CN114025787A - Car-t细胞的原位募集、重编程和释放 - Google Patents
Car-t细胞的原位募集、重编程和释放 Download PDFInfo
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Abstract
本发明公开了用于CAR T细胞、CAR NK细胞、CAR NK T细胞、CAR巨噬细胞、肿瘤浸润性NK细胞、肿瘤浸润性淋巴细胞和骨髓浸润性淋巴细胞的募集和重新编程的水凝胶基质。
Description
背景技术
嵌合抗原受体(CAR)重定向的T淋巴细胞(CAR-T细胞)的过继转移对B细胞恶性肿瘤产生了引人注目的临床应答,并且对其他癌症类型也有效。目前临床规模制造CAR-T细胞的方法需要在体外进行大量细胞操作:自体T细胞的分离、CAR编码病毒载体的转导,以及CAR-T细胞体外扩增,然后再输回患者体内。复杂且耗时的体外程序需要大量费用:该程序需要3-4周,费用约为500,000美元。这些成本限制了将该技术扩展到其他癌症和患者的潜力。需要的是募集和修饰T细胞的新方法,以避免与当前CAR T细胞相关的问题。
发明内容
本文公开了涉及水凝胶的方法和组合物,包括化学引诱剂。
一方面,本文公开了包含一种或多种化学引诱剂的水凝胶基质,其中所述一种或多种化学引诱剂包含C-C基序趋化因子配体(CCL)1(CCL1)、CCL5、CCL19、CCL21、CCL22、CCL28、C-X-C基序趋化因子配体(CXCL)1(CXCL1)、CXCL9、CXCL10、CXCL11、CXCL12、M-CSF、GM-CSF、MCP-1、MCP-3、CCL2、CCL3、CCL7、CCL20、CX3CL1、BRAK、IL-12、S1P和/或MCP2。
本文还公开了任一前述方面的水凝胶基质,其进一步包含编码嵌合抗原受体(CAR)、NK细胞受体(包括但不限于抗CD3抗体、CD1d、免疫球蛋白的Fc片段或抗Fcγ受体(FcRIII)抗体)、NK T细胞受体和/或T细胞受体(例如抗原特异性T细胞受体)的病毒载体(诸如,例如慢病毒、逆转录病毒、腺病毒或腺相关病毒)。
一方面,本文还公开了任一前述方面的水凝胶基质,其进一步包含一种或多种抗体、细胞因子和/或共刺激分子,该共刺激分子活化T细胞、自然杀伤(NK)细胞、NK T细胞、肿瘤浸润淋巴细胞(TIL)、骨髓浸润淋巴细胞(MIL)、肿瘤浸润性NK细胞(TINK)、树突状细胞或巨噬细胞。例如,抗体可以包括抗CD3、抗CD28、抗诱导型共刺激物(ICOS)、抗CD40L、抗DAP10;并且细胞因子可以包括IL-2、IL-7、IL-15、IL-21、TNF-α或IFN-γ。
本文还公开了任何前述方面的水凝胶基质,其进一步包含化疗剂。
在一个方面,本文公开了治疗、预防、抑制和/或减弱受试者的癌症或转移的方法,该方法包括向受试者施用任何前述方面的水凝胶基质。例如,本文公开了治疗受试者的癌症的方法,包括向受试者施用包含一种或多种化学引诱剂的水凝胶基质,其中所述一种或多种化学引诱剂包括C-C基序趋化因子配体(CCL)1(CCL1)、CCL5、CCL19、CCL21、CCL22、CCL28、C-X-C基序趋化因子配体(CXCL)1(CXCL1)、CXCL9、CXCL10、CXCL11、CXCL12、M-CSF、GM-CSF、MCP-1、MCP-3、CCL2、CCL3、CCL7、CCL20、CX3CL1、BRAK、IL-12、S1P和/或MCP2;并且其中化学引诱剂将免疫细胞(诸如例如,T细胞、NK细胞、NK T细胞、TIL、MIL、TINK、树突状细胞和/或巨噬细胞)吸引并保留到水凝胶。
本文还公开了任何前述方面的治疗、预防、抑制和/或减少癌症或转移的方法,其中水凝胶基质进一步包含免疫阻断抑制剂和/或化疗剂。
一方面,本文公开的是任何前述方面的治疗、预防、抑制和/或减少癌症或转移的方法,其中水凝胶进一步包含编码嵌合抗原受体(CAR)、NK细胞受体(包括但不限于抗CD3抗体、CD1d、免疫球蛋白的Fc片段、或抗Fcγ受体(Fc RIII)抗体)、NK T细胞受体和/或T细胞受体(TCR)(包括抗原-特异性T细胞受体)的病毒载体。一方面,病毒载体转导免疫细胞;并且转导的免疫细胞从水凝胶释放到癌症。应当理解并在本文中考虑可以在向受试者施用之前或在向受试者施用水凝胶基质之后约1天至约14天将病毒载体引入到水凝胶基质中。也就是说,病毒载体可以在体内被引入到水凝胶中。
本文还公开了任何前述方面的治疗、预防、抑制和/或减少癌症或转移的方法,其中在施用水凝胶后约1周至约12周释放免疫细胞。
一方面,本文公开了治疗、预防、抑制和/或减少任何前述方面的癌症或转移的方法,其中一种或多种化学引诱剂在施用水凝胶后约1小时至施用水凝胶后约12周释放。
一方面,本文公开了在受试者中转导免疫细胞(诸如例如,T细胞、NK细胞、NK T细胞、TIL或MIL)的方法,该方法包括向受试者施用水凝胶,该水凝胶包含一种或多种化学引诱剂(诸如例如CCL1、CCL5、CCL19、CCL21、CCL22、CCL28、CXCL1、CXCL9、CXCL10、CXCL11、CXCL12、M-CSF、GM-CSF、MCP-1、MCP-3、CCL2、CCL3、CCL7、CCL20、CX3CL1、BRAK、IL-12、S1P和/或MCP2)和编码转基因(诸如例如,CAR、NK细胞受体(包括但不限于抗CD3抗体、CD1d、免疫球蛋白的Fc片段或抗Fcγ受体(Fc RIII)抗体)、NK T细胞受体和/或TCR(包括但不限于抗原特异性TCR))的病毒载体(诸如,慢病毒、逆转录病毒、腺病毒或腺相关病毒)。应当理解并在本文中考虑可以在向受试者施用之前或在向受试者施用水凝胶基质之后约1天至约14天将病毒载体引入到水凝胶基质中。也就是说,病毒载体可以在体内被引入到水凝胶中。
本文还公开了任何前述方面的转导免疫细胞的方法,其中一种或多种化学引诱剂在施用水凝胶后约1小时至施用水凝胶后约12周释放。
一方面,本文公开了任何前述方面的转导免疫细胞的方法,其中水凝胶进一步包含一种或多种抗体、细胞因子和/或共刺激分子,该共刺激分子活化T细胞、NK细胞、NK T细胞、TIL或MIL。例如,抗体可包含抗CD28、CD3、B7-1、B7-2、抗诱导型共刺激物(ICOS)、ICOS配体、抗CD27、CD70、4-1BBL、抗41-BB、抗CD40L、CD40、抗DAP10、抗CD30、CD30L、抗TIM-1、抗TIM-2、抗TIM-3、抗CD44、抗NK1.1、凝集素样转录物-1(LLT-1)、抗CD137、CD48、MICA、抗2B4、抗糖皮质激素诱导的肿瘤坏死因子受体相关蛋白(GITR);并且细胞因子可以包括IL-2、IL-7、IL-15、IL-21、TNF-α或IFN-γ。
附图说明
并入本说明书并构成本说明书一部分的附图示出了几个实施例,并且与说明书一起示出了所公开的组合物和方法。
图1是CAR-T细胞原位生成的示意图。植入的支架释放趋化因子以募集宿主T细胞。病毒载体用肿瘤特异性CAR构建体重新编程T细胞,CAR修饰的T细胞迁移出去以对抗癌症。
图2显示了通过冷冻凝胶化制备大孔凝胶的示意图。
图3显示了冻干法制备的凝胶的SEM图片(-20℃)。
图4A和4B显示CXCL10介导T细胞募集到植入支架。图4A显示了实验时间线,图4B显示了募集到空白(对照)或CXCL10释放支架的CD3+T细胞的FACS分析。
图5A、5B、5C和5D显示预接种和募集的T细胞可以在植入支架内进行转导。预接种到支架中或由CXCL10募集到支架中的GFP+T细胞的实验时间线(5A、5C)和FACS分析(5B、5D)。D显示CD3/CD28和IL-2在支架中的额外影响。
图6显示了CAR T细胞的原位生成。
图7显示了用CD19 CAR病毒在体内转导募集的T细胞。
图8显示了创建小鼠Burkitt淋巴瘤肿瘤模型的示意图。
图9A显示了未接受治疗、接受静脉注射CD19 CAR T细胞、或接受CCI-藻酸盐支架(CCI-Alg)的动物在接种肿瘤后19、24、29、33和43天时肿瘤大小的发光图像。
图9B显示了在未接受治疗、接受静脉注射CD19 CAR T细胞或接受CCI-藻酸盐支架(CCI-Alg)的动物在接种肿瘤后不同时间点的总通量和体重百分比变化。
图10显示了在植入CCI支架或静脉注射CAR-T细胞的小鼠中每100ul血液中的CAR+细胞数量。通过脸颊出血对小鼠取血,裂解红细胞,用Hu-CD45、Hu-CD3和CAR.19抗体染色细胞并通过流式细胞术进行分析。
具体实施方式
在公开和描述本发明的化合物、组合物、制品、装置和/或方法之前,应当理解,除非另有规定,否则它们不限于特定的合成方法或特定的重组生物技术方法,或者除非另有规定,否则它们不限于特定的试剂,因而,它们当然也可有所变化。另外应当了解,本文使用的术语只是出于描述特定实施例的目的,并非旨在进行限制。
A.定义
在本说明书及随后的权利要求书中,将引用多个术语,将其定义为具有以下含义:
如在说明书和所附权利要求书中所用,单数形式“一个”“一种”“该”和“所述”包括复数指代物,除非上下文另外明确规定不是这样。因此,例如,对“药物载体”的提及包括两个或更多这样的载体的混合物等。
范围可以在本文中表示为从“约”一个特定值和/或到“约”另一特定值。当表达此类范围时,另一实施例包括从一个特定值和/或至另一个特定值。相似地,在利用前词“约”将值表示为近似值时,应当理解,该特定值形成另一个实施例。还应当理解,每一个范围的端点在相对于另一个端点和独立于另一个端点方面都是显著的。还应当理解,本文公开了许多值,并且每一个值在本文中除值本身之外还被公开为“约”该特定值。例如,如果公开了值“10”,则还公开了“约10”。还应理解,当公开了“小于或等于”值、“大于或等于”值时,也公开了如本领域技术人员所恰当理解的介于值之间的可能范围。例如,如果公开了值“10”,则还公开了“小于或等于10”以及“大于或等于10”。还应理解,在整个申请中,数据以多种不同格式提供,并且该数据表示端点和起点,以及数据点的任何组合的范围。例如,如果公开了特定数据点“10”和特定数据点15,则应理解认为公开了大于、大于或等于、小于、小于或等于以及等于10和15以及介于10和15之间。还应理解,还公开了两个特定单元之间的每一个单元。例如,如果公开了10和15,则还公开了11、12、13和14。
对受试者的“施用”包括向受试者引入或递送药剂的任何途径。可通过任何合适的途径进行施用,包括口服、局部、静脉、皮下、经皮、穿皮、肌肉内、关节内(intra-joint)、肠外、小动脉内、皮内、脑室内、颅内、腹腔内、病灶内、鼻内、直肠、阴道、通过吸入、通过植入的存贮器、肠外(例如,皮下、静脉、肌肉内、关节内(intra-articular)、滑膜内、胸骨内、鞘内、腹腔内、肝内、病灶内和颅内注射或输注技术)等。如本文所用,“并行施用”、“联合施用”、“同时施用(simultaneous administration或administered simultaneously)”意指化合物在同一时间点施用或基本上紧接着施用。在后一种情况下,该两种化合物的施用时间足够接近,以至于观察到的结果与在同一时间点施用化合物时获得的结果不可区分。“全身施用”是指通过将药剂引入或递送到受试者身体的广泛区域(例如,超过身体的50%)的途径,例如通过进入循环或淋巴系统,将药剂引入或递送给受试者。相比之下,“局部施用”是指通过一条途径向受试者引入或递送药剂,该途径将该药剂引入或递送到紧邻施用点的一个或多个区域,并且不以治疗上显著的量系统地引入该药剂。例如,局部施用的药剂在局部施用点的附近很容易被检测到,但在受试者身体的远侧部分不可检测到或检测到的量可以忽略不计。施用包括自我施用和他人施用。
“生物相容的”通常是指材料及其任何代谢物或降解产物通常对受试者无毒并且不对受体造成显著的副作用。
“包含”意指组合物、方法等包括所提到的元素,但不排除其他元素。当用于定义组合物和方法时,“基本上由...组成”应指包括所提到的元素,但不包括对组合具有任何重要意义的其他元素。因此,基本上由本文所定义的元素组成的组合物不排除来自分离和纯化方法的痕量污染物和药用载体,诸如磷酸盐缓冲盐水、防腐剂等。“由...组成”应指排除多于其他成分的痕量元素和用于给予本发明的组合物的实质性方法步骤。由这些过渡术语中的每一个所定义的实施例都在本发明的范围内。
“对照”是在实验中出于比较目的的替代受试者或样品。对照可为“阳性对照”或“阴性对照”。
“控释”或“缓释”是指为了在体内达到所需的药代动力学曲线,以可控的方式从给定剂型释放药剂。“控释”药剂递送的一个方面是操纵制剂和/或剂型以建立所需的药剂释放动力学的能力。
药剂的“有效量”是指药剂提供所需的效果的足够数量。“有效的”药剂的量将在不同受试者之间变化,取决于受试者的年龄和一般情况、特定的一种或多种药剂等许多因素。因此,并不总是能够指定量化的“有效量”。然而,任何受试者病例中的适当的“有效量”可由本领域的普通技术人员使用常规实验方法确定。此外,如本文所用,并且除非另外特别说明,否则药剂的“有效量”也可以指涵盖治疗有效量和预防有效量的量。实现治疗效应所需的药剂的“有效量”可根据诸如受试者的年龄、性别和体重等因素而变化。可调整剂量方案以提供最佳治疗反应。例如,可每天施用若干分开的剂量,或者可按照治疗情况的紧急程度按比例减少剂量。
“增加”可以指导致更大量的症状、疾病、组合物、病症或活性的任何变化。减少可以是统计学上显著的量的病症、症状、活动、组合物中的任何个体、中位数或平均增加。因此,只要增加非常显著,增加可以是1、2、3、4、5、6、7、8、9、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95或100%。增加也可以倍数增加来参考。例如,增加可以包括2、3、4、5、6、7、8、9、10、15、20、30、40、50、60、70、80、90、100、200、300、400、500、600、700、800、900、103、104、105、106、107、108、109、1010-倍增加。
“减少”可以指导致较少的基因表达、蛋白质表达、症状数量、疾病、组合物、病症或活动的任何变化。当含有该物质的基因产物的遗传产量与不含该物质的基因产物的遗传产量相比较小时,物质也被理解为减少基因的遗传产量。此外,举例来说,减少可以是一种障碍症状的改变,使得症状比以前观察到的要少。减少可以是统计学上显著的量的病症、症状、活动、组合物中的任何个体、中位数或平均减少。因此,只要减少非常显著,减少可以是1%、2%、3%、4%、5%、6%、7%、8%、9%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%或100%。减少也可以倍数减少来参考。例如,减少可以包括2、3、4、5、6、7、8、9、10、15、20、30、40、50、60、70、80、90、100、200、300、400、500、600、700、800、900、103、104、105、106、107、108、109、1010-倍减少。
“抑制(Inhibit、inhibiting和inhibition)”意指降低活性、反应、病症、疾病或其他生物参数。这可以包括但不限于活动、反应、病症或疾病的完全消融。这也可以包括,例如,与未经处理的或对照水平相比,活动、反应、病症或疾病减少10%。因此,与未经处理的或对照水平相比,减少量可以是10%、20%、30%、40%、50%、60%、70%、80%、90%、100%或介于两者之间的任何减少量。
如本文所用,术语“预防(prevent、preventing或prevention)”及其语法变体是指部分或完全延迟或阻止疾病和/或其一个或多个伴随症状的发生或复发,或阻止受试者获得或重新获得疾病或减少受试者获得或重新获得疾病或一个或多个伴随症状的风险的方法。
“药学上可接受的”组分可指并非生物学上或以其他方式不可取的组分,即该组分可掺入本发明的药物制剂中并施用到如本文所述的受试者,而不引起显著的不良生物效应或以有害的方式与包含该组分的制剂的任何其他组分相互作用。当用于提及对人类的施用时,该术语通常意味着该组分已达到毒理学和制造试验的要求标准,或者它包括在美国食品药品监督管理局所制定的非活性成分指南中。
“药学上可接受的载体”(有时称为“载体”)意指可用于制备通常安全且无毒的药物或治疗组合物的载体或赋形剂,并且包括兽医和/或人类药用或治疗用的可接受的载体。术语“载体”或“药学上可接受的载体”可以包括但不限于磷酸盐缓冲盐水溶液、水、乳液(诸如油/水或者水/油乳液)和/或各种类型的润湿剂。如本文所用,术语“载体”包括但不限于任何赋形剂、稀释剂、填充剂、盐、缓冲液、稳定剂、增溶剂、脂质或本领域中熟知的用于药物制剂的其他材料,并且如本文中进一步描述。
“药理活性”(或仅“活性”),正如在“药理活性”衍生物或类似物中所用的那样,可指具有与母体化合物相同类型的药理活性并且程度大致相等的衍生物或类似物(例如,盐、酯、酰胺、缀合物、代谢物、异构体、片段等)。
“治疗剂”是指任何具有有益生物效应的组合物。有益的生物效应包括治疗效应和预防效应,其中治疗效应例如治疗障碍或其他不良生理病症,预防效应例如预防障碍或其他不良生理病症(例如,非免疫原性癌症)。该术语还涵盖本文中具体提及的有益剂在药用的药理活性衍生物,包括但不限于盐、酯、酰胺、前体药剂、活性代谢物、异构体、片段、类似物等。当使用术语“治疗剂”时,或者当明确标识特定的药剂时,应当理解,该术语包括药剂本身以及在药用的药理活性盐、酯、酰胺、前体药剂、缀合物、活性代谢物、异构体、片段、类似物等。
组合物(例如,包含药剂的组合物)的“治疗有效量”或“治疗有效剂量”是指有效地达到所需的治疗结果的量。在一些实施例中,所需的治疗结果是控制I型糖尿病。在一些实施例中,所需的治疗结果是控制肥胖。给定治疗剂的治疗有效量通常将根据诸如所治疗的障碍或疾病的类型和严重程度以及受试者的年龄、性别和体重等因素而变化。术语还可指有效促进所需的治疗效应(诸如疼痛缓解)的治疗剂的量或治疗剂的递送速率(例如,随时间推移的量)。精确的所需治疗效应将根据待治疗的病症、受试者的耐受性、待施用的药剂和/或药剂制剂(例如,治疗剂的效力、制剂中的药剂浓度等),以及本领域中的普通技术人员所理解的各种其他因素而变化。在一些情况下,在向受试者连续几天、几周或几年施用多种剂量的该组合物后,可获得所需的生物或医学反应。
在本说明书及随后的权利要求书中,将引用多个术语,将其定义为具有以下含义:
“任选的”或“任选地”意指随后描述的事件或情况可能发生或可能不发生,并且该描述包括所述事件或情况发生的情况和所述事件或情况不发生的情况。
在整个本申请中,引用了各种出版物。这些出版物的全部公开内容据此以引用方式并入本申请,以便更全面地描述本申请所涉及的技术现状。所公开的参考文献也单独并且具体地以引用方式并入本文,参考文献中包含的材料在参考文献所依据的句子中予以讨论。
B.组合物
本发明公开了用于制备本发明所公开的组合物,以及在本文所公开的方法中使用的组合物本身。本文公开了这些及其他材料,并且应当理解,当本发明公开这些材料的组合、子集、相互作用、基团等时,虽然可能未明确公开这些化合物的各种不同的个体和集体组合和排列的具体参考,但是其中每一个在本文中均予以特别考虑和描述。例如,如果公开和讨论了包含化学引诱剂的特定水凝胶基质,并且讨论了可以对包括化学引诱剂的水凝胶基质在内的许多分子进行的许多修饰,则具体考虑的是水凝胶基质的每个和每一个组合和排列,其包含化学引诱剂以及可能的修饰,除非有具体的相反指示。因此,如果公开了一类分子A、B和C以及一类分子D、E和F以及组合分子的实例,则公开了A-D,那么即使未单独引用其中每一项,也认为公开了个体和集体考虑的含义组合A-E、A-F、B-D、B-E、B-F、C-D、C-E和C-F。同样,还公开了这些组合的任何子集或组合。因此,例如,将认为公开了A-E、B-F和C-E的子组。该概念适用于本申请的所有方面,包括但不限于制备和使用本发明所公开的组合物的方法中的步骤。因此,如果存在可以执行的各种附加步骤,则应当理解,这些附加步骤中的每一个均可用本发明所公开的方法的任何特定实施例或实施例的组合来执行。
嵌合抗原受体(CAR)免疫疗法是一种癌症免疫疗法,涉及将患者的自体T细胞、NK细胞和/或巨噬细胞基因分别改造为CAR-T细胞、CAR-NK细胞、CAR-NK-T细胞、或CAR巨噬细胞(CARMA)。这些CAR细胞表达基于抗体的嵌合抗原受体,可以靶向特定的肿瘤抗原。该过程包括自体T细胞、NK细胞、NK T细胞或巨噬细胞的分离,用CAR编码病毒载体转导,以及CAR-T细胞、CAR-NK细胞、CAR-NK-T细胞或CARMA体外扩增然后输注回患者。尽管取得了显著的临床成功,但根据严格的监管标准与生成临床级CAR免疫细胞(例如CAR T细胞)相关的费力、耗时和昂贵的程序仍然是实施CAR免疫细胞疗法作为癌症治疗的标准护理的主要障碍。可以消除与生成CAR免疫细胞相关的时间和成本的方法具有巨大的临床意义,并且可以显著扩大CAR T细胞、CAR-NK细胞、CAR-NK-T细胞和/或CARMA疗法的可用性。
原位生成肿瘤特异性CAR免疫细胞可以克服与体外生成CAR-T细胞相关的许多挑战。嵌合抗原受体(CAR)是合成受体,可将免疫细胞(例如,CAR T细胞、CAR-NK细胞、CAR-NK-T细胞或CARMA)特异性重新导向至肿瘤相关抗原。CD19的输注。CAR-T细胞在第一个CD19的临床试验中显示出显著的抗肿瘤作用。CAR-T疗法于2017年获得FDA批准。T细胞收集、体外活化、细胞的基因改造和扩增、以及随后向患者输注,既耗时(约4周)又昂贵(约500,000美元)。鉴于癌症已经给医疗保健系统带来了负担,为数百万癌症患者提供CAR免疫细胞疗法是一项巨大的挑战。本文表明,CAR免疫细胞可以在装载有T细胞募集因子和CAR编码病毒载体的大孔支架中原位生成。这种方法消除了与生成CAR免疫细胞(例如,CAR T细胞、CAR-NK细胞、CAR-NK-T细胞或CARMA)相关的时间和成本,具有巨大的临床意义,并且可以显著扩大CAR免疫细胞疗法的可用性。
本文公开了一种使用生物活性大孔支架在患者体内原位生成CAR免疫细胞的策略。支架募集免疫细胞,将它们活化并重新编程为CAR免疫细胞,并将CAR免疫细胞释放到体内以找到肿瘤(图1)。趋化因子从支架的受控释放产生一个梯度,吸引T细胞(包括但不限于TIL和MIL)NK细胞(包括但不限于TINK)、NK T细胞、树突状细胞和/或巨噬细胞到支架。大孔支架促进趋化因子介导的T细胞、NK细胞、NK T细胞、树突状细胞和/或巨噬细胞浸润,并与嵌入的细胞因子和抗体一起促进T细胞、NK细胞、NK T细胞、树突状细胞和/或巨噬细胞的存活和扩增,并为病毒颗粒的转导提供界面。一旦趋化因子完全释放,其耗竭会促进CAR-T细胞、CAR-NK细胞、CAR-NK-T细胞或CARMA迁移出支架。在这种方法中,T细胞、NK细胞、NK T细胞、树突状细胞和/或巨噬细胞被募集到生物材料支架,通过病毒载体用CAR基因重新编程,然后从支架释放到循环中,从而实现CAR-T细胞、CAR-NK细胞、CAR-NK-T细胞或CARMA的原位无缝生成。因此,在本文中公开的一方面是包含一种或多种化学引诱剂的水凝胶基质。
应理解并在本文中预期化学引诱剂的目的是吸引免疫细胞(例如,T细胞、自然杀伤(NK)细胞、NK T细胞、肿瘤浸润淋巴细胞(TIL)、骨髓浸润淋巴细胞(MIL)、肿瘤浸润NK细胞(TINK)、树突状细胞和/或巨噬细胞)到水凝胶。用于所公开的水凝胶的一种或多种化学引诱剂的实例包括但不限于C-C基序趋化因子配体(CCL)1(CCL1)、CCL5、CCL19、CCL21、CCL22、CCL28、C-X-C基序趋化因子配体(CXCL)1(CXCL1)、CXCL9、CXCL10、CXCL11、CXCL12、M-CSF、GM-CSF、MCP-1、MCP-3、CCL2、CCL3、CCL7、CCL20、CX3CL1、BRAK、IL-12、S1P和/或MCP2。
本文公开的水凝胶可以使用任何合适的生物可降解聚合物制成。“聚合物”是指相对高分子量的天然或合成有机化合物,其结构可由重复的小单元、单体表示。聚合物的非限制性实例包括聚乙烯、橡胶、纤维素。合成聚合物通常由单体的加成或缩聚形成。术语“共聚物”是指由两种或更多种不同的重复单元(单体残基)形成的聚合物。以举例的方式并且非限制性地,共聚物可为交替共聚物、无规共聚物、嵌段共聚物或接枝共聚物。还可设想,在某些方面,嵌段共聚物的各种嵌段链段本身可包含共聚物。术语“聚合物”包括所有形式的聚合物,包括但不限于天然聚合物、合成聚合物、均聚物、杂聚物或共聚物、加成聚合物等。
在一个方面,水凝胶可包含生物相容性聚合物(诸如例如,海藻酸盐)。此类聚合物还可用于将CAR T细胞、CAR NK细胞、CAR NK T细胞、CARMA、TIL、MIL、TINK和/或MIL缓慢释放到组织中。如本文所使用的,生物相容性聚合物包括但不限于多糖,诸如海藻酸盐、壳聚糖、透明质酸;亲水性多肽;蛋白质,如胶原蛋白、纤维蛋白和明胶;聚(氨基酸)诸如聚-L-谷氨酸(PGS)、γ-聚谷氨酸、聚-L-天冬氨酸、聚-L-丝氨酸或聚-L-赖氨酸;聚亚烷基二醇和聚环氧烷诸如聚乙二醇(PEG)、聚丙二醇(PPG)和聚(环氧乙烷)(PEO);聚(氧乙烯化多元醇);聚(烯烃醇);聚乙烯吡咯烷酮;聚(羟烷基甲基丙烯酰胺);聚(羟烷基甲基丙烯酸);聚(糖);聚(羟基酸);聚(乙烯醇)、多羟基酸诸如聚(乳酸)、聚(乙醇酸)和聚(乳酸-共-乙醇酸);聚羟基脂肪酸酯诸如聚3-羟基丁酸或聚4-羟基丁酸;聚己内酯;聚(正酯);聚酸酐;聚(磷腈);聚(丙交酯-己内酯);聚碳酸酯诸如酪氨酸聚碳酸酯;聚酰胺(包括合成和天然聚酰胺)、多肽和聚(氨基酸);聚酯酰胺;聚酯;聚(二氧环己酮);聚(烷基烯);疏水性聚醚;聚氨酯;聚醚酯;聚缩醛;聚氰基丙烯酸酯;聚丙烯酸酯;聚甲基丙烯酸甲酯;聚硅氧烷;聚(氧乙烯)/聚(氧丙烯)共聚物;聚缩酮;聚磷酸盐;聚羟基戊酸盐;聚亚烷基草酸酯;聚亚烷基琥珀酸盐;聚(马来酸)及其共聚物。生物相容性聚合物还可包括聚酰胺、聚碳酸酯、聚亚烷基、聚亚烷基二醇、聚亚烷基氧化物、聚烷基对苯二甲酸酯、聚乙烯醇(PVA)、甲基丙烯酸酯PVA(m-PVA)、聚乙烯醚、聚乙烯酯、聚乙烯卤化物、聚乙烯吡咯烷酮、聚乙二醇、聚硅氧烷、聚氨酯及其共聚物、烷基纤维素、羟基烷基纤维素、纤维素醚、纤维素酯、乙基纤维素、丙烯酸和甲基丙烯酸酯的聚合物、甲基纤维素、乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羟丁基甲基纤维素、醋酸纤维素、丙酸纤维素、醋酸丁酸纤维素、邻苯二甲酸醋酸纤维素、羧乙基纤维素、三醋酸纤维素、硫酸纤维素钠盐、聚(甲基丙烯酸甲酯)、聚(甲基丙烯酸乙酯)、聚(甲基丙烯酸丁酯)、聚(甲基丙烯酸异丁酯)、聚(甲基丙烯酸己酯)、聚(甲基丙烯酸异癸酯)、聚(甲基丙烯酸月桂酯)、聚(甲基丙烯酸苯酯)、聚(丙烯酸甲酯)、聚(丙烯酸异丙酯)、聚(丙烯酸异丁酯)、聚(丙烯酸十八酯)、聚乙烯、聚丙烯、聚(乙二醇)、聚(环氧乙烷)、聚(对苯二甲酸乙二醇酯)、聚(乙烯醇)、聚(醋酸乙烯酯、聚氯乙烯聚苯乙烯和聚乙烯吡咯烷酮及其衍生物、线性和支链共聚物及其嵌段共聚物,以及其共混物。示例性可生物降解聚合物包括聚酯、聚(邻位酯)、聚(乙烯胺)、聚(己内酯)、聚(羟基丁酸酯)、聚(羟基戊酸酯)、聚酸酐、聚(丙烯酸)、聚乙二醇、聚(氨基甲酸乙酯)、聚碳酸酯、聚磷酸酯、聚磷腈及其衍生物、线性和支链共聚物及其嵌段共聚物(包括三嵌段共聚物),以及其共混物。
在一些实施例中,该颗粒包含生物相容性和/或可生物降解聚酯或聚酸酐,诸如聚(乳酸)、聚(乙醇酸)和聚(乳酸-乙醇酸)。该颗粒可包含以下聚酯中的一种/多种:包括乙醇酸单元(本文称为“PGA”)的均聚物和乳酸单元(诸如聚-L-乳酸、聚-D-乳酸、聚-D,L-乳酸、聚-L-丙交酯、聚-D-丙交酯、和聚-D,L-丙交酯5,本文统称为“PLA”)和己内酯单元(诸如聚(己内酯),在本文中统称为“PCL”);和包括乳酸和乙醇酸单元的共聚物(诸如以乳酸与乙醇酸之比为特征的各种形式的聚(乳酸-共-乙醇酸)和聚(丙交酯-乙交酯),在本文中统称为“PLGA”);和聚丙烯酸酯,以及其衍生物。示例性聚合物还包括聚乙二醇(PEG)和上述聚酯的共聚物,诸如各种形式的PLGA-PEG或PLA-PEG共聚物,在此统称为“PEG化聚合物”。在某些实施例中,该PEG区域可与聚合物共价缔合以通过可裂解的接头产生“PEG化聚合物”。在一个方面,该聚合物包含至少60%、65%、70%、75%、80%、85%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或99%的缩醛侧基。
本文所公开的三嵌段共聚物包含核心聚合物,诸如,例如,聚乙二醇(PEG)、聚醋酸乙烯酯、聚乙烯醇、聚乙烯吡咯烷酮(PVP)、聚环氧乙烷(PEO)、聚(乙烯吡咯烷酮-醋酸乙烯酯)、聚甲基丙烯酸酯、聚氧乙烯烷基醚、聚氧乙烯蓖麻油、聚己内酰胺、聚乳酸、聚乙醇酸、聚(乳酸-乙醇酸)、聚(乳酸-共-乙醇酸)(PLGA)、纤维素衍生物(诸如羟甲基纤维素、羟丙基纤维素等)。
一方面,水凝胶基质还可包含免疫活化和/或维持抗体、趋化因子和细胞因子,诸如,例如CD28、CD3、IL-2、IL-7、IL-15、IL-21、IFN-γ和TNF-α。
应当理解并且本文设想,所公开的水凝胶基质可进一步包含一种或多种免疫检查点抑制剂和/或化疗剂。可用于所公开的水凝胶基质的化学治疗剂可包括本领域已知的任何化学治疗剂,包括但不限于玻玛西林、醋酸阿比特龙、Abitrexate(甲氨蝶呤)、Abraxane(紫杉醇白蛋白稳定的纳米颗粒制剂)、ABVD、ABVE、ABVE-PC、AC、AC-T、Adcetris(本妥昔单抗韦多汀)、ADE、Ado-曲妥珠单抗美坦新、阿霉素(盐酸多柔比星)、阿法替尼二马来酸盐、Afinitor(依维莫司)、Akynzeo(奈托匹坦和盐酸帕洛诺司琼)、Aldara(咪喹莫特)、阿地白介素、Alecensa(阿来替尼)、阿来替尼、阿仑单抗、Alimta(培美曲塞二钠)、Aliqopa(库潘尼西盐酸盐)、注射用爱克兰(马法兰盐酸盐)、爱克兰片剂(马法兰)、Aloxi(盐酸帕洛诺司琼)、Alunbrig(布加替尼)、Ambochlorin(苯丁酸氮芥)、Amboclorin苯丁酸氮芥)、氨磷汀、氨基酮戊酸、阿那曲唑、阿瑞匹坦、Aredia(帕米膦酸二钠)、Arimidex(阿那曲唑)、Aromasin(依西美坦)、Arranon(奈拉滨)、三氧化二砷、Arzerra(奥法木单抗)、天冬酰胺酶菊欧文氏菌、阿特珠单抗、Avastin(贝伐单抗)、阿维鲁单抗、阿昔替尼、阿扎胞苷、Bavencio(阿维鲁单抗)、BEACOPP、Becenum(卡莫司汀)、Beleodaq(贝利司他)、贝利司他、盐酸苯达莫司汀、BEP、Besponsa(伊诺图珠单抗-奥佐伽米星)、贝伐单抗、贝沙罗汀、Bexxar(托西妥单抗和碘I 131托西妥单抗)、比卡鲁胺、BiCNU(卡莫司汀)、博来霉素、博纳吐单抗、Blincyto(博纳吐单抗)、硼替佐米、Bosulif(博舒替尼)、博舒替尼、本妥昔单抗韦多汀、布加替尼、BuMel、白消安、Busulfex(白消安)、卡巴他赛、Cabometyx(苹果酸卡博替尼)、苹果酸卡博替尼、CAF、Campath(阿仑单抗)、Camptosar、(盐酸伊立替康)、卡培他滨、CAPOX、Carac(氟尿嘧啶--局部)、卡铂、卡铂-TAXOL、卡菲偌米布、Carmubris(卡莫司汀)、卡莫司汀、卡莫司汀移植、Casodex(比卡鲁胺)、CEM、色瑞替尼、Cerubidine(多柔比星盐酸盐)、Cervarix(重组HPV二价疫苗)、西妥昔单抗、CEV、苯丁酸氮芥、苯丁酸氮芥-强的松、CHOP、顺铂、克拉屈滨、Clafen(环磷酰胺)、氯法拉滨、Clofarex(氯法拉滨)、Clolar(氯法拉滨)、CMF、卡比替尼、Cometriq(苹果酸卡博替尼)、库潘尼西盐酸盐、COPDAC、COPP、COPP-ABV、Cosmegen(放线菌素D)、Cotellic(卡比替尼)、克唑替尼、CVP、环磷酰胺、Cyfos(异环磷酰胺)、Cyramza(雷莫芦单抗)、阿糖胞苷、阿糖胞苷脂质体、Cytosar-U(阿糖胞苷)、Cytoxan(环磷酰胺)、达拉非尼、达卡巴嗪、Dacogen(地西他滨)、放线菌素D、达雷妥尤单抗、Darzalex(达雷妥尤单抗)、达沙替尼、多柔比星盐酸盐、多柔比星盐酸盐和阿糖胞苷脂质体、地西他滨、去纤苷钠、Defitelio(去纤苷钠)、Degarelix、地尼白介素、地诺单抗、DepoCyt(阿糖胞苷脂质体)、地塞米松、盐酸右雷佐生、地诺妥昔单抗、多西他赛、Doxil(盐酸多柔比星脂质体)、盐酸多柔比星、盐酸多柔比星脂质体、Dox-SL(盐酸多柔比星脂质体)、DTIC-Dome(达卡巴嗪)、德瓦鲁单抗、Efudex(氟尿嘧啶--局部)、Elitek(拉布立酶)、Ellence(盐酸表柔比星)、埃罗妥珠单抗、Eloxatin(奥沙利铂)、艾曲泊帕、Emend(阿瑞匹坦)、Empliciti(埃罗妥珠单抗)、甲磺酸依那西汀、恩杂鲁胺、盐酸表柔比星、EPOCH、Erbitux(西妥昔单抗)、甲磺酸艾瑞布林、Erivedge(维莫德吉)、盐酸厄洛替尼、Erwinaze(天冬酰胺酶菊欧文氏菌)、Ethyol(阿米福汀)、Etopophos(磷酸依托泊苷)、依托泊苷、磷酸依托泊苷、Evacet(盐酸多柔比星脂质体)、依维莫司、易维特、(盐酸雷洛昔芬)、Evomela(盐酸马法兰)、依西美坦、5-FU(氟尿嘧啶注射)、5-FU(氟尿嘧啶--局部)、Fareston(托瑞米芬)、Farydak(帕比司他)、Faslodex(氟维司群)、FEC、Femara(来曲唑)、非格司亭、Fludara(磷酸氟达拉滨)、磷酸氟达拉滨、Fluoroplex(氟尿嘧啶--局部)、氟尿嘧啶注射、氟尿嘧啶--局部、氟他胺、Folex(甲氨蝶呤)、Folex PFS(甲氨蝶呤)、FOLFIRI、FOLFIRI-贝伐单抗、FOLFIRI-西妥昔单抗、FOLFIRINOX、FOLFOX、Folotyn(普拉曲沙)、FU-LV、氟维司群、加德西(重组HPV四价疫苗)、加德西9(重组HPV九价疫苗)、Gazyva(奥滨尤妥珠单抗)、吉非替尼、盐酸吉西他滨、吉西他滨-顺铂、吉西他滨-奥沙利铂、吉妥单抗奥佐米星、Gemzar(盐酸吉西他滨)、Gilotrif(阿法替尼二马来酸盐)、Gleevec(甲磺酸伊马替尼)、Gliadel(卡莫司汀移植)、Gliadel wafer(卡莫司汀移植)、谷卡匹酶、醋酸戈舍瑞林、Halaven(甲磺酸艾瑞布林)、Hemangeol(盐酸普萘洛尔)、Herceptin(曲妥珠单抗)、重组HPV二级疫苗、重组HPV九价疫苗、、重组HPV四价疫苗、Hycamtin(盐酸拓扑替康)、Hydrea(羟基脲)、羟基脲、Hyper-CVAD、Ibrance(帕博西尼)、替坦异贝莫单抗、依鲁替尼、ICE、Iclusig(盐酸帕纳替尼)、Idamycin(盐酸伊达比星)、盐酸伊达比星、艾代拉里斯、Idhifa(甲磺酸依那西汀)、Ifex(异环磷酰胺)、异环磷酰胺、Ifosfamidum(异环磷酰胺)、IL-2(阿地白介素)、甲磺酸伊马替尼、Imbruvica(依鲁替尼)、Imfinzi(德瓦鲁单抗)、咪喹莫特、Imlygic(Talimogene Laherparepvec)、Inlyta(阿西替尼)、奥英妥珠单抗奥加米星、重组干扰素α-2b、白介素-2(阿地白介素)、Intron A(重组干扰素α-2b)、碘I 131托西妥单抗和托西妥单抗、伊匹单抗、Iressa(吉非替尼)、盐酸伊立替康、盐酸伊立替康脂质体、Istodax(罗米地辛)、伊沙匹隆、枸橼酸艾沙佐米、Ixempra(伊沙匹隆)、Jakafi(磷酸鲁索利替尼)、JEB、Jevtana(卡巴他赛)、Kadcyla(Ado-曲妥珠单抗美坦新)、Keoxifene(盐酸雷洛昔芬)、Kepivance(帕利夫明)、Keytruda(派姆单抗)、Kisqali(瑞博西尼)、Kymriah(Tisagenlecleucel)、Kyprolis(卡菲偌米布)、醋酸兰瑞肽、二甲苯磺酸拉帕替尼、Lartruvo(奥拉木单抗)、来那度胺、甲磺酸仑伐替尼、Lenvima(甲磺酸仑伐替尼)、来曲唑、亚叶酸钙、Leukeran(苯丁酸氮芥)、醋酸亮丙瑞林、Leustatin(克拉屈滨)、Levulan(氨基酮戊酸)、Linfolizin(苯丁酸氮芥)、LipoDox(盐酸多柔比星脂质体)、洛莫司汀、Lonsurf(三氟尿苷和盐酸替吡拉西)、Lupron(醋酸亮丙瑞林)、Lupron Depot(醋酸亮丙瑞林)、LupronDepot-Ped(醋酸亮丙瑞林)、Lynparza(奥拉帕尼)、Marqibo(硫酸长春新碱脂质体)、Matulane(盐酸甲基苄肼)、盐酸氮芥、醋酸甲地孕酮、Mekinist(曲美替尼)、马法兰、盐酸马法兰、巯嘌呤、美司钠、Mesnex(美司钠)、Methazolastone(替莫唑胺)、甲氨蝶呤、甲氨蝶呤LPF(甲氨蝶呤)、溴化甲基纳曲酮、Mexate(甲氨蝶呤)、Mexate-AQ(甲氨蝶呤)、米哚妥林、丝裂霉素C、盐酸米托蒽醌、Mitozytrex(丝裂霉素C)、MOPP、Mozobil(普乐沙福)、Mustargen(盐酸氮芥)、Mutamycin(丝裂霉素C)、Myleran(白消安)、Mylosar(氮杂胞苷)、Mylotarg(吉妥单抗奥佐米星)、纳米颗粒紫杉醇(紫杉醇白蛋白稳定的纳米颗粒制剂)、Navelbine(酒石酸长春瑞滨)、耐昔妥珠单抗、奈拉滨、Neosar(环磷酰胺)、马来酸奈拉替尼、Nerlynx(马来酸奈拉替尼)、奈托匹坦和盐酸帕洛诺司琼、Neulasta(培非格司亭)、Neupogen(非格司亭)、Nexavar(甲苯磺酸索拉非尼)、Nilandron(尼鲁米特)、尼洛替尼、尼鲁米特、Ninlaro(枸橼酸艾沙佐米)、对甲苯磺酰尼拉普利一水合物、纳武单抗、Nolvadex(枸櫞酸他莫昔芬)、Nplate(罗米司亭)、奥滨尤妥珠单抗、Odomzo(索尼德吉)、OEPA、奥法木单抗、OFF、奥拉帕尼、奥拉木单抗、高三尖杉酯碱、Oncaspar(培门冬酶)、盐酸昂丹司琼、Onivyde(盐酸伊立替康脂质体)、Ontak(地尼白介素)、Opdivo(纳武单抗)、OPPA、奥希替尼、奥沙利铂、紫杉醇、紫杉醇白蛋白稳定的纳米颗粒制剂、PAD、帕博西尼、帕利夫明、盐酸帕洛诺司琼、盐酸帕洛诺司琼和奈妥匹坦、帕米膦酸二钠、帕尼单抗、帕比司他、Paraplat(卡铂)、Paraplatin(卡铂)、盐酸帕佐帕尼、PCV、PEB、培门冬酶、培非格司亭、聚乙二醇干扰素α-2b、PEG-Intron(聚乙二醇干扰素α-2b)、派姆单抗、培美曲塞二钠、Perjeta(帕妥珠单抗)、帕妥珠单抗、Platinol(顺铂)、Platinol-AQ(顺铂)、普乐沙福、泊马度胺、Pomalyst(泊马度胺)、盐酸帕纳替尼、Portrazza(耐昔妥珠单抗)、普拉曲沙、强的松、盐酸甲基苄肼、Proleukin(阿地白介素)、Prolia(地诺单抗)、Promacta(艾曲泊帕)、盐酸普萘洛尔、Provenge(Sipuleucel-T)、Purinethol(巯嘌呤)、Purixan(巯嘌呤)、二氯化镭223、盐酸雷洛昔芬、雷莫芦单抗、拉布立酶、R-CHOP、R-CVP、重组人乳头瘤病毒(HPV)二价疫苗、重组人乳头瘤病毒(HPV)九价疫苗、重组人乳头瘤病毒(HPV)四价疫苗、重组干扰素α-2b、瑞戈菲尼、Relistor(溴化甲基纳曲酮)、R-EPOCH、Revlimid(来那度胺)、Rheumatrex(甲氨蝶呤)、瑞博西尼、R-ICE、Rituxan(利妥昔单抗)、Rituxan Hycela(利妥昔单抗和人透明质酸酶)、利妥昔单抗、利妥昔单抗和人透明质酸酶、、罗拉匹坦盐酸盐、罗米地辛、罗米司亭、Rubidomycin(多柔比星盐酸盐)、Rubraca(瑞卡帕布樟脑磺酸盐)、瑞卡帕布樟脑磺酸盐、磷酸鲁索利替尼、Rydapt(米哚妥林)、胸膜内硬化剂气雾胶(Talc)、塞妥昔单抗、Sipuleucel-T、Somatuline Depot(醋酸兰瑞肽)、索尼德吉、甲苯磺酸索拉非尼、Sprycel(达沙替尼)、STANFORD V、无菌滑石粉(Talc)、Steritalc(Talc)、Stivarga(瑞戈菲尼)、苹果酸舒尼替尼、Sutent(苹果酸舒尼替尼)、Sylatron(聚乙二醇干扰素α-2b)、Sylvant(塞妥昔单抗)、Synribo(高三尖杉酯碱)、Tabloid(硫鸟嘌呤)、TAC、Tafinlar(达拉非尼)、Tagrisso(奥希替尼)、Talc、TalimogeneLaherparepvec、枸櫞酸他莫昔芬、Tarabine PFS(阿糖胞苷)、Tarceva(盐酸厄洛替尼)、Targretin(贝沙罗汀)、Tasigna(尼洛替尼)、Taxol(紫杉醇)、Taxotere(多西他赛)、Tecentriq、(阿特珠单抗)、Temodar(替莫唑胺)、替莫唑胺、替西罗莫司、沙利度胺、Thalomid(沙利度胺)、硫鸟嘌呤、噻替派、Tisagenlecleucel、Tolak(氟尿嘧啶--局部)、盐酸拓扑替康、托瑞米芬、Torisel(替西罗莫司)、托西妥单抗和碘I 131托西妥单抗、Totect(盐酸右雷佐生)、TPF、曲贝替定、曲美替尼、曲妥珠单抗、Treanda(盐酸苯达莫司汀)、三氟尿苷和盐酸替吡拉西、Trisenox(三氧化二砷)、Tykerb(二甲苯磺酸拉帕替尼)、Unituxin(地诺妥昔单抗)、三醋酸尿苷、VAC、凡德他尼、VAMP、Varubi(罗拉匹坦盐酸盐)、Vectibix(帕尼单抗)、VeIP、Velban(硫酸长春碱)、Velcade(硼替佐米)、Velsar(硫酸长春碱)、威罗非尼、Venclexta(维奈妥拉)、维奈妥拉、Verzenio(玻玛西林)、Viadur(醋酸亮丙瑞林)、Vidaza(氮杂胞苷)、硫酸长春碱、Vincasar PFS(硫酸长春新碱)、硫酸长春新碱、硫酸长春新碱脂质体、酒石酸长春瑞滨、VIP、维莫德吉、Vistogard(三醋酸尿苷)、Voraxaze(谷卡匹酶)、伏立诺他、Votrient(盐酸帕佐帕尼)、Vyxeos(多柔比星盐酸盐和阿糖胞苷脂质体)、Wellcovorin(亚叶酸钙)、Xalkori(克唑替尼)、Xeloda(卡培他滨)、XELIRI、XELOX、Xgeva(地诺单抗)、Xofigo(二氯化镭223)、Xtandi(恩杂鲁胺)、Yervoy(伊匹单抗)、Yondelis(曲贝替定)、Zaltrap(Ziv-阿柏西普)、Zarxio(非格司亭)、Zejula(对甲苯磺酰尼拉普利一水合物)、Zelboraf(威罗非尼)、Zevalin(替坦异贝莫单抗)、Zinecard(盐酸右雷佐生)、Ziv-阿柏西普、Zofran(盐酸昂丹司琼)、Zoladex(醋酸戈舍瑞林)、唑来膦酸、Zolinza(伏立诺他)、Zometa(唑来膦酸)、Zydelig(艾代拉里斯)、Zykadia(色瑞替尼)和/或Zytiga(醋酸阿比特龙)。检查点抑制剂包括但不限于阻断PD-1的抗体(纳武单抗(BMS-936558或MDX1106)、CT-011、MK-3475)、PD-L1(MDX-1105(BMS-936559)、MPDL3280A、MSB0010718C)、PD-L2(rHIgM12B7)、CTLA-4(伊匹单抗(MDX-010)、曲美木单抗(CP-675,206))、IDO、B7-H3(MGA271)、B7-H4、TIM3、LAG-3(BMS-986016)。
一方面,本文还公开了如本文公开的水凝胶基质,其进一步包含一种或多种抗体、细胞因子和/或共刺激分子,该共刺激分子活化T细胞、自然杀伤(NK)细胞、NK T细胞、树突状细胞、巨噬细胞、肿瘤浸润性NK细胞(TINK)、肿瘤浸润性淋巴细胞(TIL)或骨髓浸润性淋巴细胞(MIL)。例如,抗体可包含抗CD28、CD3、B7-1、B7-2、抗诱导型共刺激物(ICOS)、ICOS配体、抗CD27、CD70、4-1BBL、抗41-BB、抗CD40L、CD40、抗DAP10、抗CD30、CD30L、抗TIM-1、抗TIM-2、抗TIM-3、抗CD44、抗NK1.1、凝集素样转录物-1(LLT-1)、抗CD137、CD48、MICA、抗2B4、抗糖皮质激素诱导的肿瘤坏死因子受体相关蛋白(GITR);并且细胞因子可以包括IL-2、IL-7、IL-15、IL-21、TNF-α或IFN-γ。
所公开的水凝胶的一个优点是一旦免疫细胞与水凝胶接触,免疫细胞就可以被转导以包含转基因,例如嵌合抗原受体(例如,靶向肿瘤特异性抗原的抗体或scFv)、T细胞受体(例如抗原特异性T细胞受体)、NK细胞受体(包括但不限于抗CD3抗体、CD1d、免疫球蛋白的Fc片段或抗Fcγ受体(Fc RIII)抗体)、NK T细胞受体。肿瘤抗原是由肿瘤细胞产生的蛋白质,可引发免疫应答,尤其是T细胞介导的免疫应答。额外的抗原结合结构域可以是抗体,或肿瘤抗原的天然配体,或识别源自MHC分子呈递的肿瘤抗原的肽的分子。额外抗原结合结构域的选择将取决于待治疗的癌症的特定类型。肿瘤抗原是本领域众所周知的,包括例如神经胶质瘤相关抗原、癌胚抗原(CEA)、EGFRvIII、IL-11Ra、IL-13Ra、EGFR、FAP、B7H3、Kit、CA LX、CS-1、MUC1、BCMA、bcr-abl、HER2、β-人绒毛膜促性腺激素、甲胎蛋白(AFP)、ALK、CD19、CD123、细胞周期蛋白B1、凝集素反应性AFP、Fos相关抗原1、ADRB3、甲状腺球蛋白、EphA2、RAGE-1、RU1、RU2、SSX2、AKAP-4、LCK、OY-TESl、PAX5、SART3、CLL-1、岩藻糖基GM1、GloboH、MN-CA IX、EPCAM、EVT6-AML、TGS5、人端粒酶逆转录酶、唾液酸、PLAC1、RU1、RU2(AS)、肠羧基酯酶、lewisY、sLe、LY6K、mut hsp70-2、M-CSF、MYCN、RhoC、TRP-2、CYPIBI、BORIS、前列腺酶、前列腺特异性抗原(PSA)、PAX3、PAP、NY-ESO-1、LAGE-la、LMP2、NCAM、p53、p53突变体、Ras突变体、gplOO、前列腺素、OR51E2、PANX3、PSMA、PSCA、Her2/neu、hTERT、HMWMAA、HAVCR1、VEGFR2、PDGFR-β、存活蛋白和端粒酶、legumain、HPV E6、E7、精子蛋白17、SSEA-4、酪氨酸酶、TARP、WT1、前列腺癌肿瘤抗原-1(PCTA-1)、ML-IAP、MAGE、MAGE-A1、MAD-CT-1、MAD-CT-2、MelanA/MART 1、XAGE1、ELF2M、ERG(TMPRSS2 ETS融合基因)、NA17、中性粒细胞弹性蛋白酶、肉瘤易位断点、NY-BR-1、ephnnB2、CD20、CD22、CD24、CD30、CD33、CD38、CD44v6、CD97、CD171、CD179a、雄激素受体、FAP、胰岛素生长因子(IGF)-I、IGFII、IGF-I受体、GD2、o-乙酰基-GD2、GD3、GM3、GPRC5D、GPR20、CXORF61、叶酸受体(FRa)、叶酸受体β、ROR1、Flt3、TAG72、TN Ag、Tie 2、TEM1、TEM7R、CLDN6、TSHR、UPK2和间皮素。
1.将组合物递送至细胞
免疫细胞的转导可以通过本领域已知的任何方式发生。一方面,免疫细胞的转导可以通过编码转基因(诸如例如CAR)的病毒载体发生。因此,一方面,本文公开的是任何公开的水凝胶,进一步包含编码转基因,诸如例如嵌合抗原受体(CAR)、T细胞受体、NK细胞受体和/或NK T细胞受体的病毒载体(诸如例如慢病毒、逆转录病毒、腺病毒或腺相关病毒)。
有许多组合物和方法可用于在体外或体内将核酸递送至细胞。这些方法和组合物可大致分为两类:基于病毒的递送系统和基于非病毒的递送系统。例如,可以通过许多直接递送系统递送核酸,例如电穿孔、脂转染、磷酸钙沉淀、质粒、病毒载体、病毒核酸、噬菌体核酸、噬菌体、粘粒、或通过遗传物质在细胞或载体如阳离子脂质体中的转移。合适的转染方法,包括病毒载体、化学转染剂或物理机械方法,例如电穿孔和DNA的直接扩散,例如描述于Wolff,J.A.,et al.,Science,247,1465-1468,(1990);和Wolff,J.A.Nature,352,815-818,(1991)。这样的方法在本领域中是众所周知的,并且容易地适用于本文所述的组合物和方法。在某些情况下,将修改这些方法以使其与大的DNA分子特异性结合。此外,通过使用载体的靶向特征,这些方法可用于靶向某些疾病和细胞种群。
(1)逆转录病毒载体
逆转录病毒是属于逆转录病毒科病毒家族的动物病毒,包括任何类型、亚科、属或趋性。通常,逆转录病毒载体由Verma,I.M.描述,用于基因转移的逆转录病毒载体。
逆转录病毒本质上是在其中包装了核酸货物的包装。核酸货物与它一起带有包装信号,其可确保将复制的子分子有效包装在包装外壳中。除了包装信号外,顺式还需要许多分子来复制和包装复制的病毒。典型地,逆转录病毒基因组包含gag、pol和env基因,其与蛋白外壳的制备有关。正是gag、pol和env基因通常被外源DNA取代,将其转移至靶细胞。逆转录病毒载体通常包含包装信号,用于掺入到包装外壳中,该序列指示gag转录单位的开始,逆转录必需的元件,包括结合逆转录tRNA引物的引物结合位点、指导DNA合成过程中RNA链的转换的末端重复序列、富含嘌呤的5’到3’LTR序列(用作合成DNA合成的第二条链的起始位点),和LTR末端附近的特定序列,其能实现逆转录病毒DNA状态的插入以插入宿主基因组。去除gag,pol和env基因允许将约8kb的外源序列插入病毒基因组,变为逆转录的,并在复制后包装成新的逆转录病毒颗粒。取决于每个转录物的大小,该核酸量足以递送一个至多个基因。优选在插入物中包括正或负选择性标记以及其他基因。
由于大多数逆转录病毒载体中的复制机制和包装蛋白均已被去除(gag,pol和env),因此通常通过将其放入包装细胞系中来产生载体。包装细胞系是已经用含有复制和包装机制但没有任何包装信号的逆转录病毒转染或转化的细胞系。当携带选择的DNA的载体被转染到这些细胞系中时,含有感兴趣的基因的载体通过辅助细胞顺式提供的机制被复制并包装成新的逆转录病毒颗粒。用于机制的基因组未被包装,因为它们缺少必要的信号。
(2)腺病毒载体
复制缺陷腺病毒的构建已被描述(Berkner et al.,J.Virology 61:1213-1220(1987);Massie et al.,Mol.Cell.Biol.6:2872-2883(1986);Haj-Ahmad et al.,J.Virology 57:267-274(1986);Davidson et al.,J.Virology 61:1226-1239(1987);Zhang"Generation and identification of recombinant adenovirus by liposome-mediated transfection and PCR analysis"BioTechniques 15:868-872(1993))。使用这些病毒作为载体的益处是,它们可以传播到其他细胞类型的程度受到限制,因为它们可以在初始感染的细胞内复制,但不能形成新的感染性病毒颗粒。已显示重组腺病毒在体内直接递送至气道上皮、肝细胞、血管内皮、中枢神经系统薄壁组织和许多其他组织部位后,可实现高效的基因转移(Morsy,J.Clin.Invest.92:1580-1586(1993);Kirshenbaum,J.Clin.Invest.92:381-387(1993);Roessler,J.Clin.Invest.92:1085-1092(1993);Moullier,Nature Genetics 4:154-159(1993);La Salle,Science 259:988-990(1993);Gomez-Foix,J.Biol.Chem.267:25129-25134(1992);Rich,Human Gene Therapy 4:461-476(1993);Zabner,Nature Genetics 6:75-83(1994);Guzman,Circulation Research73:1201-1207(1993);Bout,Human Gene Therapy 5:3-10(1994);Zabner,Cell 75:207-216(1993);Caillaud,Eur.J.Neuroscience 5:1287-1291(1993)和Ragot,J.Gen.Virology74:501-507(1993))。重组腺病毒通过与特定细胞表面受体结合实现基因转导,然后病毒以与野生型或复制缺陷型腺病毒相同方式通过受体介导的内吞作用被内化(Chardonnet andDales,Virology 40:462-477(1970);Brown and Burlingham,J.Virology 12:386-396(1973);Svensson and Persson,J.Virology55:442-449(1985);Seth,et al.,J.Virol.51:650-655(1984);Seth,et al.,Mol.Cell.Biol.4:1528-1533(1984);Varga etal.,J.Virology 65:6061-6070(1991);Wickham et al.,Cell 73:309-319(1993))。
病毒载体可以是基于已经去除了E1基因的腺病毒的载体,这些病毒体在诸如人293细胞系的细胞系中产生。在另一个优选的实施例中,E1和E3基因均从腺病毒基因组中去除。
(3)腺相关病毒载体
另一种类型的病毒载体基于腺相关病毒(AAV)。这种有缺陷的细小病毒是优选的载体,因为它可以感染许多细胞类型,并且对人类无致病性。AAV型载体可以转运约4至5kb,而已知野生型AAV可以稳定地插入到19号染色体中(诸如例如在AAV整合位点1(AAVS1))。包含此位点特异性整合性质的载体是优选的。该类型载体的一个特别优选的实施例是由Avigen,San Francisco,CA生产的P4.1 C载体,它可以包含单纯疱疹病毒胸苷激酶基因HSV-tk和/或标记基因,例如编码绿色荧光蛋白GFP的基因。
在另一种类型的AAV病毒中,AAV包含一对反向末端重复序列(ITR),其位于至少一个含有启动子的盒的侧面,所述启动子指导与异源基因可操作地连接的细胞特异性表达。在本上下文中,异源是指对于AAV或B19细小病毒不是天然的任何核苷酸序列或基因。
通常,AAV和B19编码区已被删除,形成了安全的无细胞毒性的载体。AAV ITR或其修饰赋予感染性和位点特异性整合,但不赋予细胞毒性,且启动子指导细胞特异性表达。对于与AAV载体有关的材料,通过引用将美国专利号6,261,834并入本文。
因此,所公开的载体提供了能够整合到哺乳动物染色体中而没有实质毒性的DNA分子。
病毒和逆转录病毒中插入的基因通常包含启动子和/或增强子,以帮助控制期望的基因产物的表达。启动子通常是在相对于转录起始位点处于相对固定位置时起作用的一个或多个DNA序列。启动子包含RNA聚合酶和转录因子的基本相互作用所需的核心元件,并且可以包含上游元件和响应元件。
(4)大有效载荷病毒载体
用大型人疱疹病毒进行的分子遗传实验提供了一种手段,借此可以在允许疱疹病毒感染的细胞中克隆、繁殖和建立大的异源DNA片段(Sun et al.,Nature genetics 8:33-41,1994;Cotter and Robertson,.Curr Opin Mol Ther5:633-644,1999)。这些大型DNA病毒(单纯疱疹病毒(HSV)和爱泼斯坦巴尔病毒(EBV))具有将>150kb的人类异源DNA片段递送至特定细胞的潜力。EBV重组体可以将感染的B细胞中的大块DNA保持作为附加体DNA。携带高达330kb的人类基因组插入片段的单个克隆似乎具有遗传稳定性。这些附加体的维持需要特定的EBV核蛋白EBNA1,在EBV感染期间组成型表达。另外,这些载体可以用于转染,其中可以在体外瞬时产生大量蛋白质。疱疹病毒扩增子系统还被用于包装>220kb的DNA片段,并感染可以稳定地将DNA保持为附加体的细胞。
其他有用的系统包括,例如,复制型和宿主限制性非复制型痘苗病毒载体。
2.表达系统
递送至细胞的核酸通常包含表达控制系统。例如,病毒和逆转录病毒系统中插入的基因通常包含启动子和/或增强子,以帮助控制期望的基因产物的表达。启动子通常是在相对于转录起始位点处于相对固定位置时起作用的一个或多个DNA序列。启动子包含RNA聚合酶和转录因子的基本相互作用所需的核心元件,并且可以包含上游元件和响应元件。
a)病毒启动子和增强子
优选的控制哺乳动物宿主细胞中载体转录的启动子可以从各种来源获得,例如病毒的基因组,诸如:多瘤病毒、猿猴病毒40(SV40)、腺病毒、逆转录病毒、乙型肝炎病毒和最优选巨细胞病毒,或来自异源的哺乳动物启动子,例如-型肝炎病毒和最优选巨细胞病毒,或来自异源的哺乳动物启动子,例如β肌动蛋白启动子。方便地获得SV40病毒的早期和晚期启动子作为SV40限制性片段,其也包含SV40病毒复制起点(Fiers et al.,Nature,273:113(1978))。人巨细胞病毒的立即早期启动子可以方便地以HindIII E限制性片段的形式获得(Greenway,P.J.et al.,Gene 18:355-360(1982))。当然,来自宿主细胞或相关物种的启动子也可用于本文。
增强子通常是指在距转录起始位点不固定距离处起作用的DNA序列,并且相对转录单位可以是5’(Laimins,L.et al.,Proc.Natl.Acad.Sci.78:993(1981))或3'(Lusky,M.L.,et al.,Mol.Cell Bio.3:1108(1983))。此外,增强子可以位于内含子内(Banerji,J.L.et al.,Cell 33:729(1983))以及编码序列本身(Osborne,T.F.,et al.,Mol.CellBio.4:1293(1984)。它们的长度通常在10至300bp之间,并且它们以顺式起作用。增强子起作用以增加附近启动子的转录。增强子通常还包含介导转录调控的反应元件。启动子还可以包含介导转录调控的反应元件。增强子通常决定基因表达的调控。虽然现在从哺乳动物基因(球蛋白、弹性蛋白酶、白蛋白、-甲胎蛋白和胰岛素)中已知许多增强子序列,但通常会使用来自真核细胞病毒的增强子进行一般表达。优选的实例是在复制起点的后侧(bp 100-270)上的SV40增强子、巨细胞病毒早期启动子增强子、复制起点的后侧上的多瘤增强子和腺病毒增强子。
启动子和/或增强子可以被光或触发其功能的特定化学事件特异性活化。系统可以通过诸如四环素和地塞米松的试剂进行调节。还存在通过暴露于辐射(例如,γ辐射)或烷基化化疗药物来增强病毒载体基因表达的方法。
在某些实施例中,启动子和/或增强子区域可以用作组成型启动子和/或增强子,以最大化要转录的转录单位区域的表达。在某些构建体中,启动子和/或增强子区域在所有真核细胞类型中均具有活性,即使它仅在特定时间在特定类型的细胞中表达。这种类型的优选启动子是CMV启动子(650个碱基)。其他优选的启动子是SV40启动子,巨细胞病毒(全长启动子)和逆转录病毒载体LTR。
已经表明,可以克隆所有特异性调控元件,并用于构建在特定细胞类型例如黑素瘤细胞中选择性表达的表达载体。胶质原纤维乙酸蛋白(GFAP)启动子已用于在胶质来源的细胞中选择性表达基因。
真核宿主细胞(酵母、真菌、昆虫、植物、动物、人或有核细胞)中使用的表达载体也可能包含终止转录所必需的序列,这可能会影响mRNA的表达。这些区域在编码组织因子蛋白的mRNA的未转译部分中转录为聚腺苷酸化片段。3’非转译区还包括转录终止位点。优选地,转录单元还包含聚腺苷酸化区域。该区域的一个益处是,它增加了转录单位像mRNA一样被加工和运输的可能性。在表达构建体中多腺苷酸化信号的鉴定和使用已被很好地建立。优选地,在转基因构建体中使用同源的聚腺苷酸化信号。在某些转录单位中,聚腺苷酸化区衍生自SV40早期聚腺苷酸化信号,并且由约400个碱基组成。还优选的是转录的单元单独或与上述序列组合包含其他标准序列,以改善构建体的表达或稳定性。
b)标记物
病毒载体可以包括编码标记产物的核酸序列。该标记产物用于确定基因是否已被递送至细胞并且一旦被递送就被表达。优选的标记基因是大肠杆菌(E.Coli)lacZ基因,它编码β-半乳糖苷酶和绿色荧光蛋白。
在一些实施例中,标记可以是选择性标记。哺乳动物细胞的合适选择性标记的实例是二氢叶酸还原酶(DHFR)、胸苷激酶、新霉素、新霉素类似物G418、潮霉素和嘌呤霉素。当这样的选择性标记成功地转移到哺乳动物宿主细胞中时,如果置于选择性压力下,则转化的哺乳动物宿主细胞可以存活。有两种广泛使用的不同类别的选择制度。第一类是基于细胞的新陈代谢和突变细胞系的使用,该突变细胞系缺乏独立于补充培养基生长的能力。两个实例是:CHO DHFR-细胞和小鼠LTK-细胞。这些细胞缺乏不添加诸如胸苷或次黄嘌呤的营养物的生长能力。由于这些细胞缺乏完整核苷酸合成途径必需的某些基因,因此除非在补充培养基中提供缺失的核苷酸,否则它们将无法生存。补充培养基的替代方法是将完整的DHFR或TK基因导入缺乏相应基因的细胞中,从而改变其生长要求。未用DHFR或TK基因转化的单个细胞将无法在非补充培养基中存活。
第二类是显性选择,其是指在任何细胞类型中使用的选择方案,并且不需要使用突变细胞系。这些方案通常使用药物来阻止宿主细胞的生长。具有新基因的那些细胞将表达传递耐药性的蛋白质,并使选择存活下来。这种显性选择的实例使用药物新霉素,(Southern P.and Berg,P.,J.Molec.Appl.Genet.1:327(1982)),霉酚酸,(Mulligan,R.C.and Berg,P.Science 209:1422(1980))或潮霉素(Sugden,B.et al.,Mol.Cell.Biol.5:410-413(1985))。这三个实例采用了在真核生物对照下的细菌基因来分别传递对适当药物G418或新霉素(遗传霉素)、xgpt(霉酚酸)或潮霉素的耐药性。其他包括新霉素类似物G418和嘌呤霉素。
3.药物载体/药品的递送
如上所述,这些组合物也可以药学上可接受的载体施用到体内。“药学上可接受”意指非生物学上或其他方面不良的材料,即,该材料可与核酸或载体一起施用到受试者,不会造成任何不良生物效应或以有害方式与含其的药物组合物的任何其他组分相互作用。如本领域技术人员所熟知,该载体将自然地被选择,以最小化该活性成分的任何降解,并最小化该受试者中的任何不利副作用。
可经口服、肠胃外(例如静脉)、肌肉注射、腹腔注射、经皮、体外、局部等方式施用组合物,包括局部鼻内施用或通过吸入剂施用。如本文所用,“局部鼻内施用”意指通过一个或两个鼻孔将该组合物递送至鼻腔和鼻腔通道,且可包括通过喷雾机制或液滴机制递送,或通过核酸或载体的雾化递送。通过吸入剂的组合物的施用是经鼻腔或口腔、通过喷雾或液滴机制递送。通过插管,递送也可以直接到达呼吸系统的任何区域(例如肺)。所需组合物的确切数量因受试者而异,具体取决于受试者的物种、年龄、体重和一般情况、所治疗过敏性障碍的严重程度、所使用的特定核酸或载体、其施用方式等。因此,不可能为每种组合物指定确切数量。然而,适当的量可以由本领域的普通技术人员通过仅使用本文给出教导的常规实验来确定。
该组合物的肠外施用(如果使用)通常以注射为特征。注射剂可以制备成常规形式,可以是液体溶液或悬浮液,也可以是适合在注射前于液体中溶解悬浮液的固体形式,或者是乳剂。最近修订的肠外施用方法包括使用缓释或缓释系统,以保持恒定剂量。参见,例如,美国专利号3,610,795,其通过引用并入本文。
材料可以是溶液、悬浮液(例如,并入微粒、脂质体或细胞中)。它们可能通过抗体、受体或受体配体靶向于特定的细胞类型。以下参考文献是利用该技术将特定蛋白质靶向肿瘤组织的实例(Senter,et al.,Bioconjugate Chem.,2:447-451,(1991);Bagshawe,K.D.,Br.J.Cancer,60:275-281,(1989);Bagshawe,et al.,Br.J.Cancer,58:700-703,(1988);Senter,et al.,Bioconjugate Chem.,4:3-9,(1993);Battelli,et al.,CancerImmunol.Immunother.,35:421-425,(1992);Pietersz and McKenzie,Immunolog.Reviews,129:57-80,(1992);and Roffler,et al.,Biochem.Pharmacol,42:2062-2065,(1991))。“隐形”和其他抗体缀合的脂质体(包括脂质介导的针对结肠癌的药物)、通过细胞特异性配体的受体介导的DNA靶向、淋巴细胞介导的肿瘤靶向和体内小鼠胶质瘤细胞的高特异性治疗性逆转录病毒靶向等载体。以下参考文献是利用该技术将特定蛋白质靶向肿瘤组织的实例(Hughes et al.,Cancer Research,49:6214-6220,(1989);和Litzinger and Huang,Biochimica et Biophysica Acta,1104:179-187,(1992))。一般来说,受体参与内吞作用的通路,无论是组成性的还是配体诱导的。这些受体聚集在网格蛋白所包被的小窝中,通过网格蛋白所包被的囊泡进入细胞,通过对受体进行分类的酸化的核内体,然后循环到细胞表面、在细胞内储存,或在溶酶体中降解。内化通路具有多种功能,如营养吸收、活化蛋白去除、大分子清除、病毒和毒素的机会性进入、配体的解离和降解、以及受体水平的调节等。根据细胞类型、受体浓度、配体类型、配体价态和配体浓度,许多受体遵循不止一个细胞内通路。综述了受体介导的内吞作用的分子和细胞机制(Brown和Greene,DNA and Cell Biology 10:6,399-409(1991))。
a)药学上可接受的载体
组合物包括抗体,可在治疗上与药学上可接受的载体结合使用。
合适的载体及其制剂在以下文献中有所描述:Remington:The Science andPractice of Pharmacy(第19版),A.R.Gennaro,Mack Publishing Company,Easton,PA1995。通常,在该制剂中使用适当量的药学上可接受的盐以使该制剂等渗。药学上可接受的载体的实例包括但不限于生理盐水、林格氏溶液和葡萄糖溶液。该溶液的pH值优选为约5至约8,且更优选为约7至约7.5。载体还包括缓释制剂,诸如含有抗体的固体疏水性聚合物的半透膜基质,其基质为成型制品的形式,例如,膜、脂质体或微粒。对于本领域技术人员来说,显而易见的是,某些载体可能更可取,例如取决于施用途径和所施用的组合物的浓度。
本领域技术人员已知药物载体。这些通常是给人类施用药物的标准载体,包括无菌水、生理盐水和生理pH下的缓冲液等溶液。这些组合物可以肌内施用或皮下施用。其他化合物将根据本领域技术人员使用的标准程序施用。
除了所选择的分子,药物组合物可包括载体、增稠剂、稀释剂、缓冲剂、防腐剂、表面活性剂等。药物组合物还可包括一种或多种活性成分,诸如抗菌剂、抗炎剂、麻醉剂等。
根据是否需要局部或全身治疗以及治疗区域的不同,药物组合物可以多种方式施用。施用可以是局部(包括眼、阴道、直肠、鼻内)、口服、吸入或肠胃外,例如静脉滴注、皮下、腹腔或肌肉注射。所公开的抗体可经静脉、腹腔、肌肉、皮下、腔内或经皮施用。
用于肠外施用的制剂包括无菌水溶液或非水溶液、悬浮液和乳剂。非水溶剂的实例有丙二醇、聚乙二醇、植物油(如橄榄油)和可注射有机酯(如油酸乙酯)。水载体包括水、酒精/水溶液、乳剂或悬浮液,包括生理盐水和缓冲介质。肠外载体包括氯化钠溶液、林格氏葡萄糖、葡萄糖和氯化钠、乳酸林格氏液或固定油。静脉注射载体包括液体和营养补充剂、电解质补充剂(如基于林格氏葡萄糖的补充剂)等。防腐剂和其他添加剂也可以存在,诸如例如,抗菌剂、抗氧化剂、螯合剂和惰性气体等。
局部施用制剂可包括软膏、乳液、面霜、凝胶、滴剂、栓剂、喷雾剂、液体和粉末。传统的药物载体、水、粉末或油性碱、增稠剂等可能是必要的或可取的。
口服施用组合物包括粉末或颗粒、水或非水介质中的悬浮液或溶液、胶囊、袋剂或片剂。增稠剂、香料、稀释剂、乳化剂、分散助剂或粘合剂可能是可取的。
一些组合物可潜在地作为药学上可接受的酸或碱加成盐给施用,并通过无机酸(如盐酸、氢溴酸、高氯酸、硝酸、硫氰酸、硫酸和磷酸)和有机酸(如甲酸、乙酸、丙酸、乙醇酸、乳酸、丙酮酸、草酸、丙二酸、琥珀酸、马来酸和延胡索酸)反应形成,或无机碱(如氢氧化钠、氢氧化铵、氢氧化钾)和有机碱(如一、二、三烷基和芳基胺及取代乙醇胺)反应形成。
b)治疗用途
可以凭经验确定施用组合物的有效剂量和时间表,并且进行这种确定在本领域技术范围内。组合物的施用剂量范围应足够大,以产生所需的效果,从而影响障碍的症状。剂量不应太大以致引起不利副作用,例如不希望的交叉反应、过敏反应等。通常,剂量将随患者的年龄、病症、性别和疾病程度、施用途径或方案中是否包括其他药物而变化,并且可以通过本领域技术人员来确定。如果有任何禁忌症,也可以由个体医生来调整剂量。剂量可以变化,并且可以每天一剂量或多剂量施用,持续一天或几天。对于给定类别的药品,可以在文献中找到针对适当剂量的指南。例如,在抗体治疗用途的文献中可以找到选择适当剂量抗体的指南,例如,Handbookof Monoclonal Antibodies,Ferrone et al.,eds.,NogesPublications,Park Ridge,N.J.,(1985)ch.22and pp.303-357;Smith et al.,Antibodies in Human Diagnosis and Therapy,Haber et al.,eds.,Raven Press,NewYork(1977)pp.365-389。根据上述因素,单独使用的抗体的典型每日剂量可能在每天约1μg/kg至100mg/kg体重或以上的范围内。
C.转导免疫细胞的方法
应理解并在本文中预期所公开的水凝胶可用于将免疫细胞(诸如例如,T细胞、NK细胞、NK T细胞、树突状细胞、巨噬细胞、TINK、TIL和/或MIL)吸引至水凝胶,在那里可以体内进行免疫细胞转导。一方面,本文公开了在受试者中转导免疫细胞(诸如例如,T细胞、NK细胞、NK T细胞、树突状细胞、巨噬细胞、TINK、TIL或MIL)的方法,该方法包括向受试者施用水凝胶,该水凝胶包含一种或多种化学引诱剂(诸如例如,CCL1、CCL5、CCL19、CCL21、CCL22、CCL28、CXCL1、CXCL9、CXCL10、CXCL11、CXCL12、M-CSF、GM-CSF、MCP-1、MCP-3、CCL2、CCL3、CCL7、CCL20、CX3CL1、BRAK、IL-12、S1P和/或MCP2)和编码转基因(诸如例如,CAR、NK细胞受体(包括但不限于抗CD3抗体、CD1d、免疫球蛋白的Fc片段或抗Fcγ受体(Fc RIII)抗体)、T细胞受体(例如抗原特异性T细胞受体)或NK T细胞受体)的病毒载体(例如慢病毒、逆转录病毒、腺病毒或腺相关病毒)。
应当理解并在本文中考虑可以在向受试者施用之前或在向受试者施用水凝胶基质之后约1天至约14天将病毒载体引入到水凝胶基质中。也就是说,病毒载体可以在体内被引入到水凝胶中。例如,病毒载体可以在水凝胶凝胶化过程中引入;在凝胶化之后,但在向受试者施用水凝胶之前;或向受试者施用水凝胶后1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20或21天。
应理解并在本文中预期所公开的化学引诱剂将随着时间从水凝胶中浸出或从水凝胶中释放并将免疫细胞吸引至水凝胶,其中所述免疫细胞(例如,T细胞、NK细胞、NK T细胞、树突状细胞、巨噬细胞、TINK、TIL或MIL)可以用转基因例如嵌合抗原受体、NK T细胞受体、NK细胞受体(包括但不限于抗CD3抗体、CD1d、免疫球蛋白的Fc片段或抗Fcγ受体(FcRIII)抗体)或T细胞受体(包括但不限于抗原特异性T细胞受体)来转导。一方面,化学引诱剂的释放可以在施用水凝胶之后1小时至施用水凝胶之后约12周。例如,化学引诱剂的释放可从施用水凝胶之后约1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、28、30、36、42、48、60、72小时,4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、28、30、31天,5、6、7、8、9、10、11或12周。因此,一方面,本文公开了转导免疫细胞的方法,其中一种或多种化学引诱剂在施用水凝胶后约1小时至施用水凝胶后约12周释放。可以通过在胶凝之前或之后将化学引诱剂施加到水凝胶聚合物来修改化学引诱剂的释放时间,其中在胶凝之后施加导致更快的释放时间并且在胶凝期间或之前将化学引诱剂施加到聚合物导致更慢的释放。
一方面,认识到免疫细胞可受益于额外的刺激以维持细胞或活化所述免疫细胞以用于治疗。因此,一方面,本文公开的是转导方法,其中水凝胶进一步包含一种或多种抗体、细胞因子和/或共刺激分子,该共刺激分子活化T细胞、NK细胞、NK T细胞、树突状细胞、巨噬细胞、TINK、TIL或MIL。例如,抗体可包含抗CD28、CD3、B7-1、B7-2、抗诱导型共刺激物(ICOS)、ICOS配体、抗CD27、CD70、4-1BBL、抗41-BB、抗CD40L、CD40、抗DAP10、抗CD30、CD30L、抗TIM-1、抗TIM-2、抗TIM-3、抗CD44、抗NK1.1、凝集素样转录物-1(LLT-1)、抗CD137、CD48、MICA、抗2B4、抗糖皮质激素诱导的肿瘤坏死因子受体相关蛋白(GITR);并且细胞因子可以包括IL-2、IL-7、IL-15、IL-21、TNF-α或IFN-γ。
D.治疗癌症的方法
在一个方面,本文公开了治疗、预防、抑制和/或减弱受试者的癌症或转移的方法,该方法包括向受试者施用本文所公开的任何水凝胶基质。例如,本文公开了治疗受试者的癌症的方法,包括向受试者施用包含一种或多种化学引诱剂的水凝胶基质,其中所述一种或多种化学引诱剂包括C-C基序趋化因子配体(CCL)1(CCL1)、CCL5、CCL19、CCL21、CCL22、CCL28、C-X-C基序趋化因子配体(CXCL)1(CXCL1)、CXCL9、CXCL10、CXCL11或CXCL CXCL12、M-CSF、GM-CSF、MCP-1、MCP-3、CCL2、CCL3、CCL7、CCL20、CX3CL1、BRAK、IL-12、S1P和/或MCP212;并且其中化学引诱剂将免疫细胞(诸如例如,T细胞、NK细胞、NK T细胞、树突状细胞、巨噬细胞、TINK、TIL或MIL)吸引并保留到水凝胶。
一方面,本文公开治疗、预防、抑制和/或减少癌症或转移的方法中使用的水凝胶可进一步包含编码嵌合抗原受体(CAR)、NK细胞受体(包括但不限于抗CD3抗体、CD1d、免疫球蛋白的Fc片段、或抗Fcγ受体(Fc RIII)抗体)、NK T细胞受体或T细胞受体(TCR)(包括但不限于抗原-特异性T细胞受体)的病毒载体。一方面,病毒载体转导免疫细胞;并且转导的免疫细胞从水凝胶释放到癌症。应当理解并在本文中考虑可以在向受试者施用之前或在向受试者施用水凝胶基质之后约1天至约14天将病毒载体引入到水凝胶基质中。也就是说,病毒载体可以在体内被引入到水凝胶中。例如,病毒载体可以在水凝胶凝胶化过程中引入;在凝胶化之后,但在向受试者施用水凝胶之前;或向受试者施用水凝胶后1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20或21天。
应理解并在本文中预期所公开的化学引诱剂将随着时间从水凝胶中浸出或从水凝胶中释放并将免疫细胞吸引至水凝胶,其中所述免疫细胞(例如,T细胞、NK细胞、NK T细胞、树突状细胞、巨噬细胞、TINK、TIL或MIL)可以用转基因例如嵌合抗原受体、T细胞受体、NK细胞受体和/或NK T细胞受体来转导。一方面,化学引诱剂的释放可以在施用水凝胶之后1小时至施用水凝胶之后约12周。例如,化学引诱剂的释放可从施用水凝胶之后约1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、28、30、36、42、48、60、72小时,4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、28、30、31天,5、6、7、8、9、10、11或12周。因此一方面,本文公开了治疗、预防、抑制和/或减少癌症或转移的方法,其中一种或多种化学引诱剂在施用水凝胶后约1小时至施用水凝胶后约12周释放。可以通过在胶凝之前或之后将化学引诱剂施加到水凝胶聚合物来修改化学引诱剂的释放时间,其中在胶凝之后施加导致更快的释放时间并且在胶凝期间或之前将化学引诱剂施加到聚合物导致更慢的释放。
类似地,应当理解并在本文中考虑了所公开的水凝胶相对于传统CAR疗法的一个优点是CAR T细胞、CAR NK细胞、CAR NK T细胞、CARMA、TINK、MIL或TIL缓慢释放到肿瘤微环境中。应理解并在本文中考虑免疫细胞(诸如例如,T细胞、NK细胞、NK T细胞、树突状细胞、巨噬细胞、TINK、TIL或MIL)的释放可在施用水凝胶之后1小时至约12周。例如,化学引诱剂的释放可从施用水凝胶之后约1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、28、30、36、42、48、60、72小时,4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、28、30、31天,5、6、7、8、9、10、11或12周。因此,一方面,本文公开了治疗、预防、抑制和/或减少癌症或转移的方法,其中在施用水凝胶后约1周至约12周释放免疫细胞。
应当理解并在本文中考虑到,在所公开的治疗、预防、抑制和/或减少癌症或转移的方法中使用的所公开的水凝胶基质可以进一步包含一种或多种免疫阻断抑制剂和/或化疗剂。可用于所公开的水凝胶基质的化学治疗剂可包括本领域已知的任何化学治疗剂,包括但不限于玻玛西林、醋酸阿比特龙、Abitrexate(甲氨蝶呤)、Abraxane(紫杉醇白蛋白稳定的纳米颗粒制剂)、ABVD、ABVE、ABVE-PC、AC、AC-T、Adcetris(本妥昔单抗韦多汀)、ADE、Ado-曲妥珠单抗美坦新、阿霉素(盐酸多柔比星)、阿法替尼二马来酸盐、Afinitor(依维莫司)、Akynzeo(奈托匹坦和盐酸帕洛诺司琼)、Aldara(咪喹莫特)、阿地白介素、Alecensa(阿来替尼)、阿来替尼、阿仑单抗、Alimta(培美曲塞二钠)、Aliqopa(库潘尼西盐酸盐)、注射用爱克兰(马法兰盐酸盐)、爱克兰片剂(马法兰)、Aloxi(盐酸帕洛诺司琼)、Alunbrig(布加替尼)、Ambochlorin(苯丁酸氮芥)、Amboclorin苯丁酸氮芥)、氨磷汀、氨基酮戊酸、阿那曲唑、阿瑞匹坦、Aredia(帕米膦酸二钠)、Arimidex(阿那曲唑)、Aromasin(依西美坦)、Arranon(奈拉滨)、三氧化二砷、Arzerra(奥法木单抗)、天冬酰胺酶菊欧文氏菌、阿特珠单抗、Avastin(贝伐单抗)、阿维鲁单抗、阿昔替尼、阿扎胞苷、Bavencio(阿维鲁单抗)、BEACOPP、Becenum(卡莫司汀)、Beleodaq(贝利司他)、贝利司他、盐酸苯达莫司汀、BEP、Besponsa(伊诺图珠单抗-奥佐伽米星)、贝伐单抗、贝沙罗汀、Bexxar(托西妥单抗和碘I 131托西妥单抗)、比卡鲁胺、BiCNU(卡莫司汀)、博来霉素、博纳吐单抗、Blincyto(博纳吐单抗)、硼替佐米、Bosulif(博舒替尼)、博舒替尼、本妥昔单抗韦多汀、布加替尼、BuMel、白消安、Busulfex(白消安)、卡巴他赛、Cabometyx(苹果酸卡博替尼)、苹果酸卡博替尼、CAF、Campath(阿仑单抗)、Camptosar、(盐酸伊立替康)、卡培他滨、CAPOX、Carac(氟尿嘧啶--局部)、卡铂、卡铂-TAXOL、卡菲偌米布、Carmubris(卡莫司汀)、卡莫司汀、卡莫司汀移植、Casodex(比卡鲁胺)、CEM、色瑞替尼、Cerubidine(多柔比星盐酸盐)、Cervarix(重组HPV二价疫苗)、西妥昔单抗、CEV、苯丁酸氮芥、苯丁酸氮芥-强的松、CHOP、顺铂、克拉屈滨、Clafen(环磷酰胺)、氯法拉滨、Clofarex(氯法拉滨)、Clolar(氯法拉滨)、CMF、卡比替尼、Cometriq(苹果酸卡博替尼)、库潘尼西盐酸盐、COPDAC、COPP、COPP-ABV、Cosmegen(放线菌素D)、Cotellic(卡比替尼)、克唑替尼、CVP、环磷酰胺、Cyfos(异环磷酰胺)、Cyramza(雷莫芦单抗)、阿糖胞苷、阿糖胞苷脂质体、Cytosar-U(阿糖胞苷)、Cytoxan(环磷酰胺)、达拉非尼、达卡巴嗪、Dacogen(地西他滨)、放线菌素D、达雷妥尤单抗、Darzalex(达雷妥尤单抗)、达沙替尼、多柔比星盐酸盐、多柔比星盐酸盐和阿糖胞苷脂质体、地西他滨、去纤苷钠、Defitelio(去纤苷钠)、Degarelix、地尼白介素、地诺单抗、DepoCyt(阿糖胞苷脂质体)、地塞米松、盐酸右雷佐生、地诺妥昔单抗、多西他赛、Doxil(盐酸多柔比星脂质体)、盐酸多柔比星、盐酸多柔比星脂质体、Dox-SL(盐酸多柔比星脂质体)、DTIC-Dome(达卡巴嗪)、德瓦鲁单抗、Efudex(氟尿嘧啶--局部)、Elitek(拉布立酶)、Ellence(盐酸表柔比星)、埃罗妥珠单抗、Eloxatin(奥沙利铂)、艾曲泊帕、Emend(阿瑞匹坦)、Empliciti(埃罗妥珠单抗)、甲磺酸依那西汀、恩杂鲁胺、盐酸表柔比星、EPOCH、Erbitux(西妥昔单抗)、甲磺酸艾瑞布林、Erivedge(维莫德吉)、盐酸厄洛替尼、Erwinaze(天冬酰胺酶菊欧文氏菌)、Ethyol(阿米福汀)、Etopophos(磷酸依托泊苷)、依托泊苷、磷酸依托泊苷、Evacet(盐酸多柔比星脂质体)、依维莫司、易维特、(盐酸雷洛昔芬)、Evomela(盐酸马法兰)、依西美坦、5-FU(氟尿嘧啶注射)、5-FU(氟尿嘧啶--局部)、Fareston(托瑞米芬)、Farydak(帕比司他)、Faslodex(氟维司群)、FEC、Femara(来曲唑)、非格司亭、Fludara(磷酸氟达拉滨)、磷酸氟达拉滨、Fluoroplex(氟尿嘧啶--局部)、氟尿嘧啶注射、氟尿嘧啶--局部、氟他胺、Folex(甲氨蝶呤)、Folex PFS(甲氨蝶呤)、FOLFIRI、FOLFIRI-贝伐单抗、FOLFIRI-西妥昔单抗、FOLFIRINOX、FOLFOX、Folotyn(普拉曲沙)、FU-LV、氟维司群、加德西(重组HPV四价疫苗)、加德西9(重组HPV九价疫苗)、Gazyva(奥滨尤妥珠单抗)、吉非替尼、盐酸吉西他滨、吉西他滨-顺铂、吉西他滨-奥沙利铂、吉妥单抗奥佐米星、Gemzar(盐酸吉西他滨)、Gilotrif(阿法替尼二马来酸盐)、Gleevec(甲磺酸伊马替尼)、Gliadel(卡莫司汀移植)、Gliadel wafer(卡莫司汀移植)、谷卡匹酶、醋酸戈舍瑞林、Halaven(甲磺酸艾瑞布林)、Hemangeol(盐酸普萘洛尔)、Herceptin(曲妥珠单抗)、重组HPV二级疫苗、重组HPV九价疫苗、、重组HPV四价疫苗、Hycamtin(盐酸拓扑替康)、Hydrea(羟基脲)、羟基脲、Hyper-CVAD、Ibrance(帕博西尼)、替坦异贝莫单抗、依鲁替尼、ICE、Iclusig(盐酸帕纳替尼)、Idamycin(盐酸伊达比星)、盐酸伊达比星、艾代拉里斯、Idhifa(甲磺酸依那西汀)、Ifex(异环磷酰胺)、异环磷酰胺、Ifosfamidum(异环磷酰胺)、IL-2(阿地白介素)、甲磺酸伊马替尼、Imbruvica(依鲁替尼)、Imfinzi(德瓦鲁单抗)、咪喹莫特、Imlygic(TalimogeneLaherparepvec)、Inlyta(阿西替尼)、奥英妥珠单抗奥加米星、重组干扰素α-2b、白介素-2(阿地白介素)、Intron A(重组干扰素α-2b)、碘I 131托西妥单抗和托西妥单抗、伊匹单抗、Iressa(吉非替尼)、盐酸伊立替康、盐酸伊立替康脂质体、Istodax(罗米地辛)、伊沙匹隆、枸橼酸艾沙佐米、Ixempra(伊沙匹隆)、Jakafi(磷酸鲁索利替尼)、JEB、Jevtana(卡巴他赛)、Kadcyla(Ado-曲妥珠单抗美坦新)、Keoxifene(盐酸雷洛昔芬)、Kepivance(帕利夫明)、Keytruda(派姆单抗)、Kisqali(瑞博西尼)、Kymriah(Tisagenlecleucel)、Kyprolis(卡菲偌米布)、醋酸兰瑞肽、二甲苯磺酸拉帕替尼、Lartruvo(奥拉木单抗)、来那度胺、甲磺酸仑伐替尼、Lenvima(甲磺酸仑伐替尼)、来曲唑、亚叶酸钙、Leukeran(苯丁酸氮芥)、醋酸亮丙瑞林、Leustatin(克拉屈滨)、Levulan(氨基酮戊酸)、Linfolizin(苯丁酸氮芥)、LipoDox(盐酸多柔比星脂质体)、洛莫司汀、Lonsurf(三氟尿苷和盐酸替吡拉西)、Lupron(醋酸亮丙瑞林)、Lupron Depot(醋酸亮丙瑞林)、Lupron Depot-Ped(醋酸亮丙瑞林)、Lynparza(奥拉帕尼)、Marqibo(硫酸长春新碱脂质体)、Matulane(盐酸甲基苄肼)、盐酸氮芥、醋酸甲地孕酮、Mekinist(曲美替尼)、马法兰、盐酸马法兰、巯嘌呤、美司钠、Mesnex(美司钠)、Methazolastone(替莫唑胺)、甲氨蝶呤、甲氨蝶呤LPF(甲氨蝶呤)、溴化甲基纳曲酮、Mexate(甲氨蝶呤)、Mexate-AQ(甲氨蝶呤)、米哚妥林、丝裂霉素C、盐酸米托蒽醌、Mitozytrex(丝裂霉素C)、MOPP、Mozobil(普乐沙福)、Mustargen(盐酸氮芥)、Mutamycin(丝裂霉素C)、Myleran(白消安)、Mylosar(氮杂胞苷)、Mylotarg(吉妥单抗奥佐米星)、纳米颗粒紫杉醇(紫杉醇白蛋白稳定的纳米颗粒制剂)、Navelbine(酒石酸长春瑞滨)、耐昔妥珠单抗、奈拉滨、Neosar(环磷酰胺)、马来酸奈拉替尼、Nerlynx(马来酸奈拉替尼)、奈托匹坦和盐酸帕洛诺司琼、Neulasta(培非格司亭)、Neupogen(非格司亭)、Nexavar(甲苯磺酸索拉非尼)、Nilandron(尼鲁米特)、尼洛替尼、尼鲁米特、Ninlaro(枸橼酸艾沙佐米)、对甲苯磺酰尼拉普利一水合物、纳武单抗、Nolvadex(枸櫞酸他莫昔芬)、Nplate(罗米司亭)、奥滨尤妥珠单抗、Odomzo(索尼德吉)、OEPA、奥法木单抗、OFF、奥拉帕尼、奥拉木单抗、高三尖杉酯碱、Oncaspar(培门冬酶)、盐酸昂丹司琼、Onivyde(盐酸伊立替康脂质体)、Ontak(地尼白介素)、Opdivo(纳武单抗)、OPPA、奥希替尼、奥沙利铂、紫杉醇、紫杉醇白蛋白稳定的纳米颗粒制剂、PAD、帕博西尼、帕利夫明、盐酸帕洛诺司琼、盐酸帕洛诺司琼和奈妥匹坦、帕米膦酸二钠、帕尼单抗、帕比司他、Paraplat(卡铂)、Paraplatin(卡铂)、盐酸帕佐帕尼、PCV、PEB、培门冬酶、培非格司亭、聚乙二醇干扰素α-2b、PEG-Intron(聚乙二醇干扰素α-2b)、派姆单抗、培美曲塞二钠、Perjeta(帕妥珠单抗)、帕妥珠单抗、Platinol(顺铂)、Platinol-AQ(顺铂)、普乐沙福、泊马度胺、Pomalyst(泊马度胺)、盐酸帕纳替尼、Portrazza(耐昔妥珠单抗)、普拉曲沙、强的松、盐酸甲基苄肼、Proleukin(阿地白介素)、Prolia(地诺单抗)、Promacta(艾曲泊帕)、盐酸普萘洛尔、Provenge(Sipuleucel-T)、Purinethol(巯嘌呤)、Purixan(巯嘌呤)、二氯化镭223、盐酸雷洛昔芬、雷莫芦单抗、拉布立酶、R-CHOP、R-CVP、重组人乳头瘤病毒(HPV)二价疫苗、重组人乳头瘤病毒(HPV)九价疫苗、重组人乳头瘤病毒(HPV)四价疫苗、重组干扰素α-2b、瑞戈菲尼、Relistor(溴化甲基纳曲酮)、R-EPOCH、Revlimid(来那度胺)、Rheumatrex(甲氨蝶呤)、瑞博西尼、R-ICE、Rituxan(利妥昔单抗)、Rituxan Hycela(利妥昔单抗和人透明质酸酶)、利妥昔单抗、利妥昔单抗和人透明质酸酶、、罗拉匹坦盐酸盐、罗米地辛、罗米司亭、Rubidomycin(多柔比星盐酸盐)、Rubraca(瑞卡帕布樟脑磺酸盐)、瑞卡帕布樟脑磺酸盐、磷酸鲁索利替尼、Rydapt(米哚妥林)、胸膜内硬化剂气雾胶(Talc)、塞妥昔单抗、Sipuleucel-T、Somatuline Depot(醋酸兰瑞肽)、索尼德吉、甲苯磺酸索拉非尼、Sprycel(达沙替尼)、STANFORD V、无菌滑石粉(Talc)、Steritalc(Talc)、Stivarga(瑞戈菲尼)、苹果酸舒尼替尼、Sutent(苹果酸舒尼替尼)、Sylatron(聚乙二醇干扰素α-2b)、Sylvant(塞妥昔单抗)、Synribo(高三尖杉酯碱)、Tabloid(硫鸟嘌呤)、TAC、Tafinlar(达拉非尼)、Tagrisso(奥希替尼)、Talc、Talimogene Laherparepvec、枸櫞酸他莫昔芬、Tarabine PFS(阿糖胞苷)、Tarceva(盐酸厄洛替尼)、Targretin(贝沙罗汀)、Tasigna(尼洛替尼)、Taxol(紫杉醇)、Taxotere(多西他赛)、Tecentriq、(阿特珠单抗)、Temodar(替莫唑胺)、替莫唑胺、替西罗莫司、沙利度胺、Thalomid(沙利度胺)、硫鸟嘌呤、噻替派、Tisagenlecleucel、Tolak(氟尿嘧啶--局部)、盐酸拓扑替康、托瑞米芬、Torisel(替西罗莫司)、托西妥单抗和碘I 131托西妥单抗、Totect(盐酸右雷佐生)、TPF、曲贝替定、曲美替尼、曲妥珠单抗、Treanda(盐酸苯达莫司汀)、三氟尿苷和盐酸替吡拉西、Trisenox(三氧化二砷)、Tykerb(二甲苯磺酸拉帕替尼)、Unituxin(地诺妥昔单抗)、三醋酸尿苷、VAC、凡德他尼、VAMP、Varubi(罗拉匹坦盐酸盐)、Vectibix(帕尼单抗)、VeIP、Velban(硫酸长春碱)、Velcade(硼替佐米)、Velsar(硫酸长春碱)、威罗非尼、Venclexta(维奈妥拉)、维奈妥拉、Verzenio(玻玛西林)、Viadur(醋酸亮丙瑞林)、Vidaza(氮杂胞苷)、硫酸长春碱、VincasarPFS(硫酸长春新碱)、硫酸长春新碱、硫酸长春新碱脂质体、酒石酸长春瑞滨、VIP、维莫德吉、Vistogard(三醋酸尿苷)、Voraxaze(谷卡匹酶)、伏立诺他、Votrient(盐酸帕佐帕尼)、Vyxeos(多柔比星盐酸盐和阿糖胞苷脂质体)、Wellcovorin(亚叶酸钙)、Xalkori(克唑替尼)、Xeloda(卡培他滨)、XELIRI、XELOX、Xgeva(地诺单抗)、Xofigo(二氯化镭223)、Xtandi(恩杂鲁胺)、Yervoy(伊匹单抗)、Yondelis(曲贝替定)、Zaltrap(Ziv-阿柏西普)、Zarxio(非格司亭)、Zejula(对甲苯磺酰尼拉普利一水合物)、Zelboraf(威罗非尼)、Zevalin(替坦异贝莫单抗)、Zinecard(盐酸右雷佐生)、Ziv-阿柏西普、Zofran(盐酸昂丹司琼)、Zoladex(醋酸戈舍瑞林)、唑来膦酸、Zolinza(伏立诺他)、Zometa(唑来膦酸)、Zydelig(艾代拉里斯)、Zykadia(色瑞替尼)和/或Zytiga(醋酸阿比特龙)。检查点抑制剂包括但不限于阻断PD-1的抗体(纳武单抗(BMS-936558或MDX1106)、CT-011、MK-3475)、PD-L1(MDX-1105(BMS-936559)、MPDL3280A、MSB0010718C)、PD-L2(rHIgM12B7)、CTLA-4(伊匹单抗(MDX-010)、曲美木单抗(CP-675,206))、IDO、B7-H3(MGA271)、B7-H4、TIM3、LAG-3(BMS-986016)。
所公开的组合物可用于治疗任何发生不受控制的细胞增殖的疾病,如癌症。所公开的组合物可用于治疗的代表性但不限于以下的癌症列表:淋巴瘤、B细胞淋巴瘤、T细胞淋巴瘤、蕈样肉芽肿、霍奇金病、骨髓性白血病、膀胱癌、脑癌、神经系统癌、头颈部癌、头颈部鳞状细胞癌、小细胞肺癌和非小细胞肺癌等肺癌、神经母细胞瘤/胶质母细胞瘤、卵巢癌、皮肤癌、肝癌、黑素瘤、口腔鳞癌、咽喉鳞癌、喉癌和肺鳞癌、宫颈癌、子宫颈癌、乳腺癌、以及上皮癌、肾癌、泌尿生殖道癌、肺癌、食管癌、头颈癌、大肠癌、造血癌、睾丸癌、结肠癌、直肠癌、前列腺癌或胰腺癌。
E.实例
提出以下实例是为了向本领域普通技术人员提供关于如何制备和评估本文所要求保护的化合物、组合物、制品、装置和/或方法的完整公开和描述,并且旨在纯粹地示范而非旨在限制公开。已经努力确保关于数字(例如,量、温度等)的准确性,但是应该考虑一些误差和偏差。除非另有说明,否则份数是重量份,温度为℃或处于环境温度,并且压力为大气压或接近大气压。
实例1:通过冷冻凝胶制备微孔凝胶
海藻酸盐与葡萄糖酸钙交联并在-20℃下冷冻。冰晶周围发生凝胶化,这些冰晶充当致孔剂(图2)。支架的大孔性促进趋化因子介导的T细胞浸润,并为病毒颗粒的转导提供界面。图3显示了以这种方式制备的凝胶的扫描电子显微照片。
实例2:宿主T细胞的介导募集和重编程
本文证明植入的CXCL10释放大孔支架有效地募集移植的T细胞(图4A和4B)。本文还证明了病毒载体转导了大约20%的预加载在藻酸盐支架上的活化人类T细胞。(图5A和5B),以及当与凝胶内的CD3/CD28抗体和IL-2结合时,从循环中募集的2-3百万移植人PBMC中的1-2%(图5C和5D)。CD3/CD28抗体和IL-2提供了促进T细胞活化的环境因子。
实例3:优化支架介导的T细胞重编程参数。
结果表明,化学引诱剂CXCL10的受控释放导致循环T细胞募集到植入支架。此外,本文显示预载有活化T细胞的支架可被病毒转导。病毒载体使用GFP和CAR-T载体体内转导募集的T细胞的效率。
实例4:通过编码GFP的病毒载体对T细胞的体内转导进行优化和表征。
可以测试封装的逆转录病毒载体转导募集的T细胞的能力。NSG小鼠中的人PBMC(1x 107个细胞/小鼠)可以移植20天。装载有CXCL10(4μg/mg藻酸盐)和GFP编码逆转录病毒载体(两种不同浓度)的藻酸盐支架可以植入小鼠(n=4)的皮下空间。在不同的时间点(支架植入后的第4、6、8天),支架可以被移出,CD45+CD3+GFP+细胞的频率可以通过流式细胞术进行评估。对照可以包括:1)不含趋化因子的空白凝胶和2)施用假病毒。
实例5:CAR-T细胞的原位生成:
CAR转导可以使用加载趋化因子的支架和CAR编码病毒载体原位完成。可以使用CAR编码病毒构建体测试T细胞的最佳募集和重编程条件。可以使用n=10(参见统计部分)。支架可以移出,细胞募集和CD19的百分比。CAR+细胞可以通过流式细胞术进行评估。对照可以包括:1)不含趋化因子的空白凝胶和2)施用假病毒。病毒载体可能会随着时间的推移在体内降解。在这种情况下,可以通过一次或多次缓慢的支架内输注来施用病毒。从GFP和CAR编码病毒载体中观察到类似的结果。
Hu-PBMC-NSG小鼠被植入带有CXCL10的支架(CCI-Alg)。人CD19.CAR编码的γ逆转录病毒通过缓慢的支架内注射施用。施用病毒后三天,支架被移出、消化,分离的细胞用CD3和CD19抗体染色,以通过流式细胞术进行分析(图6)。图7显示了用CD19 CAR病毒在体内转导募集的T细胞。
实例6:经转导T细胞迁移的表征:
在T细胞募集和重新编程后,重新编程的细胞有效释放到循环中对治疗功能至关重要。可以表征经转导T细胞迁移到体循环的效率和动力学。
为了评估转导的T细胞向血流中的迁移,可以在携带用于T细胞募集和转导的支架的小鼠(n=12)中测量GFP+或CAR+T细胞。可以在不同时间点(支架植入后第5、10、15天)处死小鼠,并量化全身T细胞中的GFP或CAR表达。最佳条件可用于T细胞募集和重新编程。在不同的时间点,可以从血液、脾脏、骨髓、引流和外周淋巴结中分离T细胞,并通过流式细胞术评估CD45+CD3+GFP+或CD45+CD3+CAR+细胞的频率和数量。对照可以包括:1)没有病毒的支架2)用GFP+T细胞预接种的支架。支架的大孔性质促进了CAR-T细胞从支架中迁移到血液中。如果迁移缓慢或T细胞被困在支架内,则可以用胶原蛋白模拟肽修饰支架,因为已知淋巴细胞会沿胶原纤维迁移。此外,海藻酸盐可以进行化学修饰以仔细调整生物降解率,支架的降解可用于增加CAR-T的释放。
实例7:统计分析
GFP实验的动物数量是基于80%的能力来确定的,以检测0.05的2侧α水平的上述差异。基于CD19平均百分比的2侧95%置信区间(CI)确定原位生成CAR T细胞的动物数量,CI的半宽约为3.6%,假设sd约为5%。
实例8:肿瘤模型
通过使用Daudi.ffluc细胞(CD19+肿瘤细胞),NSG小鼠被用于开发人Burkitt淋巴瘤(一种B细胞淋巴瘤)的小鼠模型(图8)。在肿瘤接种后19、24、29、33和43天监测小鼠。如图9A所示,通过发光观察小鼠的肿瘤大小,并在未治疗的对照和接受使用藻酸盐支架或静脉注射治疗的小鼠之间进行比较。还测量了小鼠的体重增加和总通量(图9B),显示治疗组之间没有可观察到的差异。此外,在植入CCI支架或静脉注射CAR-T细胞的小鼠中,接受静脉注射CD19 CAR T细胞或接受CCI-藻酸盐支架(CCI-Alg)的动物在接种肿瘤后不同时间点的每100ul血液中CAR-T细胞数量。通过脸颊出血对小鼠取血,裂解红细胞,用Hu-CD45、Hu-CD3和CAR.19抗体染色细胞并通过流式细胞术进行分析(图10)。
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Claims (29)
1.一种水凝胶基质,其包含一种或多种化学引诱剂,其中所述一种或多种化学引诱剂包含C-C基序趋化因子配体(CCL)1(CCL1)、CCL5、CCL19、CCL21、CCL22、CCL28、C-X-C基序趋化因子配体(CXCL)1(CXCL1)、CXCL9、CXCL10、CXCL11、CXCL12、M-CSF、GM-CSF、MCP-1、MCP-3、CCL2、CCL3、CCL7、CCL20、CX3CL1、BRAK、IL-12、S1P和/或MCP2。
2.根据权利要求1所述的水凝胶基质,其进一步包含编码嵌合抗原受体(CAR)、NK细胞受体、NK T细胞受体或T细胞受体的病毒载体。
3.根据权利要求2所述的水凝胶基质,其中所述病毒载体包括慢病毒、逆转录病毒、腺病毒或腺相关病毒。
4.根据权利要求1-3中任一项所述的水凝胶基质,其进一步包含一种或多种抗体、细胞因子和/或共刺激分子,所述共刺激分子活化T细胞、巨噬细胞、自然杀伤(NK)细胞、NK T细胞、肿瘤浸润性NK细胞(TINK)、肿瘤浸润性淋巴细胞(TIL)或骨髓浸润性淋巴细胞(MIL)。
5.根据权利要求4中任一项所述的水凝胶基质,其中所述抗体包含抗CD3、CD28、B7-1、B7-2、抗诱导型共刺激物(ICOS)、ICOS配体、抗CD27、CD70、4-1BBL、抗41-BB、抗CD40L、CD40、抗DAP10、抗CD30、CD30L、抗TIM-1、抗TIM-2、抗TIM-3、抗CD44、抗NK1.1、凝集素样转录物1(LLT-1)、抗CD137、CD48、MICA、抗2B4和抗糖皮质激素诱导的肿瘤坏死因子受体相关蛋白(GITR)。
6.根据权利要求4中任一项所述的水凝胶基质,其中所述细胞因子包括IL-2、IL-7、IL-15、IL-21、TNF-α或IFN-γ。
7.根据权利要求1-6中任一项所述的水凝胶基质,其进一步包含化疗剂。
8.一种治疗受试者的癌症的方法,其包括向所述受试者施用根据权利要求1-7中任一项所述的水凝胶基质。
9.一种治疗受试者的癌症的方法,其包括向所述受试者施用包含一种或多种化学引诱剂的水凝胶基质,其中所述一种或多种化学引诱剂包括C-C基序趋化因子配体(CCL)1(CCL1)、CCL5、CCL19、CCL21、CCL22、CCL28、C-X-C基序趋化因子配体(CXCL)1(CXCL1)、CXCL9、CXCL10、CXCL11、CXCL12、M-CSF、GM-CSF、MCP-1、MCP-3、CCL2、CCL3、CCL7、CCL20、CX3CL1、BRAK、IL-12、S1P和/或MCP2;并且其中所述化学引诱剂将免疫细胞吸引并保留到所述水凝胶。
10.根据权利要求9所述的治疗癌症的方法,其中所述免疫细胞包括T细胞、NK细胞、NKT细胞、巨噬细胞、树突状细胞、TINK、TIL或MIL。
11.根据权利要求9或10中任一项所述的治疗癌症的方法,其中所述水凝胶基质进一步包含免疫阻断抑制剂。
12.根据权利要求9-11中任一项所述的治疗癌症的方法,其中所述水凝胶基质进一步包含化疗剂。
13.根据权利要求9-12中任一项所述的治疗癌症的方法,其中所述水凝胶进一步包含编码嵌合抗原受体(CAR)、NK细胞受体、NK T细胞受体或T细胞受体的病毒载体。
14.根据权利要求13所述的治疗癌症的方法,其中所述病毒载体转导所述免疫细胞;并且其中经转导免疫细胞从所述水凝胶释放到所述癌症。
15.根据权利要求14所述的治疗癌症的方法,其中在将所述水凝胶施用于所述受试者之后约1天至约14天,将所述病毒载体在体内引入到所述水凝胶中。
16.根据权利要求14所述的治疗癌症的方法,其中在将所述水凝胶施用于所述受试者之前将所述病毒载体引入到所述水凝胶中。
17.根据权利要求14-16中任一项所述的治疗癌症的方法,其中在施用所述水凝胶后约1周至约12周释放所述免疫细胞。
18.根据权利要求9-17中任一项所述的治疗癌症的方法,其中在施用所述水凝胶后约1小时至施用所述水凝胶后约12周释放所述一种或多种化学引诱剂。
19.一种在受试者中转导免疫细胞的方法,所述方法包括向所述受试者施用水凝胶,所述水凝胶包含一种或多种化学引诱剂和编码转基因的病毒载体。
20.根据权利要求19所述的转导免疫细胞的方法,其中在将所述水凝胶施用于所述受试者之后约1天至约14天,将所述病毒载体在体内引入到所述水凝胶中。
21.根据权利要求19所述的转导免疫细胞的方法,其中在将所述水凝胶施用于所述受试者之前将所述病毒载体引入到所述水凝胶中。
22.根据权利要求19-21中任一项所述的转导免疫细胞的方法,其中所述一种或多种化学引诱剂包括C-C基序趋化因子配体(CCL)1(CCL1)、CCL5、CCL19、CCL21、CCL22、CCL28、C-X-C基序趋化因子配体(CXCL)1(CXCL1)、CXCL9、CXCL10、CXCL11、CXCL12、M-CSF、GM-CSF、MCP-1、MCP-3、CCL2、CCL3、CCL7、CCL20、CX3CL1、BRAK、IL-12、S1P和/或MCP2。
23.根据权利要求19-22中任一项所述的转导免疫细胞的方法,其中在施用所述水凝胶后约1小时至施用所述水凝胶后约12周释放所述一种或多种化学引诱剂。
24.根据权利要求19-23中任一项所述的转导免疫细胞的方法,其中所述病毒载体编码的所述转基因包括CAR、NK细胞受体、NK T细胞受体或T细胞受体。
25.根据权利要求19-24中任一项所述的转导免疫细胞的方法,其中所述病毒载体包括慢病毒、逆转录病毒、腺病毒或腺相关病毒。
26.根据权利要求19-25中任一项所述的转导免疫细胞的方法,其中所述免疫细胞包括T细胞、NK细胞、NK T细胞、巨噬细胞、树突状细胞、TINK、TIL或MIL。
27.根据权利要求19-26中任一项所述的转导免疫细胞的方法,其中所述水凝胶进一步包含一种或多种抗体、细胞因子和/或共刺激分子,所述共刺激分子活化T细胞、NK细胞、NKT细胞、巨噬细胞、树突状细胞、TINK、TIL或MIL。
28.根据权利要求27所述的转导免疫细胞的方法,其中所述抗体包含抗CD28、CD3、B7-1、B7-2、抗诱导型共刺激物(ICOS)、ICOS配体、抗CD27、CD70、4-1BBL、抗41-BB、抗CD40L、CD40、抗DAP10、抗CD30、CD30L、抗TIM-1、抗TIM-2、抗TIM-3、抗CD44、抗NK1.1、凝集素样转录物1(LLT-1)、抗CD137、CD48、MICA、抗2B4和抗糖皮质激素诱导的肿瘤坏死因子受体相关蛋白(GITR)。
29.根据权利要求27所述的转导免疫细胞的方法,其中所述细胞因子包括IL-2、IL-7、IL-15、IL-21、TNF-α或IFN-γ。
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CN116240173A (zh) * | 2023-02-02 | 2023-06-09 | 西安电子科技大学 | 一种冷热肿瘤调控型car-单核/巨噬细胞及其制备方法和应用 |
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JP2022536983A (ja) | 2022-08-22 |
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