7转化NK92细胞系培养1天的培养液。
在37℃和5%CO2条件下在细胞培养箱中培养1天后,移除上层室并进一步培养3天。为了测量下层室中的细胞数量,将每孔500μl的培养基以800xg离心5分钟以去除上清液以获得浓缩样品。10μL台盼蓝与10μL浓缩样品按1:1的比例混合,用CountessTMII测定,结果换算成细胞总数,见下表3。
[表3]
转化的NK92细胞系引起的PBMC来源的T细胞趋化性
如表2和3所示,与导入阴性对照空载体的NK92细胞系相比,IL-7/CCL19和CCL19/IL-7NK92细胞系组中迁移至下腔室的T细胞数量显著增加。由此证实,转化了IL-7和CCL19的NK92细胞诱导了T细胞的趋化性和迁移性T细胞的增殖。
实施例4:转化的NK92细胞系及通过其迁移的T细胞引起的癌细胞杀伤和相关因子分泌的测定
将HepG2肝癌细胞系(ATCC#HB-8065)在含10%FBS的RPMI1640培养基中稀释成2×105个细胞/mL的浓度,然后在96孔板的每个孔中分装0.1mL并平板培养1天。利用与实施例3相同的方式,将含有与实施例2相同的方式电穿孔培养1天的转化NK92细胞系的0.5mLRPMI1640培养基转移到transwell的下室,从而诱导T细胞迁移1天。转移分2x105个细胞/0.1mL的分离自PBMC的T细胞到上层室。此时,将1x105 CD3/CD28 Dynabeads和100U IL-2添加到下室以激活迁移的T细胞。培养1天后,去除上腔室,每孔0.1mL转移至培养HepG2肝癌细胞系的96孔板中。培养3天,用PBS(Phosphate Buffer Saline)洗涤3次后,将培养基更换为含有1%CCK-8的0.1mL10%FBS-RPMI1640培养基,进一步培养2小时。为了测量HepG2肝癌细胞系的细胞活性,在450nm处测量吸光度并按照[式1]计算细胞活性度,如表4所示。
[式1]
此外,使用收集自上述细胞活性检测的培养基,通过酶联免疫吸附测定(ELISA;GrzB,艾博抗#ab235635;IFN-γ,komabiotech#K0331121;TNF-α,komabiotech#K0331131)测量活化的T细胞和活化的NK细胞的颗粒酶-B(Grz-B)、干扰素-γ(IFN-γ)和肿瘤坏死因子-α(TNF-α)分泌,结果见表5。表4和表5中各值表示为平均值±标准差。
[表4]
对HepG2肝癌细胞株的细胞毒性
[表5]
Grz-B、IFN-γ及TNF-α分泌
*N.D:未检出
如表4所示,与引入空载体的阴性对照NK92细胞系相比,在IL-7/CCL19和CCL19/IL-7NK92细胞系的实验组中观察到了显著更高的HepG2细胞杀伤活性。如表5所示,与阴性对照组相比,与对HepG2细胞系的细胞毒性相关的因子也在IL-7/CCL19和CCL19/IL-7NK92细胞系组中显示出更高的分泌水平。因此,证实了IL-7/CCL19 NK细胞系和CCL19/IL-7NK细胞系均可用作有效的抗癌治疗。
在以上对本发明的具体实施方式进行了详细描述之后,应当理解,属于本发明精神的变体和修改对于本领域技术人员来说可能是显而易见的。因此,本发明的范围将由所附权利要求及其等同物限定。
<110> TSD生命科学有限公司
<120> 诱导异质免疫细胞趋化的转化免疫细胞
<130> POPB214508PCTCN
<150> KR 10-2020-0141039
<151> 2020-10-28
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Claims (7)
1.一种免疫细胞,其表达编码IL-7(白介素-7)或其功能部分的核酸分子、编码CCL19(C-C基序趋化因子配体19)或其功能部分的核酸分子、或其组合。
2.根据权利要求1所述的免疫细胞,其中,所述免疫细胞为除T细胞以外的免疫细胞。
3.根据权利要求2所述的免疫细胞,其中,所述除T细胞以外的免疫细胞为自然杀伤细胞。
4.一种用于预防或治疗癌症或传染病的组合物,其包含权利要求1至3中任一项所述的免疫细胞作为活性成分。
5.一种用于诱导异质免疫细胞增殖或归巢的组合物,其包含作为活性成分的编码IL-7(白介素-7)或其功能部分的核酸分子、编码CCL19(C-C基序趋化因子配体19)或其功能部分的核酸分子、或其组合。
6.根据权利要求5所述的组合物,其中,所述异质免疫细胞为T细胞或树突状细胞。
7.根据权利要求5所述的组合物,其中,所述核酸分子通过一起插入单个基因递送系统或分别插入两个不同的基因递送系统而包含在所述组合物中。
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