本发明一般涉及工程化为表达对于白细胞介素3受体α链(il-3ra，分化群123cd123)特异性的嵌合抗原受体(car)的tcr基因敲除t细胞及其用途，例如，用于治疗与il-3ra，cd123的表达相关的疾病或病症，即急性髓细胞白血病(aml)和原发性浆细胞样树突状细胞肿瘤(bpdcn)。本发明涉及t细胞受体(tcrα或β基因)和/或人脱氧胞苷激酶(dck基因或dck基因)敲除(ko)免疫t细胞，其工程化为表达：-包含至少一个来自可选地人源化的klon43的胞外配体结合结构域、铰链、细胞内结构域和共刺激结构域的对于分化簇123(cd123)特异性的嵌合抗原受体(car)，-可选地插入所述铰链中的自杀域(suicidedomain)，所述cd123car对于人cd123特异性并赋予抗cd123阳性细胞的特异性免疫，在一个实施方式中；提供了该目的用于治疗急性髓细胞白血病aml或aml并发症的用途，在一个实施方式中；通过该目的用于治疗原发性浆细胞样树突状细胞肿瘤(bpdcn)。在一个实施方式中；通过该目的作为骨髓移植前作为移植过渡的治疗。与先前的cd123car相比，根据本发明的赋予工程化免疫细胞的cd123car在治疗淋巴瘤和白血病方面表现出高效能，并可以在嘌呤类似物的存在下使用，比以前在患者中的治疗副作用更少。
背景技术：
：：淋巴增生性疾病如白血病，且特别是急性髓细胞白血病(aml)的诱导治疗在近50年内基本保持不变。这种标准诱导化疗可以诱导完全缓解，但许多患者最终会复发并罹难于疾病，需要开发用于aml，特别是复发性难治性aml的新疗法。对于侵袭性淋巴增殖性疾病如bpdcn，也报道了相似的观察。这些疾病的预后仍然很差。这些癌细胞的免疫表型已经表明，白细胞介素3受体α链(il-3rα；cd123-ncbi参考号：np_001254642)是潜在的免疫疗法靶标，因为它与正常细胞相比会过表达于这些肿瘤细胞上。另外，针对cd123特异性疗法的两个i期临床试验已经完成，其中两种药物都表现出良好的安全特性(clinicaltrials.govid：nct00401739和nct00397579)。不幸的是，这些cd123靶向药物具有的功效有限，表明需要可替代的且更有效和特异性的靶向cd123的疗法以观察到抗白血病活性。用于治疗白血病的可能更有效的替代疗法可以是使用表达以mhc独立的方式选择性地将免疫细胞特异性定向于细胞表面肿瘤相关的抗原(taa)(jena，dottietal。2010)并将其摧毁的嵌合抗原受体(car)的免疫细胞。car是由与单个或多个融合分子中的一个或多个信令结构域相关的靶向部分组成的合成受体。通常，car的结合部分由单链抗体(scfv)的抗原结合结构域组成，其包含通过柔性接头连接的单克隆抗体的轻链和可变片段。基于受体或配体结构域的结合部分也已成功应用。第一代car的信令结构域源自cd3ζ或fc受体γ链的细胞质区。已经表明第一代car成功地重定向t细胞的细胞毒性，然而，它们未能在体内提供延长的扩增和抗肿瘤活性。来自包括ox-40(cd134)和4-1bb(cd137)的共刺激分子的信令结构域已经单独或组合加入以增强car改造的t细胞在体外的存活并提高其增殖。然而，不是所有的结合域的组合都会导致体内可以将免疫细胞定向于靶向细胞的car。在人类癌症的小鼠模型中，car可以重新定向抗在肿瘤细胞表面表达的抗原的car表达细胞，其中效率取决于每个结构域的性质和长度(condominem.etal.，2015plosone10(6)：e0130518)。迄今为止，单独的表达car的特异性t细胞的自体转移已证明在治疗特定形式的癌症方面是成功的，尽管存在多种副作用。如细胞因子风暴，细胞群的非特异性破坏，或不良特异性免疫反应的(park，rosenbergetal.，2011)。同种异体cd123car工程化t细胞是否可以安全有效地用于治疗aml仍然未知(clinicaltrials.govid：nct02159495)。因此，为了拓展可能受益于这种治疗的患者群体，已经制备所谓的表达car的同种异体t细胞，用于其在患癌症的人类中的使用。在这种情况下，从健康供体中分离免疫细胞，工程化，随后用作对其需要的几种不同的所选患者中的治疗。为了这个目的并降低潜在的移植物抗宿主疾病的风险，将所选择的基因小心地敲除以提供工程化的表达car的免疫细胞，其中涉及免疫响应的分子，例如，mhc分子或tcr分子的亚单元的表达降低。这些工程化的细胞在任何宿主中仍然增殖和存活的程度仍然基本未知，特别是在已经用化疗药物治疗的患者中。使用这种靶向cd123的表达car的免疫t细胞与细胞毒性化疗剂组合作为通常用作抗癌治疗的治疗仍然成问题，因为抗癌治疗也会影响t细胞的增殖和/或存活。因此，还需要开发特异性效果并与使用药物，特别是抗癌化学疗药物，如影响细胞增殖的那些相容的靶向cd123的t细胞，其仍将可以增殖和存活而达到其靶标(癌细胞)。为了使用“现成”的同种异体治疗细胞与化学疗法相结合，本发明人确定了提供同种异体工程化t细胞，其较不同种异体并是患癌症和/或已经用化疗药剂治疗的患者的免疫系统容许的。治疗益处由所要求保护的对象的化学疗法和免疫疗法之间的协同效应提供。本发明还涉及抗-cd123嵌合抗原受体(抗-cd123car)，其胞外结合结构域(scfv)以允许细胞分选和细胞消除二者的方式改造。允许其的结构是由单克隆抗体识别的表位(命名为mab驱动的分选/消除系统或由特异性单克隆抗体或模拟表位识别的表位)，并包含插入到scfv和/或铰链内的胞外结构域中的所选表位。这种表位具有特异性而由特异性抗体(优选单克隆抗体(mab)，可选地人源化的)识别。考虑到主要将car的外部配体结合结构域改造以包括表位的事实，可以设想不同的car结构：如pctus2013/058005中所公开的单链或多链。由vh和vl多肽和特异性表位形成的本发明的嵌合scfv本身可以具有不同的结构，取决于表位的插入位置和接头的使用(图3)。本发明还涉及用于分选和/或消除赋予改性car的工程化免疫细胞的所获得的方法。几种表位-mab配偶体可以用于产生这种系统；特别是已经批准用于医疗用途的那些，如作为非限制性实例的cd20/利妥昔单抗。最后，本发明涵盖治疗方法，其中赋予抗cd123car的工程化免疫细胞的数目、活性和存活通过使用引导car的外部配体结合结构域的抗体消除细胞来调节。技术实现要素：白细胞介素3受体α链(cd123)已经被确定为特别是在急性髓细胞白血病(aml)的情况下，与相同谱系的正常细胞相比在白血病肿瘤细胞上频繁过度表达。本发明人已经产生了工程化为表达cd123特异性car的免疫细胞，其包含来自klon43抗体的scfv，来自fcγriiiα的铰链和赋予宿主细胞体内增殖、达到cd123靶细胞并改变其存活的能力的细胞内结构域，所述细胞包含一旦靶细胞被包含就允许它们特异性破坏的另外的标记或自杀结构域。这些cd123特异性car无差别地标识为cd123特异性car或抗cd123car，或123car，或“本发明的car”。在本发明中，使用对这种il-3受体亚单元特异性的一种抗体，即klon43或源自这种klon43抗体的人源化序列，制备表达特异性和选择性的耐受原tcrkocd123car的t细胞，用于治疗患有aml、b细胞淋巴增生性疾病(bc-lpd)或bpdcn的患者。伴随的是，这些细胞允许破坏癌前期细胞，阻止难治性/复发性癌症的进展和出现。由于它们在体内增殖并达到组织或微环境(niche)的能力，这些细胞比癌细胞本身行动更快，并甚至可以根除侵袭性淋巴增殖性疾病。在体外非特异性活化后(例如，用抗cd3/cd28涂覆的珠和重组il2)，来自供体的t-细胞已经用本发明的表达car的多核苷酸使用病毒转导而转化。通过破坏t细胞受体tcr(αβ-t细胞受体)的组件而减少移植物抗宿主反应，将t细胞进一步工程化而产生较少同种异体反应性的t细胞。在优选的实施方式中，通过删除表9中确定的基因的特定组合而进一步工程化t细胞，以产生对抗癌药物抗性的耐受原t细胞，以与所述经典抗癌药物，即嘌呤类似物组合使用。得到的工程化t细胞表现出对cd123阳性细胞的反应性，表明本发明的car有助于t细胞的抗原依赖性活化以及增殖，使其对免疫疗法有用。得到的工程化t细胞表现出体内抗cd123阳性细胞的反应性，并显著降低了体内癌细胞的数量。在具体实施方式中，可以进行本发明的工程化t细胞的几次给予，使其作为第一治疗(诱导)，作为巩固治疗，作为与经典抗癌化疗相组合的治疗有用于免疫疗法。编码本发明的car的多肽和多核苷酸序列在本说明书中进行详细描述。本发明的工程化免疫细胞特别有用于治疗应用，如b细胞淋巴瘤或白血病治疗，并可以从生物体中选择性地消除。附图说明图1：根据本发明的工程化免疫细胞的示意图。图中所示的工程化免疫细胞是用编码car的逆转录病毒多肽转导的t细胞。这种t细胞进一步工程化以允许更好且更安全地植入患者体内，这是本发明框架的一部分。x基因是表达tcr的组件的基因(tcrα或tcrβ基因)，y是涉及t细胞对嘌呤类似物敏感性的基因dck。图2：包含可选地人源化的cd123scfv，来自fcriii或cd8α的铰链，来自cd8α的跨膜结构域和两个来自4-1bb和cd3ζ的细胞内结构域的本发明两种car(123car)的示意图。图3：显示根据本发明的car的实例。l：(ggggs)n的vh和vl之间的接头(seqidno：10)，其中n＝1至4，优选n＝3li：对应于gggs或sggggs或gsggggs的接头序列，tm：跨膜结构域。制备了本发明的包含来自可选地人源化的klon43的vh，接头l，来自可选地人源化的klon43的vl，自杀结构域(例如，序列cpysnpslcs(seqidno：161)的cd20模拟表位的两个拷贝和seqidno169的拷贝)的cd123car，所述模拟表位优选位于scfv，cd8铰链或其部分，来自cd8α的跨膜结构域(cd8tm)，以及共刺激结构域(4-1bb)和刺激结构域(itamcd3ζ)。在本发明的cd123car中，将相互连接并通过接头li连接至vl的序列cpysnpslcs的cd20模拟表位的两个拷贝插入到抗cd123scfv和来自cd8α的铰链之间，可选的接头li将模拟表位连接至铰链(seqidno160)。设想了表位(例如scfv中)插入的其他可能性，并如图3中的圆圈所示。图4：当将car+t细胞与表达cd123的细胞(rpmi8226)，或与不表达cd123的细胞(k562)共培养6小时时，对于一种结构(v3：cd8-铰链/cd8-跨膜)根据本发明的不同scfv的脱粒活性。图5：与表达不同水平的cd123的细胞(kg1a或rpmi8226)，或与不表达cd123的细胞(k562)共培养24小时时，通过t-细胞的ifnγ释放图6：用pna(20mg/kg)腹腔内处理的小鼠体内car-t细胞的特异性溶胞活性的剂量响应。图7：用pna(20mg/kg)腹腔内处理的小鼠体内car-t细胞的特异性溶胞活性的剂量响应。表1表2：对于本发明的cd123car在本发明的抗cd123scfv中使用的来自klon43的抗体片段的序列表3：对于本发明的cd123car在本发明的抗cd123scfv中使用的来自klon43的人源化抗体片段的序列表4：结构v-1的car表5：结构v-3的car表6：结构v-5的car表7：可以用于本发明的car的胞外结构域中的也称为模拟表位的mab特异性表位(及其相应的mab)的实例，如例如模拟表位和具有其对应mab的表位本发明的抗cd123car的序列(seqidno：31-160)，优选的序列是seqidno：31、32、160和34-117，在34-117中更优选的是76-117，更加优选的是seqidno：32、seqidno：89、seqidno：94、seqidno：95、seqidno：96、seqidno：97。具体实施方式本发明提供：1.一种cd123特异性嵌合抗原受体(cd123car)，包含■胞外结构域，包含胞外配体结合结构域，其依次包含可选地人源化的vh，接头，优选序列(ggggs)n的接头，其中n＝1至4，优选n＝3，和可选地人源化的vl，铰链，■跨膜结构域和■细胞质结构域。■至少一个对于单克隆抗体特异性的表位(模拟表位)。2.根据1的cd123car，包含■胞外结构域，包含胞外配体结合域，其依次包括选自seqidno12、seqidno24、seqidno25、seqidno26、seqidno27、seqidno28、seqidno29和seqidno30的可选地人源化的vh，接头，优选序列(ggggs)n的接头，其中n＝1-4，优选n＝3，选自seqidno11、seqidno18、seqidno19、seqidno20、seqidno21、seqidno22和seqidno23的可选地人源化的vl，铰链，■来自cd8α的跨膜结构域■包含cd3ζ信令结构域和来自4-1bb的共刺激结构域的细胞质结构域。3.根据1或2的cd123car，其不包含与人cd28np_006130.1具有一致性的序列。4.根据1至3中任一项的cd123car，其包含选自seqidno172、seqidno173、seqidno174、seqidno175、seqidno176、seqidno177、seqidno178、seqidno179、seqidno180、seqidno181、seqidno182、seqidno183、seqidno184、seqidno185、seqidno186和seqidno187的序列，可选地进一步包含至少一个seqidn°161。5.根据1至4中任一项的cd123car，其中所述胞外结构域包含至少一个对单克隆抗体特异性的表位(模拟表位)，选自由seqidno161、seqidno162、seqidno163、seqidno164、seqidno165、seqidno166、seqidno167、seqidno168、seqidno169和seqidno170组成的列表，优选seqidno161和seqidno169。6.根据1至5中任一项的cd123car，包含选自seqidno160、seqidno171、seqidno188、seqidno189、seqidno190、seqidno191、seqidno192、seqidno193、seqidno194、seqidno195、seqidno196和seqidno197的序列。7.一种编码根据权利要求1至6中任一项所述的cd123特异性嵌合抗原受体(cd123car)的多核苷酸。8.一种包含根据权利要求7所述的多核苷酸的表达载体。9.一种包含骨架和至少一个编码权利要求1至6中任一项中限定的任意一种cd123car的序列的表达载体。10.一种表达载体，包含骨架、ef1启动子、rqr8开放阅读框(rqr8orf)、编码1至6中任一项的cd123car的序列。11.一种在细胞表面膜表达根据1至6中任一项的cd123car的t细胞受体(tcr)敲除(ko)或tcr和人脱氧胞苷激酶(dck)ko工程化的免疫细胞。12.一种包含编码根据1至6中任一项的cd123特异性嵌合抗原受体(cd123car)的多核苷酸的tcrko或tcr和dckko工程化的免疫细胞。13.一种在细胞表面进一步表达自杀结构域的根据4的tcrko或tcrko和dckko表达cd123car的工程化的免疫细胞。14.根据11至13中任一项的tcrko或tcrko和dckko表达cd123car的工程化免疫细胞，其中至少一种mhc蛋白的表达受到抑制。15.根据11至14中任一项的tcrko或tcrko和dckko表达cd123car的工程化的免疫细胞，用于治疗。16.根据15的tcrko或tcrko和dckko表达cd123car的工程化的免疫细胞，其中病症是急性髓细胞白血病(aml)，优选难治/复发性aml，bpdnl，或在骨髓移植期间或之前使用。17.根据15的tcrko或tcrko和dckko表达cd123car的工程化的免疫细胞，用作治疗，优选用作淋巴增生性病症的治疗，更优选用作淋巴瘤的白血病或用于选自由急性髓细胞白血病，慢性髓细胞白血病，骨髓增生异常综合征，急性淋巴细胞白血病，慢性淋巴细胞白血病和骨髓增生异常综合征和bpdnl组成的组的治疗。18.根据15的tcrko或tcrko和dckko表达cd123car的工程化免疫细胞，用作aml的治疗。本发明还提供：1a.编码对包含至少一个胞外结合结构域的cd123特异性的嵌合抗原受体(car)的多肽，所述胞外结构域包含至少一个scfv。所述scfv包含与cd123特异性结合的至少一个vh链和vl链，其中所述细胞外结合结构域包含至少一个mab特异性表位或模拟表位。2a.根据1a的多肽，其中所述mab特异性表位位于vh和vl链之间，或vh和vl之前。在一个实施方式中，编码cd123特异性的嵌合抗原受体(car)的多肽包含跨膜结构域(tm)和铰链，并且mab-特异性表位位于scfv和铰链之间。本发明提供：3a.根据1a或2a的多肽，其中所述vh和vl链和mab特异性表位通过至少一个接头结合在一起并通过铰链结合至所述car的跨膜结构域。4a.根据3a的多肽，其中mab表位通过两个接头连接到vh和vl链上。5a.根据1a至3a中任一项的多肽，其中mab-特异性表位是由用于体外细胞分选和/或表达包含这种表位的car的t细胞的体内细胞消除的表位特异性mab结合的表位。6a.根据1a至5a中任一项的多肽，其中多肽包含一个胞外结合结构域，跨膜结构域和胞内结构域，其中所述胞外结合结构域包含至少一个mab特异性表位。7a.根据1a至6a中任一项的多肽，其中胞外结合结构域包括1、2、3、4、5、6、7、8、9或10个mab-特异性表位。8a.根据1a至7a中任一项的多肽，其中胞外结合结构域包含1、2、3或4个mab特异性表位。9a.根据1a至8a中任一项的多肽，其中胞外结合结构域包含2、3或4个mab特异性表位。10a.根据1a至9a中任一项的多肽，其中胞外结合结构域包含以下序列。v1-l1-v2-(l)x-表位1-(l)x-；v1-l1-v2-(l)x-表位1-(l)x-表位2-(l)x-；v1-l1-v2-(l)x-表位1-(l)x-表位2-(l)x-表位3-(l)x-；(l)x-表位1-(l)x-v1-l1-v2；(l)x-表位1-(l)x-表位2-(l)x-v1-l1-v2；表位1-(l)x-表位2-(l)x-表位3-(l)x-v1-l1-v2；(l)x-表位1-(l)x-v1-l1-v2-(l)x-表位2-(l)x；(l)x-表位1-(l)x-v1-l1-v2-(l)x-表位2-(l)x-表位3-(l)x-；(l)x-表位1-(l)x-v1-l1-v2-(l)x-表位2-(l)x-表位3-(l)x-表位4-(l)x-；(l)x-表位1-(l)x-表位2-(l)x-v1-l1-v2-(l)x-表位3-(l)x-；(l)x-表位1-(l)x-表位2-(l)x-v1-l1-v2-(l)x-表位3-(l)x-表位4-(l)x-；v1-(l)x-表位1-(l)x-v2；v1-(l)x-表位1-(l)x-v2-(l)x-表位2-(l)x；v1-(l)x-表位1-(l)x-v2-(l)x-表位2-(l)x-表位3-(l)x；v1-(l)x-表位1-(l)x-v2-(l)x-表位2-(l)x-表位3-(l)x-表位4-(l)x；(l)x-表位1-(l)x-v1-(l)x-表位2-(l)x-v2；or，(l)x-表位1-(l)x-v1-(l)x-表位2-(l)x-v2-(l)x-表位3-(l)x；其中，v1是vl且v2是vh或v1是vh且v2是vl；l1是适合于将vh链连接至vl链的接头；l是包含甘氨酸和丝氨酸残基的接头，且胞外结合结构域中l的每次出现可以与相同的胞外结合结构域中l的其它出现是相同的或不同的，并且x是0或1，并x的每次出现独立于其它；并且表位1、表位2和表位3是mab特异性表位，并可以是相同的或不同的。11a.根据10a的多肽，其中胞外结合结构域包含以下序列v1-l1-v2-l-表位1；v1-l1-v2-l-表位1-l；v1-l1-v2-l-表位1-l-表位2；v1-l1-v2-l-表位1-l-表位2-l；v1-l1-v2-l-表位1-l-表位2-l-表位3；v1-l1-v2-l-表位1-l-表位2-l-表位3-l；v1-l1-v2-表位1；v1-l1-v2-表位1-l；v1-l1-v2-表位1-l-表位2；v1-l1-v2-表位1-l-表位2-l；v1-l1-v2-表位1-l-表位2-l-表位3；v1-l1-v2-表位1-l-表位2-l-表位3-l；表位1-v1-l1-v2；表位1-l-v1-l1-v2；l-表位1-v1-l1-v2；l-表位1-l-v1-l1-v2；表位1-l-表位2-v1-l1-v2；表位1-l-表位2-l-v1-l1-v2；l-表位1-l-表位2-v1-l1-v2；l-表位1-l-表位2-l-v1-l1-v2；表位1-l-表位2-l-表位3-v1-l1-v2；表位1-l-表位2-l-表位3-l-v1-l1-v2；l-表位1-l-表位2-l-表位3-v1-l1-v2；l-表位1-l-表位2-l-表位3-l-v1-l1-v2；v1-l-表位1-l-v2；l-表位1-l-v1-l-表位2-l-v2；v1-l-表位1-l-v2-l-表位2-l；v1-l-表位1-l-v2-l-表位2-l-表位3；v1-l-表位1-l-v2-l-表位2-表位3；v1-l-表位1-l-v2-l-表位2-l-表位3-表位4；l-表位1-l-v1-l-表位2-l-v2-l-表位3-l；表位1-l-v1-l-表位2-l-v2-l-表位3-l；l-表位1-l-v1-l-表位2-l-v2-l-表位3；l-表位1-l-v1-l1-v2-l-表位2-l；l-表位1-l-v1-l1-v2-l-表位2-l-表位3；l-表位1-l-v1-l1-v2-l-表位2-表位3，或表位1-l-v1-l1-v2-l-表位2-l-表位3-表位4，其中v1是vl且v2是vh或者v1是vh且v2是vl；l1是适用于将vh链与vl链连接的任何接头；l是包含甘氨酸和丝氨酸残基的接头，并且胞外结合结构域中l的每次出现与相同的胞外结合结构域中l的其它出现可以是相同的或不同的，表位1、表位2和表位3是mab特异性表位，并可以是相同的或不同的。12a.根据10a的多肽，其中l1是包含甘氨酸和/或丝氨酸的接头。13a.根据12a的多肽，其中l1是包含氨基酸序列(gly-gly-gly-ser)n或(gly-gly-gly-gly-ser)n的接头，其中n是1，2，3，4或5或包含氨基酸序列(gly4ser)4或(gly4ser)3的接头。14a.根据10a至13a中任一项的多肽，其中l是包含甘氨酸和/或丝氨酸的接头。15a.根据14a的多肽，其中l是具有选自sgg、ggs、sggs、ssggs、gggg、sgggg、ggggs、sggggs、gggggs、sgggggs、sggggg、gsggggs、gggggggs、sggggggg、sgggggggs、或sggggsggggs的氨基酸序列的接头。16a.根据14a的多肽，其中l是sgggg，ggggs或sggggs。17a.根据10a至16a中任一项的多肽，其中表位1、表位2、表位3和表位4独立地选自替伊莫单抗(ibritumomab、tiuxetan)、莫罗单抗(muromonab)-cd3、托西莫单抗(tositumomab)、阿昔单抗(abciximab)、巴利昔单抗(basiliximab)、布伦昔单抗(brentuximabvedotin)、西妥昔单抗(cetuximab)、英夫利昔单抗(infliximab)、利妥昔单抗(rituximab)、阿伦单抗(alemtuzumab)、贝伐单抗(bevacizumab)、赛妥珠单抗(certolizumabpegol)、达利珠单抗(daclizumab)、艾库组单抗(eculizumab)、依法珠单抗(efalizumab)、吉妥珠单抗(gemtuzumab)、那他珠单抗(natalizumab)、奥马珠单抗(omalizumab)、帕利珠单抗、雷珠单抗(ranibizumab)、托美珠单抗(tocilizumab)、曲妥珠单抗(trastuzumab)、韦多珠单抗(vedolizumab)、阿达木单抗(adalimumab)、贝利木单抗(belimumab)、卡那单抗(canakinumab)、地诺单抗(denosumab)、戈利木单抗(golimumab)、伊匹单抗(ipilimumab)、奥法木单抗(ofatumumab)、帕尼单抗(panitumumab)、qbend-10和优特克单抗(ustekinumab)特异性识别的mab-特异性表位。在优选的实施方式中，所述表位1、表位2由利妥抗单抗特异性识别，而表位3由qbend-10特异性识别。18a.根据10a至16a中任一项的多肽，其中表位1、表位2、表位3和表位4独立地选自具有seqidno161至170的氨基酸序列的mab特异性表位。19a.根据10a至18a中任一项的多肽，其中表位1是具有seqidno161的氨基酸序列的mab特异性表位。20a.根据权利要求10a至19a中任一项的多肽，其中表位2是具有seqidno161的氨基酸序列的mab特异性表位。21a.根据权利要求10至20中任一项的多肽，其中表位3是具有seqidno161或seqidno169的氨基酸序列的mab特异性表位。22a.根据权利要求10a至21a中任一项的多肽，其中表位4是具有seqidno161的氨基酸序列的mab特异性表位。23a.根据权利要求22a的多肽，其中表位1、表位2和表位4是具有seqidno161的氨基酸序列的mab特异性表位，并且表位3是具有seqidno169的氨基酸序列的mab-特异性表位。24a.根据1a至9a中任一项的多肽，其中mab-特异性表位来自选自表7中列出的那些中的一种多肽。25a.根据1a至9a中任一项的多肽、其中mab-特异性表位选自由替伊莫单抗、、莫罗单抗-cd3、托西莫单抗、阿昔单抗、巴利昔单抗、布伦昔单抗、西妥昔单抗、英夫利昔单抗、利妥昔单抗、阿伦单抗、贝伐单抗、赛妥珠单抗、达利珠单抗、艾库组单抗、依法珠单抗、吉妥珠单抗、那他珠单抗、奥马珠单抗、帕利珠单抗、雷珠单抗、托美珠单抗、曲妥珠单抗、韦多珠单抗、阿达木单抗、贝利木单抗、卡那单抗、地诺单抗、戈利木单抗、伊匹单抗、奥法木单抗、帕尼单抗、qbend-10和优特克单抗特异性识别的mab特异性表位。26a.根据1a至9a中任一项的多肽，其中mab特异性表位选自具有seqidno161、seqidno162、seqidno163、seqidno164、seqidno165、seqidno166、seqidno167、seqidno168、seqidno169或seqidno170的氨基酸序列的mab特异性表位。27a.根据1a至9a中任一项的多肽，其中mab特异性表位具有seqidno160的氨基酸序列。28a.根据1a至27a中任一项的多肽，其中所述vh和vl链具有与seqidno11(cd123抗原vh)，seqidno12(cd123抗原vl)超过80％，优选超过90％，更优选超过95％的一致性的抗原性靶序列。29a.根据1a至27a中任一项的多肽，其中所述cd123抗原是细胞表面标记抗原。30a.根据1a至27a中任一项的多肽，其中所述cd123抗原是肿瘤相关的表面抗原。31a.根据1a至27a中任一项的多肽，其中所述抗原是cd123，32a.根据1a至27a中任一项的多肽，其中vh和vl选自seqidno11，seqidno24至seqidno30的vh和seqidno12；-seqidno18至seqidno23的vl。33a.根据2a至32a中任一项的多肽，其中铰链包含cd8α铰链或fcγriiiα铰链。34a.根据2a至3a3中任一项的多肽，其中跨膜结构域包含一个或多个跨膜区cd8，35a.根据2a至33a中任一项的多肽，其中跨膜结构域包含cd8α的一个或多个跨膜区。36a.根据2a至33a中任一项的多肽，其中跨膜结构域包含cd8α的一个或多个跨膜区和来自cd8α的铰链。37a.根据2a至37a中任一项的多肽，其中胞内结构域包含cd3ζ信令结构域。38a.根据2a至37a中任一项的多肽，其中胞内结构域包含4-1bb结构域。39a.根据1a至38a中任一项的多肽，其中car是单链car。40a.根据1a至38a中任一项的多肽，其中car是多链car。40a根据1a至39a中任一项的多肽，其中car是选自seqidno189至seqidno197的序列。41a.一种编码根据1a至40a中任一项的多肽的多核苷酸。42a.一种编码根据1a至40a中任一项的嵌合抗原受体的多核苷酸，其中所述car包含cd3ζ信令结构域和来自4-1bb的共刺激结构域。43a.一种包含41a或42a的核酸的表达载体。44a.一种在其细胞表面表达根据1a至40a中任一项的多肽的工程化免疫细胞。45a.根据44a的工程化免疫细胞，其中所述细胞源自炎性t淋巴细胞，细胞毒性t淋巴细胞(ctl)，调节性t淋巴细胞或辅助性t淋巴细胞，优选ctl细胞。46a.根据44a或45a的工程化免疫细胞，用作药物。47a.一种用于工程化44a-46a中任一种的免疫细胞的方法，包括：(a)提供免疫细胞；(b)向所述细胞中引入至少一种编码根据1a至40a中任一项的嵌合抗原受体的多核苷酸。(c)将所述多核苷酸表达于所述细胞中。48a.用于工程化47a的免疫细胞的方法，其中免疫细胞是t细胞。49a.一种用于体外分选在其细胞表面表达根据权利要求1a至40a中任一项的包含至少一个mab特异性表位的多肽的工程化免疫细胞的方法，包括-将包含所述工程化免疫细胞的免疫细胞群体与对mab特异性表位特异性的单克隆抗体接触；-选择结合至单克隆抗体的细胞以获得富含工程化免疫细胞的细胞群。50a.根据49a的方法，其中对mab特异性表位特异性的单克隆抗体与荧光团结合，并且通过荧光活化细胞分选(facs)完成选择结合至单克隆抗体的细胞的步骤。51a.根据49a的方法，其中对mab特异性表位特异性的单克隆抗体与磁性颗粒结合，并且通过磁性活化细胞分选(macs)完成结合至单克隆抗体的细胞的选择的步骤。52a.根据49至51中任一项的方法，其中多肽包含具有seqidno160的氨基酸序列的mab特异性表位，而单克隆抗体是利妥昔单抗。53a.根据49a至51a中任一项的方法，其中多肽包含具有seqidno169的氨基酸序列的mab特异性表位，且用于接触免疫细胞群体的抗体是qbend-10。54a.根据49a至53a中任一项的方法，其中富含工程化免疫细胞的细胞群体包含至少70％、75％、80％、85％、90％、95％的表达car的免疫细胞。55a.一种用于在患者中体内消除在其细胞表面表达包含至少一种根据1a至40a中任一项的mab特异性表位的多肽的工程化免疫细胞的方法，包括使所述工程化免疫细胞与至少一个表位特异性mab接触。56a.根据56a的方法，其中mab特异性表位是cd20表位或模拟表位，且表位特异性mab是利妥昔单抗。57a.根据57a的方法，其中mab特异性表位具有seqidno160的氨基酸序列。58a.根据56a至58a中任一项的方法，其中表位特异性mab与可以活化补体系统的分子结合。59a.根据56a至58a中任一项的方法，其中将细胞毒性药物与表位特异性mab偶联。60a.一种用于在患者中体内消除在其细胞表面表达包含至少一种根据1a至40a任一项的mab特异性表位的多肽的工程化免疫细胞的方法，包括使所述工程化免疫细胞与能够与所述细胞上承载的mab特异性表位以及效应(和细胞毒性)细胞上承载的表面抗原结合的双特异性mab(bsab)接触。61a.根据47a至60a中任一项的方法，其中所述免疫细胞是t细胞。具体地，本发明还提供了1b，cd123特异性嵌合抗原受体(cd123car)，包含■胞外结构域，含有胞外配体结合域，其依次包含可选地人源化的vh，选自seqidno12、seqidno24、seqidno25、seqidno26、seqidno27、seqidno28、seqidno29和seqidno30，，接头，优选序列(ggggs)n的接头，其中n＝1-4，更优选n＝3，以及可选地人源化的vl，选自seqidno11，seqidno18，seqidno19，seqidno20，seqidno21，seqidno22和seqidno23，铰链，■来自cd8α的跨膜结构域，和■包含cd3ζ信令结构域和来自4-1bb的共刺激结构域的细胞质结构域。一种cd123特异性嵌合抗原受体(cd123car)，包含■细胞外结构域，含有胞外配体结合域，其依次包含选自seqidno12、seqidno24、seqidno25、seqidno26、seqidno27、seqidno28、seqidno29和seqidno30的vh，seqidno.10的接头和选自seqidno11、seqidno18、seqidno19、seqidno20、seqidno21、seqidno22和seqidno23的vl，铰链，■来自cd8α的跨膜结构域，和■包含cd3ζ信令结构域和来自4-1bb的共刺激结构域的细胞质结构域。2b本发明提供了根据1b的cd123car，其不包含与人cd28np_006130.1具有一致性的序列。3b本发明提供了根据1b或2b的cd123car，其中所述胞外结构域包含至少一个对选自seqidno161至seqidno170的序列的单克隆抗体，或其组合特异性的表位，优选至少一个对seqidno161的单克隆抗体特异性的表位。本发明提供一种cd123car，其中cd123car包含选自seqidno189至seqidno197的序列。本发明提供一种cd123car，其中cd123car包含seqidno190的序列本发明提供一种cd123car，其中cd123car包含seqidno191的序列本发明提供一种cd123car，其中cd123car包含seqidno192的序列本发明提供一种cd123car，其中cd123car包含seqidno193的序列本发明提供一种cd123car，其中cd123car包含seqidno194的序列本发明提供一种cd123car，其中cd123car包含seqidno195的序列本发明提供一种cd123car，其中cd123car包含seqidno196的序列本发明提供一种cd123car，其中cd123car包含seqidno197的序列。本发明提供了根据1b或2b的cd123car，其中所述胞外结构域包含含有至少一个对选自seqidno161、seqidno162、seqidno163、seqidno164、seqidno165、seqidno166、seqidno167、seqidno168和seqidno169和seqidno170的序列的单克隆抗体特异性的表位的scfv，优选地，本发明提供根据1b或2b的cd123car，其中所述胞外结构域包含含有对识别seqidno161的单克隆抗体特异性的两个表位和另外两个对识别seqidno169的单克隆抗体特异性的表位的scfv。4b.本发明提供了包含seqidno171的序列的根据3b的cd123car。5b.本发明提供了具有选自seqidno.31，seqidno.32，seqidno.33和seqidn°34至seqidn°160的序列的根据1b的cd123特异性嵌合抗原受体(cd123car)。6b.本发明提供了具有选自seqidn°34至seqidn°160的序列的根据1b至5b中任一项的cd123特异性嵌合抗原受体(cd123car)。7b.本发明提供了编码根据1b至6b中任一项的cd123特异性嵌合抗原受体(cd123car)的多核苷酸。8b.本发明提供了包含根据7b的多核苷酸的表达载体。9b)本发明提供了包含骨架和编码1b至6b中任一项中所限定的任一种cd123car的序列的表达载体。10b)本发明提供了包含骨架，优选包含ef1启动子的骨架，rqr8开放阅读框(rqr8orf)，编码上述1至8实施方式的任一种cd123car的序列的表达载体。11b)本发明提供了在细胞表面膜上表达根据1b至9b中任一项的cd123car的t-细胞受体(tcr)敲除(ko)或tcr和人脱氧胞苷激酶(dck)ko的工程化免疫细胞。12b)本发明提供了包含编码根据1b至6b中任一项的cd123特异性嵌合抗原受体(cd123car)的多核苷酸的tcrko或tcr和dckko工程化免疫细胞。一种tcrko或tcr和dckko工程化免疫细胞，其包含含有编码本发明的cd123特异性嵌合抗原受体(cd123car)的多核苷酸的表达载体。一种tcrko或tcr和dckko工程化免疫细胞，其包含含有骨架和包含编码本发明的cd123特异性嵌合抗原受体(cd123car)的多核苷酸的序列的表达载体。一种tcrko或tcr和dckko工程化免疫细胞，其包含含有骨架、ef1启动子、rqr8开放阅读框(rqr8orf)、编码本发明的任何一种cd123car的序列的表达载体。13b)本发明提供了根据11b或12b的tcrko或tcrko和dckko表达cd123car的工程化免疫细胞，其进一步在细胞表面表达自杀结构域。(14b)本发明提供了根据10b至13b中任一项的tcrko或tcrko和dckko表达cd123car的工程化免疫t细胞，其中细胞表面的所述自杀结构域插入到cd123car胞外结构域中。根据11b至14b中任一项的tcrko和dckko表达cd123car的工程化免疫细胞，其中dck基因缺失赋予对嘌呤核苷酸类似物(pna)的抗性。(15b)本发明提供了根据11b至14b中任一项的tcrko或tcrko和dckko表达cd123car的工程化免疫细胞，其中至少一种mhc蛋白的表达受到抑制。16b)本发明提供了根据(11b)至(15b)中任一项的tcrko或tcrko和dckko表达cd123car的工程化免疫细胞，用于治疗。本发明提供了包含如1b)至6b)中的cd123car的药物组合物。本发明提供了包含根据11b至15b中任一项的tcrko或tcrko和dckko表达cd123car的工程化免疫细胞的药物组合物。17b)本发明提供了根据16b的tcrko或tcrko和dckko表达cd123car的工程化免疫细胞，其中病症是急性髓细胞白血病(aml)，优选难治性/复发性aml，bpdnl，或用于骨髓移植期间使用。18b)本发明提供了根据16b的tcrko或tcrko和dckko表达cd123car的工程化免疫细胞，其用作治疗，优选用作淋巴增生性疾病的治疗，更优选用于淋巴瘤的白血病或用于选自急性髓细胞白血病、慢性髓细胞白血病、骨髓增生异常综合征、急性淋巴细胞白血病、慢性淋巴细胞白血病、以及骨髓增生异常综合征和bpdnl的治疗。本发明提供了如上的药物组合物，用于治疗。本发明提供了如上的药物组合物，用于治疗急性髓细胞白血病(aml)，优选难治性/复发性aml，bpdnl的治疗的疗法，或用于骨髓移植期间使用。本发明提供了一种药物组合物，其用作治疗，优选用作淋巴组织增生性疾病的治疗，更优选用于淋巴瘤的白血病的治疗或用于选自由急性髓细胞白血病、慢性髓细胞性白血病、骨髓增生异常综合征、急性淋巴样白血病、慢性淋巴细胞白血病、以及骨髓增生异常综合征和bpdnl组成的组的治疗。除非在本文中明确定义，所使用的所有技术和科学术语具有与本领域技术人员在基因疗法、药理学、免疫学、生物化学、遗传学和分子生物学领域通常理解的相同含义。与本文的那些相似或相当的所有方法和材料可以用于本发明的实践或测试，而合适的方法和材料将在本文中进行描述。本文提及的所有出版物、专利申请、专利和其它参考文献以其全部内容结合于本文中作为参考。在发生冲突的情况下，以本说明书为主，包括定义。此外，除非另有说明，材料、方法和实施例仅仅是说明性的而非旨在是限制性的。除非另有说明，本发明的实践将使用属于本领域技术范围内的细胞生物学、细胞培养、分子生物学、转基因生物学、微生物学、重组dna和免疫学的常规技术。这些技术在文献中充分解释。参见，例如，currentprotocolsinmolecularbiology(frederickm.ausubel，2000，wileyandsoninc，libraryofcongress，usa)；molecularcloning：alaboratorymanual，thirdedition，(sambrooketal，2001，coldspringharbor，newyork：coldspringharborlaboratorypress)；oligonucleotidesynthesis(m.j.gaited.，1984)；mullisetal.u.s.pat.no.4，683，195；nucleicacidhybridization(b.d.harries&s.j.higginseds.1984)；transcriptionandtranslation(b.d.hames&s.j.higginseds.1984)；cultureofanimalcells(r.i.freshney，alanr.liss，inc.，1987)；immobilizedcellsandenzymes(irlpress，1986)；b.perbal，apracticalguidetomolecularcloning(1984)；丛书，methodsinenzymology(j.abelsonandm.simon，eds.-in-chief，academicpress，inc.，newyork)，specifically，vols.154and155(wuetal.eds.)andvol.185，"geneexpressiontechnology"(d.goeddel，ed.)；genetransfervectorsformammaliancells(j.h.millerandm.p.caloseds.，1987，coldspringharborlaboratory)；immunochemicalmethodsincellandmolecularbiology(mayerandwalker，eds.，academicpress，london，1987)；handbookofexperimentalimmunology，volumesi-iv(d.m.weirandc.c.blackwell，eds.，1986)；和manipulatingthemouseembryo，(coldspringharborlaboratorypress，coldspringharbor，n.y.，1986)。本发明公开了表达包含含有来自单克隆抗-cd123抗体klon43的vh和vl或其人源化vh和人源化vh和vl序列、来自fcγriiiα的cd8α的铰链、来自cd8α的跨膜结构域、包括cd3ζ信令结构域和来自4-1bb的共刺激结构域的细胞质结构域的胞外配体结合域的cd123特异性嵌合抗原受体(“cd123car”或“car”)的工程化免疫细胞(tcrko和/或dckko)，所述123car具有与seqidno.31，seqidno.32，或seqidno.33，或seqidno.34至seqidno.117、seqidno.160或优选，seqidno188至seqidno197中任一种具有序列一致性。优选地，本发明公开了表达seqidn°31，32或160的cd123特异性car的遗传工程化免疫细胞(tcrko和/或dckko)，更优选地表达seqidn°31的cd123特异性car的工程化免疫细胞(tcrko)，而更加优选表达seqidn°32的cd123特异性car的工程化免疫细胞(tcrko和dckko)。有利地，本发明公开了表达seqidn°31，32或160和自杀结构域的cd123特异性car的工程化免疫细胞(tcrko和/或dckko)，更优选地表达seqidn°31的cd123特异性car和自杀结构域的工程化免疫细胞(tcrko)，更加优选表达seqidn°32的cd123特异性car的工程化免疫细胞(tcrko和dckko)，而甚至更加优选地表达seqidn°160或以下序列seqidno188至seqidno197中的一种的cd123特异性car的工程化免疫细胞(tcrko和dckko)。本发明公开了表达具有如图2所示的选自v1、v3的多肽结构中的一种的cd123特异性car的工程化免疫细胞(tcrko和/或dckko)，所述结构包含含有来自单克隆抗-cd123抗体klon43的vh和vl、来自cd8α或fcγriiia的铰链、来自cd8α的跨膜结构域、包括cd3ζ信令结构域和来自4-1bb的共刺激结构域的细胞质结构域且无来自cd28的序列的胞外配体结合结构域，所述123car具有与seqidno.31，seqidno.32，优选seqidno.32至少80％的序列一致性。本发明公开了表达具有如图2中所示的选自v1、v3的多肽结构中的一种的cd123特异性car的工程化免疫细胞(tcrko和/或dckko)，所述结构包含含有来自单克隆抗-cd123抗体klon43的vh和vl、来自cd8α或fcγriiia的铰链、来自cd8α的跨膜结构域、包括cd3ζ信令结构域和来自4-1bb的共刺激结构域的细胞质结构域且无来自cd28的序列的胞外配体结合域，123car具有与seqidno34至seqidno159，优选seqidno34至seqidno117，优选seqidno76至seqidno117中任一种具有至少80％的序列一致性。在一个实施方式中，本发明公开了一种表达具有选自seqidno.34、seqidno.76、seqidno.36、seqidno.78；seqidno.37、seqidno.79、seqidno.41、seqidno.83、seqidno.42、seqidno.8)、seqidno.43、seqidno.85、seqidno.46、seqidno.47、seqidno.48、seqidno.49、seqidno.88、seqidno.89、seqidno.90、seqidno.91.seqidno.52、seqidno.53、seqidno.54、seqidno.55、seqidno.94、seqidno.95、seqidno.96、seqidno.97中的序列的cd123特异性car的工程化免疫细胞(tcrko和/或dckko)。优选地，本发明公开了表达具有选自seqidno.34、seqidno.76、seqidno.36、seqidno.78；seqidno.43、seqidno.85、seqidno.46、seqidno.47、seqidno.48、seqidno.88、seqidno.89、seqidno.90、seqidno.52、seqidno.53、seqidno.54、seqidno.55、seqidno.94、seqidno.95、seqidno.96、seqidno.97的序列的cd123特异性car的工程化免疫细胞(tcrko和/或dckko)。更优选地，本发明公开了表达具有选自seqidno.47、seqidno.89、seqidno.52、seqidno.53、seqidno.54、seqidno.55、seqidno.94、seqidno.95、seqidno.96、seqidno.97的序列的cd123特异性car的工程化免疫细胞(tcrko和/或dckko)。并且更加优选地，发明公开了表达具有选自seqidno.32、seqidno.89、seqidno.94、seqidno.95、seqidno.96、seqidno.97的序列的cd123特异性123car的工程化免疫细胞(tcrko和/或dckko)。本发明最优选的实施方式公开了表达具有seqidno172的序列的cd123特异性123car的工程化免疫细胞(tcrko和/或dckko)，包含由特异性单克隆抗体识别的至少一个选自seqidno161至seqidno170的表位，优选seqidno161的两个和seqidno169的一个。另一最优选的实施方式公开了表达具有seqidno173的序列的cd123特异性123car的工程化免疫细胞(tcrko和/或dckko)，包含由特异性单克隆抗体识别的至少一个选自seqidno161至seqidno170表位，优选seqidno161的两个和seqidno169的一个。另一最优选的实施方式公开了表达具有seqidno174的序列的cd123特异性123car的工程化免疫细胞(tcrko和/或dckko)，包含由特异性单克隆抗体识别的至少一个选自seqidno161至seqidno170的表位，优选seqidno161的两个和seqidno169的一个。另一最优选的实施方式公开了表达具有seqidno175的序列的cd123特异性123car的工程化免疫细胞(tcrko和/或dckko)，包含由特异性单克隆抗体识别的至少一个选自seqidno161至seqidno170的表位，优选seqidno161的两个和seqidno169的一个。另一最优选的实施方式公开了表达具有seqidno176的序列的cd123特异性123car的工程化免疫细胞(tcrko和/或dckko)，包含由特异性单克隆抗体识别的至少一个选自seqidno161至seqidno170的表位，优选seqidno161的两个和seqidno169的一个。另一最优选的实施方式公开了表达具有seqidno177的序列的cd123特异性123car的工程化免疫细胞(tcrko和/或dckko)，包含由特异性单克隆抗体识别的至少一个选自seqidno161至seqidno170的表位，优选seqidno161的两个和seqidno169的一个。另一最优选的实施方式公开了表达具有seqidno178的序列的cd123特异性123car的工程化免疫细胞(tcrko和/或dckko)，包含由特异性单克隆抗体识别的至少一个选自seqidno161至seqidno170的表位，优选seqidno161的两个和seqidno169的一个。另一最优选的实施方式公开了表达具有seqidno179的序列的cd123特异性123car的工程化免疫细胞(tcrko和/或dckko)包含由特异性单克隆抗体识别的至少一个选自seqidno161至seqidno170的表位，优选seqidno161的两个和seqidno169的一个。另一最优选的实施方式公开了表达具有seqidno180的序列的cd123特异性123car的工程化免疫细胞(tcrko和/或dckko)，包含由特异性单克隆抗体识别的至少一个选自seqidno161至seqidno170的表位，优选seqidno161的两个和seqidno169的一个。另一最优选的实施方式公开了表达具有seqidno181的序列的cd123特异性123car的工程化免疫细胞(tcrko和/或dckko)包含由特异性单克隆抗体识别的至少一个选自seqidno161至seqidno170的表位，优选seqidno161的两个和seqidno169的一个。另一最优选的实施方式公开了表达具有seqidno182的序列的cd123特异性123car的工程化免疫细胞(tcrko和/或dckko)，包含由特异性单克隆抗体识别的至少一个选自seqidno161至seqidno170的表位，优选seqidno161的两个和seqidno169的一个。另一最优选的实施方式公开了表达具有seqidno183的序列的cd123特异性123car的工程化免疫细胞(tcrko和/或dckko)，包含由特异性单克隆抗体识别的至少一个选自seqidno161至seqidno170的表位，优选seqidno161的两个和seqidno169的一个。另一最优选的实施方式公开了表达具有seqidno184的序列的cd123特异性123car的工程化免疫细胞(tcrko和/或dckko)，包含由特异性单克隆抗体识别的至少一个选自seqidno161至seqidno170的表位，优选seqidno161的两个和seqidno169的一个。另一最优选的实施方式公开了表达具有seqidno185的序列的cd123特异性123car的工程化免疫细胞(tcrko和/或dckko)，包含由特异性单克隆抗体识别的至少一个选自seqidno161至seqidno170的表位，优选seqidno161的两个和seqidno169的一个。另一最优选的实施方式公开了表达具有seqidno186的序列的cd123特异性123car的工程化免疫细胞(tcrko和/或dckko)，包含由特异性单克隆抗体识别的至少一个选自seqidno161至seqidno170的表位，优选seqidno161的两个和seqidno169的一个。另一最优选的实施方式公开了表达具有seqidno187的序列的cd123特异性123car的工程化免疫细胞(tcrko和/或dckko)，包含由特异性单克隆抗体识别的至少一个选自seqidno161至seqidno170的表位，优选seqidno161的两个和seqidno169的一个。在另一最优选的实施方式中，本发明公开了表达具有seqidno.188的序列的cd123特异性123car的工程化免疫细胞(tcrko和/或dckko)在另一最优选的实施方式中，本发明公开了表达具有seqidno.189的序列的cd123特异性123car的工程化免疫细胞(tcrko和/或dckko)。在另一最优选的实施方式中，本发明公开了表达具有seqidno.190的序列的cd123特异性123car的工程化免疫细胞(tcrko和/或dckko)。在另一最优选的实施方式中，本发明公开了表达具有seqidno.191的序列的cd123特异性123car的工程化免疫细胞(tcrko和/或dckko)。在另一最优选的实施方式中，本发明公开了表达具有seqidno.192的序列的cd123特异性123car的工程化免疫细胞(tcrko和/或dckko)在另一最优选的实施方式中，本发明公开了表达具有seqidno.193的序列的cd123特异性123car的工程化免疫细胞(tcrko和/或dckko)。在另一最优选的实施方式中，本发明公开了表达具有seqidno.194的序列的cd123特异性123car的工程化免疫细胞(tcrko和/或dckko)在另一最优选的实施方式中，本发明公开了表达具有seqidno.195的序列的cd123特异性123car的工程化免疫细胞(tcrko和/或dckko)。在另一最优选的实施方式中，本发明公开了表达具有seqidno.196的序列的cd123特异性123car的工程化免疫细胞(tcrko和/或dckko)在另一最优选的实施方式中，本发明公开了表达具有seqidno.197的序列的cd123特异性123car的工程化免疫细胞(tcrko和/或dckko)。本发明公开了表达cd123特异性123car的工程化免疫细胞(tcrko和/或dckko)，其胞外结合结构域以允许细胞分选和细胞消除两者的方式改造。这种结构，即“mab-驱动的分选/消除系统”或“对单克隆抗体特异性的表位”或“模拟表位”，是插入到本发明的抗cd123car的细胞外结构域内，具体地插入到抗cd123scfv中；或tm和铰链之间的选择的表位；这种表位具有被特异性抗体(优选mab)识别的特异性。考虑到主要是car的外部配体结合域改造而包括该表位，可以设想不同的car结构：单链或多链。由vh和vl多肽和特异性表位形成的本发明的嵌合scfv本身可以具有不同的结构，取决于表位的插入位置和接头的使用。本发明还涉及用于分选和/或消除赋予改造的car的工程化免疫细胞的所获得的方法。在一些实施方式中，抗cd123car的胞外结合结构域包括以下序列(包括模拟表位)(n端位于左手侧)：v1-l1-v2-(l)x-表位1-(l)x；v1-l1-v2-(l)x-表位1-(l)x-表位2-(l)x；v1-l1-v2-(l)x-表位1-(l)x-表位2-(l)x-表位3-(l)x；(l)x-表位1-(l)x-v1-l1-v2；(l)x-表位1-(l)x-表位2-(l)x-v1-l1-v2；表位1-(l)x-表位2-(l)x-表位3-(l)x-v1-l1-v2；(l)x-表位1-(l)x-v1-l1-v2-(l)x-表位2-(l)x；(l)x-表位1-(l)x-v1-l1-v2-(l)x-表位2-(l)x-表位3-(l)x；(l)x-表位1-(l)x-v1-l1-v2-(l)x-表位2-(l)x-表位3-(l)x-表位4-(l)x；(l)x-表位1-(l)x-表位2-(l)x-v1-l1-v2-(l)x-表位3-(l)x；(l)x-表位1-(l)x-表位2-(l)x-v1-l1-v2-(l)x-表位3-(l)x-表位4-(l)x；v1-(l)x-表位1-(l)x-v2；v1-(l)x-表位1-(l)x-v2-(l)x-表位2-(l)x；v1-(l)x-表位1-(l)x-v2-(l)x-表位2-(l)x-表位3-(l)x；v1-(l)x-表位1-(l)x-v2-(l)x-表位2-(l)x-表位3-(l)x-表位4-(l)x；(l)x-表位1-(l)x-v1-(l)x-表位2-(l)x-v2；(l)x-表位1-(l)x-v1-(l)x-表位2-(l)x-v2-(l)x-表位3-(l)x；v1-l1-v2-l-表位1；v1-l1-v2-l-表位1-l；v1-l1-v2-l-表位1-l-表位2；v1-l1-v2-l-表位1-l-表位2-l；v1-l1-v2-l-表位1-l-表位2-l-表位3；v1-l1-v2-l-表位1-l-表位2-l-表位3-l；v1-l1-v2-表位1；v1-l1-v2-表位1-l；v1-l1-v2-表位1-l-表位2；v1-l1-v2-表位1-l-表位2-l；v1-l1-v2-表位1-l-表位2-l-表位3；v1-l1-v2-表位1-l-表位2-l-表位3-l；表位1-v1-l1-v2；表位1-l-v1-l1-v2；l-表位1-v1-l1-v2；l-表位1-l-v1-l1-v2；表位1-l-表位2-v1-l1-v2；表位1-l-表位2-l-v1-l1-v2；l-表位1-l-表位2-v1-l1-v2；l-表位1-l-表位2-l-v1-l1-v2；表位1-l-表位2-l-表位3-v1-l1-v2；表位1-l-表位2-l-表位3-l-v1-l1-v2；l-表位1-l-表位2-l-表位3-v1-l1-v2；l-表位1-l-表位2-l-表位3-l-v1-l1-v2；v1-l-表位1-l-v2；l-表位1-l-v1-l-表位2-l-v2；v1-l-表位1-l-v2-l-表位2-l；v1-l-表位1-l-v2-l-表位2-l-表位3；v1-l-表位1-l-v2-l-表位2-表位3；v1-l-表位1-l-v2-l-表位2-l-表位3-表位4；l-表位1-l-v1-l-表位2-l-v2-l-表位3-l；表位1-l-v1-l-表位2-l-v2-l-表位3-l；l-表位1-l-v1-l-表位2-l-v2-l-表位3；l-表位1-l-v1-l1-v2-l-表位2-l；l-表位1-l-v1-l1-v2-l-表位2-l-表位3；l-表位1-l-v1-l1-v2-l-表位2-表位3，或，表位1-l-v1-l1-v2-l-表位2-l-表位3-表位4。其中，v1和v2是scfv抗cd123的vh和vl(即，v1是vl且v2是vh或者v1是vh且v2是vl)；l1是适用于在scfv中将vh链连接至vl链的任何接头；l是接头，优选包含甘氨酸和丝氨酸残基，且胞外结合结构域中l的每次出现可以与相同的胞外结合结构域中l的其它出现相同或不同，并且x是0或1，且x的每次出现相互独立；并且，表位1、表位2和表位3是mab特异性表位(或模拟表位)并可以是相同的或不同的。在一些实施方式中，胞外结合结构域包含以下序列(n端位于左侧)：vh-l1-vl-l-表位1-l-表位2-l；l-表位1-l-vh-l-表位2-l-vl-l-表位3-l；vl-l1-vh-l-表位1-l-表位2-l；或，l-表位1-l-vl-l-表位2-l-vh-l-表位3-l。其中l，l1，表位1，表位2和表位3如以上定义。l1是包含甘氨酸和/或丝氨酸的接头。在一些实施方式中，l1是包含氨基酸序列(gly-gly-gly-ser)n或(gly-gly-gly-gly-ser)n的接头，其中n是1，2，3，4或5。在一些实施方式中，l1是(gly4ser)4或(gly4ser)3。l是优选地包含甘氨酸和/或丝氨酸的柔性接头。在一些实施方式中，l具有选自sgg、ggs、sggs、ssggs、gggg、sgggg、ggggs、sggggs、gggggs、sgggggs、sggggg、gsggggs、gggggggs、sggggggg、sgggggggs、或sggggsggggs，优选sgg、sggs、ssggs、gggg、sggggs、sgggggs、sggggg、gsggggs或sggggsggggs的氨基酸序列。在一些实施方式中，当胞外结合结构域包含l的多次出现时，所有的l都相同。在一些实施方式中，当胞外结合结构域包含l的多次出现时，l并不全部相同。在某些实施方式中，l是sggggs。在一些实施方式中，胞外结合结构域包括几次出现的l，且所有的l是sggggs。在一些实施方式中，表位1、表位2和表位3是相同的或不同的，并且选自具有如表7所示的氨基酸序列的mab特异性表位。在优选的实施方式中、表位1、表位2是相同的或不同的、并且选自由替伊莫单抗、莫罗单抗-cd3、托西莫单抗、阿昔单抗、巴利昔单抗、布伦昔单抗、西妥昔单抗、英夫利昔单抗、利妥昔单抗、阿伦单抗、贝伐单抗、赛妥珠单抗、达利珠单抗、艾库组单抗、依法珠单抗、吉妥珠单抗、那他珠单抗、奥马珠单抗、帕利珠单抗、雷珠单抗、托美珠单抗、曲妥珠单抗、韦多珠单抗、阿达木单抗、贝利木单抗、卡那单抗、地诺单抗、戈利木单抗、伊匹单抗、奥法木单抗、帕尼单抗、qbend-10、阿伦单抗或优特克单抗、优选已经批准医疗用途的那些，如作为非限制性实例的利妥昔单抗特异性识别的mab特异性表位。最后，本发明包括治疗方法，其中赋予car的工程化免疫细胞的数量、活化和/或存活通过使用在细胞表面直接结合至对cd123car中单克隆抗体特异性的至少一个表位的抗体来控制。本发明包括公开了各自表达本文中公开的任一种cd123特异性car，优选以下序列seqidno188至seqidno197中的一种的工程化免疫细胞(tcrko和/或dckko)的实施方式。本发明包括公开了编码允许制备各自表达上文公开的任何(每)一种cd123特异性car的工程化免疫细胞(tcrko和/或dckko)的载体的实施方式。具体地，本发明包括公开了编码以上公开的cd123特异性car中的一种(每种)，优选包含骨架的载体。本发明包括公开了编码允许制备各自表达本文中公开的任(每)一种cd123特异性car，优选以下序列seqidno188至seqidno197中的一种的工程化免疫细胞(tcrko和/或dckko)的载体的实施方式。本发明包括公开了包含各自表达上文中公开的任(每)一种cd123特异性car的工程化免疫细胞(tcrko和/或dckko)和药用载体的药物组合物的实施方式。本发明包括公开了包含各自表达以上公开的何(每)一种cd123特异性car的工程化免疫细胞(tcrko和/或dckko)的药物组合物和药用载体药物组合物用作药物的实施方式。本发明包括公开了包含104至1010/kg各自表达以上公开的任何(每)一种cd123特异性car的工程化免疫细胞(tcrko和/或dckko)和药用载体的药物组合物用作药物的实施方式。本发明公开了表达具有如图2所示和如上所述的多肽结构v3的特异性cd123car的工程化免疫细胞(tcrko和/或dckko)，其中所述cd123car与seqidno.31具有至少80％的序列一致性。本发明公开了表达具有如图2所示和如上所述的多肽结构v3的特异性cd123car的工程化免疫细胞(tcrko和/或dckko)，其中所述cd123car与seqidno.32具有至少80％的序列一致性。本发明公开了表达具有如图2所示和如上所述的多肽结构v3的特异性cd123car的工程化免疫细胞(tcrko和/或dckko)，其中cd123car与seqidno.33具有至少80％的序列一致性。本发明公开了表达具有如图2所示和如上所述的多肽结构v3的特异性cd123car的工程化免疫细胞(tcrko和/或dckko)，其中cd123car与seqidno.160具有至少80％的序列一致性。本发明公开了表达具有以下序列seqidno188至seqidno197之一的特异性cd123car的工程化免疫细胞(tcrko和/或dckko)。本发明公开了如上所述的表达cd123car的工程化免疫细胞(tcrko和/或dckko)，其中来自单克隆抗-cd123抗体的所述胞外配体结合域vh和vl分别包含至少一种以下序列：(变体vh1：seqidno.24)：evklvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsksilylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvss，(变体vh2：seqidno.25)：evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsksilylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvss，(变体vh3：seqidno.26)：evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsksiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvss，(变体vh4：seqidno.27)：evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvgfirskadgytteysasvkgrftisrddsksiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvss，(变体vh5：seqidno.28)：evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvgfirskadgytteyaasvkgrftisrddsksiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvss，(变体vh6：seqidno.29)：evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteyaasvkgrftisrddsksiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvss，(变体vh7：seqidno.30)：evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvgfirskadgytteyaasvkgrftisrddsksiaylqmnslktedtavyyctrdaayysyyspegamdywgqgtlvtvss，变体vh8evklvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsqsiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvss变体vh9：evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsqsiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvss变体vh10：evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteyaasvkgrftisrddsqsiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvss变体vh11：evqlvesggglvqpgrslrlsctasgftftdyymswvrqppgkglewvglirskadgytteysasvkgrftisrddsqsiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvss和以下序列中的一种：变体vl1：seqidno.18)：madykdivmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgrgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr，变体vl2：seqidno.19)：madykdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgrgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr，变体vl3：seqidno.20)：madykdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr，变体vl4：seqidno.21)：madykdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapklliysasyrysgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr，变体vl5：seqidno.22)：madykdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapklliysasyrqsgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr，和变体vl6：seqidno.23)：madykdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapklliysasygqsgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr，变体vl1a：divmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgrgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr变体vl2a：diqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgrgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr变体vl3a：diqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr变体vl4a：diqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapklliysasyrysgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr变体vl6a：diqmtqspssvsasvgdrvtitckasqnvdsavawyqqkpgkapklliysasyrysgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr变体vl7a：diqmtqspssvsasvgdrvtitckasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr变体vl8a：diqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgsgsgtdftltisslqpedlatyycqqyystpwtfgqgtkveikr变体vl9a：diqmtqspssvsasvgdrvtitckasqnvdsavawyqqkpgkapkaliysasyrysgvpdrfsgsgsgtdftltisslqpedlatyycqqyystpwtfgqgtkveikr本发明公开了如上所述的表达cd123特异性car的工程化免疫细胞(tcrko和/或dckko)，其中来自单克隆抗-cd123抗体的所述胞外配体结合结构域vh和vl分别包含以下序列中的至少一种：evklvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsksilylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvss(seqidno.24)，evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsksilylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvss(seqidno.25)，evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsksiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvss(seqidno.26)，evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvgfirskadgytteysasvkgrftisrddsksiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvss(seqidno.27)，evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvgfirskadgytteyaasvkgrftisrddsksiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvss(seqidno.28)，evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteyaasvkgrftisrddsksiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvss(seqidno.29)，evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvgfirskadgytteyaasvkgrftisrddsksiaylqmnslktedtavyyctrdaayysyyspegamdywgqgtlvtvss(seqidno.30)，madykdivmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgrgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr，(seqidno.18)madykdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgrgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr(seqidno.19)，madykdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr(seqidno.20)，madykdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapklliysasyrysgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr(seqidno.21)，madykdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapklliysasyrqsgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr(seqidno.22)，和madykdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapklliysasygqsgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr，(seqidno.23)或它们的组合。有利地，本发明公开了如上所述的表达cd123特异性car的工程化免疫细胞(tcrko和/或dckko)，其中来自单克隆抗cd123抗体的所述胞外配体结合结构域vh和vl分别包含以下序列至少一种：evklvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsksilylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvss，(seqidn°24)evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsksilylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvss，(seqidn°25)evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsksiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvss，(seqidn°26)evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvgfirskadgytteysasvkgrftisrddsksiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvss，(seqidn°27)evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvgfirskadgytteyaasvkgrftisrddsksiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvss，(seqidn°28)evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteyaasvkgrftisrddsksiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvss，(seqidn°29)evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvgfirskadgytteyaasvkgrftisrddsksiaylqmnslktedtavyyctrdaayysyyspegamdywgqgtlvtvss，(seqidn°30)和以下序列中的至少一种：madykdivmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgrgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr，(seqidn°18)madykdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgrgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr，(seqidn°19)madykdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr，(seqidn°20)madykdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapklliysasyrysgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr，(seqidn°21)madykdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapklliysasyrqsgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr，(seqidn°22)madykdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapklliysasygqsgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr(seqidn°23)在更优选的实施方式中，本发明提供了具有各自来自(seqidno172至seqidno187)的序列的car：huk43-vh10/vl1evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteyaasvkgrftisrddsqsiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvssggggsggggsggggsdivmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgrgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikrtttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapayqqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr(seqidno172)huk43-vh9/vl6evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsqsiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvssggggsggggsggggsdiqmtqspssvsasvgdrvtitckasqnvdsavawyqqkpgkapklliysasyrysgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikrtttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapayqqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr(seqidno173)huk43-vh10/vl3evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteyaasvkgrftisrddsqsiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvssggggsggggsggggsdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikrtttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapayqqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr(seqidno174)huk43-vh9/vl8evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsqsiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvssggggsggggsggggsdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgsgsgtdftltisslqpedlatyycqqyystpwtfgqgtkveikrtttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapayqqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr(seqidno175)huk43-vh2/vl3evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsksilylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvssggggsggggsggggsdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikrtttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapayqqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr(seqidno176)huk43-vh10/vl9evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteyaasvkgrftisrddsqsiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvssggggsggggsggggsdiqmtqspssvsasvgdrvtitckasqnvdsavawyqqkpgkapkaliysasyrysgvpdrfsgsgsgtdftltisslqpedlatyycqqyystpwtfgqgtkveikrtttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapayqqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr(seqidno177)huk43-vh9/vl3evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsqsiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvssggggsggggsggggsdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikrtttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapayqqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr(seqidno178)huk43-vh2/vl1evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsksilylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvssggggsggggsggggsdivmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgrgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikrtttpaprpptpaptiasqplslrpeacrpaaggavhtrgldfacdiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapayqqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr(seqidno179)在另一实施方式中，本发明提供了赋予以下car的工程化免疫细胞。v5huk43-vh10/vl1evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteyaasvkgrftisrddsqsiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvssggggsggggsggggsdivmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgrgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikrepkspdkthtcppcpappvagpsvflfppkpkdtlmiartpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgkiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapayqqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr(seqidno180)huk43-vh9/vl6evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsqsiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvssggggsggggsggggsdiqmtqspssvsasvgdrvtitckasqnvdsavawyqqkpgkapklliysasyrysgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikrepkspdkthtcppcpappvagpsvflfppkpkdtlmiartpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgkiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapayqqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr(seqidno181)huk43-vh10/vl3evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteyaasvkgrftisrddsqsiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvssggggsggggsggggsdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikrepkspdkthtcppcpappvagpsvflfppkpkdtlmiartpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgkiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapayqqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr(seqidno182)huk43-vh9/vl8evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsqsiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvssggggsggggsggggsdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgsgsgtdftltisslqpedlatyycqqyystpwtfgqgtkveikrepkspdkthtcppcpappvagpsvflfppkpkdtlmiartpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgkiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapayqqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr(seqidno183)huk43-vh2/vl3evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsksilylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvssggggsggggsggggsdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikrepkspdkthtcppcpappvagpsvflfppkpkdtlmiartpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgkiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapayqqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr(seqidno184)huk43-vh10/vl9evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteyaasvkgrftisrddsqsiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvssggggsggggsggggsdiqmtqspssvsasvgdrvtitckasqnvdsavawyqqkpgkapkaliysasyrysgvpdrfsgsgsgtdftltisslqpedlatyycqqyystpwtfgqgtkveikrepkspdkthtcppcpappvagpsvflfppkpkdtlmiartpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgkiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapayqqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr(seqidno185)huk43-vh9/vl3evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsqsiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvssggggsggggsggggsdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikrepkspdkthtcppcpappvagpsvflfppkpkdtlmiartpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgkiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapayqqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr(seqidno186)huk43-vh2/vl1evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsksilylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvssggggsggggsggggsdivmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgrgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikrepkspdkthtcppcpappvagpsvflfppkpkdtlmiartpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsdiavewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgkiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapayqqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr(seqidno187)。本发明公开了如上所述的表达cd123特异性car的工程化免疫细胞(tcrko和/或dckko)，其中所述结构v3(参见图2)优选包含cd8α铰链和cd8α跨膜结构域，而无cd28序列。本发明公开了如上所述的表达cd123特异性car的工程化免疫细胞(tcrko和/或dckko)，其中所述结构v3包含cd8α铰链，4-1bb胞质结构域和cd8α跨膜结构域。本发明公开了如上所述的表达cd123特异性car的工程免疫细胞(tcrko和/或dckko)，其中所述结构v3包含cd8α铰链和4-1bb跨膜结构域而无来自cd28的序列。本发明公开了如上所述的表达cd123特异性car的工程化免疫细胞，并进一步包含对cd123不是特异性的另一胞外配体结合结构域。在优选的实施方式中，对cd123不是特异性的另一胞外配体结合结构域是自杀结构域，更优选如专利申请pa201570044表2)中公开的任何一种的自杀结构域。本发明公开了如上所述的表达cd123特异性car的工程化免疫细胞(tcrko和/或dckko)，其中所述cd123特异性car包含通过含有g和s的接头li结合的含有至少一个seqidno：161，优选至少两个seqidno：161的自杀体结构域。在一个实施方式中，所述自杀结构域整合到本发明的cd123car的铰链结构域中。在一个更优选的实施方式中，本发明提供了seqidno:160的或与seqidno:160具有至少95％一致性的cd123car。如专利申请pa201570044的表2中所描述的那些的其它自杀结构域适用于本发明，将其以其全部内容通过引证结合于本文中。本发明公开了如上所述的工程化免疫细胞，其中在所述工程化免疫细胞中抑制了至少一种mhc蛋白质，优选β2m或hla的表达。β2m代表β2微球蛋白而hla代表人白细胞抗原。mhc蛋白是i类或ii类的mhc蛋白。本发明公开了如上的工程化免疫细胞，其中所述工程化免疫细胞工程化为赋予对至少一种免疫抑制药物、化疗药物或抗癌药物，优选对嘌呤类似物的抗性。本发明公开了包含药用载体和如上所述的表达cd123特异性car的工程化免疫细胞(tcrko和/或dckko)中的任一种的组合物。本发明公开了一种包含药用载体和如上所述的表达cd123特异性car的上述工程化免疫细胞(tcrko和/或dckko)和另一种药物，优选嘌呤类似物而更优选flag治疗的组合物。根据本发明的嘌呤类似物的实例可以是喷司他丁(pentostatin)，氟达拉滨2-脱氧腺苷(fludarabine2-deoxyadenosine)，克拉屈滨(cladribine)，氯法拉滨(clofarabine)，奈拉滨(nelarabine)，优选喷司他丁，氟达拉滨单磷酸酯和2-氯脱氧腺苷(2-cda)。可以与本发明的cd123t细胞相关的flag治疗的实例如下：无添加的标准flag，flag-ida，mito-flag，flamsa。根据本发明的flag治疗的实例可以是无添加的标准flagflag-idamito-flagflamsa本文公开了以下组合治疗：本发明公开了如上所述的任一种的工程化免疫细胞，包含如上文所公开的所述工程化免疫细胞的组合物，用于治疗。本发明公开了本发明的工程化免疫细胞，包含如上的所述工程化免疫细胞的组合物，用于如上所述的治疗，其中患者是人。本发明公开了工程化免疫细胞，包含如上公开的所述工程化免疫细胞的组合物，用于如上所述的治疗，其中病症是特征为表达cd123的细胞的恶性前或恶性癌症。本发明公开了工程化免疫细胞，包含如上公开的所述工程化免疫细胞的组合物，用于如上所述的治疗，其中病症是特征为过多的表达cd123的细胞的病症。本发明公开了工程化免疫细胞，包含如上公开的所述工程化免疫细胞的组合物，用于如上所述的治疗，其中恶性癌症病症是血液癌症病症。本发明公开了工程化免疫细胞，包含如上公开的所述工程化免疫细胞的组合物，用于如上所述的治疗，其中血液癌症病症是白血病或恶性淋巴增生性疾病。本发明公开了工程化免疫细胞，包含如上公开的所述工程化免疫细胞的组合物，用于如上所述的治疗，其中所述白血病选自由急性髓细胞白血病，慢性髓细胞白血病，骨髓增生异常综合征，急性淋巴细胞白血病，慢性淋巴细胞白血病和骨髓增生异常综合征组成的组。本发明公开了工程化免疫细胞，包含如上公开的所述工程化免疫细胞的组合物，用于如上所述的治疗，其中白血病是急性髓细胞白血病(aml)，优选难治性/复发性aml。在一个实施方式中，本发明公开了工程化免疫细胞，包含如上公开的所述工程化免疫细胞的组合物，用于如上所述的治疗，其中血液癌症是恶性淋巴组织增生性疾病。本发明公开了工程化免疫细胞，用于如上所述的治疗，其中所述恶性淋巴组织增生性疾病是淋巴瘤。本发明公开了工程免疫细胞，用于如上所述的治疗，其中所述淋巴瘤选自由多发性骨髓瘤，非霍奇金淋巴瘤，burkitt淋巴瘤和滤泡性淋巴瘤(小细胞和大细胞)组成的组。表达于本发明的tcrko和dckkot细胞，104至108细胞/kg中的seqidn°31或seqidn°32或seqidn°160的cd123car，与无添加flag治疗组合，用于aml，优选难治性复发性aml的治疗。表达于本发明的tcrko和dckkot细胞，104至108细胞/kg中的seqidno°31或seqidno°32或seqidno°160的cd123car，与无添加flag治疗组合，用于bpdcn的治疗。表达于本发明的tcrko和dckkot细胞，104至108细胞/kg中的seqidno°31或seqidno°32或seqidno°160的cd123car，与无添加flag治疗组合，用作骨髓移植前作为移植过渡的治疗。表达于本发明的tcrko和dckkot细胞(104至108细胞/kg)中的seqidno°31或seqidno°32或seqidno°160的cd123car，与氟达拉滨(20mg/kg至50mg/kg)组合，用于aml，优选难治性复发性aml的治疗。表达于本发明的tcrko和dckkot细胞(104至108个细胞/kg)中的seqidno°31或seqidno°32或seqidno°160的cd123car，与氟达拉滨(20mg/kg至50mg/kg)组合，用于bpdcn的治疗。表达于本发明的tcrko和dckkot细胞(104至108个细胞/kg)中的seqidno°31或seqidno°32或seqidno°160的cd123car，与氟达拉滨(20mg/kg至50mg/kg)组合，用作骨髓移植前作为移植过渡的治疗。本发明公开了减少血液癌细胞的方法，包括以有效引起所述癌细胞减少的量(104至108细胞/kg)使所述血液癌细胞与本发明的工程化细胞接触。本发明公开了工程化免疫细胞的方法，包括：1.由供体提供免疫细胞，2.敲除tcr基因，3.在所述细胞的表面上表达如以上任何一种根据本发明的cd123特异性嵌合抗原受体。供体可以是患癌症的患者本身(对于自体过继转移)或另一个人(对于过继转移同种异体t细胞)。本发明公开了工程化如上所述的免疫细胞的方法，包括：1.由供体提供免疫细胞，2.敲除tcr基因，以及dck基因3.通过将至少一种编码所述cd123特异性嵌合抗原受体的多核苷酸引入所述细胞中而在所述细胞表面表达根据上述任一项的cd123特异性嵌合抗原受体，在更优选的实施方式中，所述方法包括在细胞表面上表达自杀结构域。本发明公开了工程化如上所述的免疫细胞的方法，包括：1.提供免疫细胞，2.使用seqidno:16和seqidno:17的半tale-核酸酶talen敲除tcr基因，以及dck基因3.通过向所述细胞中引入至少一种编码所述cd123特异性嵌合抗原受体的多核苷酸，在所述细胞表面上表达根据以上的任一种cd123特异性嵌合抗原受体。在优选的实施方式中，所述方法包括在细胞表面上表达自杀结构域，优选地由以下抗体中的一种识别的自杀结构域：替伊莫单抗、莫罗单抗-cd3、托西莫单抗、阿昔单抗、巴利昔单抗、布伦昔单抗、西妥昔单抗、英夫利昔单抗、利妥昔单抗、阿伦单抗、贝伐单抗、赛妥珠单抗、达利珠单抗、艾库组单抗、依法珠单抗、吉妥珠单抗、那他珠单抗、奥马珠单抗、帕利珠单抗、雷珠单抗、托美珠单抗、曲妥珠单抗、韦多珠单抗、阿达木单抗、贝利木单抗、卡那单抗、地诺单抗、戈利木单抗、伊匹单抗、奥法木单抗、帕尼单抗、qbend-10、阿伦单抗或优特克单抗。在另一实施方式中，所述方法进一步包括将本发明的所述工程化免疫细胞结合至如本文公开的那些选自以下的特异性单克隆抗原：替伊莫单抗、莫罗单抗-cd3、托西莫单抗、阿昔单抗、巴利昔单抗、布伦昔单抗、西妥昔单抗、英夫利昔单抗、利妥昔单抗、阿伦单抗、贝伐单抗、赛妥珠单抗、达利珠单抗、艾库组单抗、依法珠单抗、吉妥珠单抗、那他珠单抗、奥马珠单抗、帕利珠单抗、雷珠单抗、托美珠单抗、曲妥珠单抗、韦多珠单抗、阿达木单抗、贝利木单抗、卡那单抗、地诺单抗、戈利木单抗、伊匹单抗、奥法木单抗、帕尼单抗、qbend-10、阿伦单抗或优特克单抗。本发明公开了治疗对其需要的受试者的方法，包括：1.提供在表面表达根据上述任一种的cd123特异性嵌合抗原受体的免疫细胞或包含其的组合物2.将所述免疫细胞给药于所述患者。在优选实施方式中，所述组合物进一步包含嘌呤类似物氟达拉滨在另一实施方式中，所述组合物与flag治疗，无添加flag治疗相关。在一个实施方式中，所述对其需要的受试者患有aml，优选难治性复发性aml，bpdnl，或必须进行骨髓移植。本发明公开了如上的治疗对其需要的受试者的方法，其中免疫细胞由供体提供。本发明公开了一种如上的治疗对其需要的受试者的方法，其中所述免疫细胞由患者本身提供。cd123特异性嵌合抗原受体本发明涉及新的抗cd123嵌合抗原受体(car)，其包含来自或源自klon43抗体的胞外配体结合结构域，来自cd8α的跨膜结构域，来自cd8α或fcγriiiα的铰链，自杀域和信令转导域。在优选的实施方式中，所述自杀结构域整合到铰链结构域中。在更优选的实施方式中，所述自杀结构域包含整合到铰链结构域中的至少两个seqidno161的序列。在优选的实施方式中，本发明的所述抗cd123car是seqidno:31，32或160的多肽，在另一实施方式中，本发明的所述抗-cd123car是seqidno:34至seqidno:15，seqidno:34至seqidno:117，seqidno:76至seqidno:117的多肽。本文所用的术语“胞外配体结合结构域”定义为能够结合cd123的寡肽或多肽。优选地，胞外配体结合结构域可以选择为识别充当与特定疾病状态相关的靶细胞上的细胞表面标记的cd123。更优选地，胞外配体结合结构域可以选择为识别充当与aml，bpdcn或涉及癌症病症中的表达cd123的细胞相关的靶细胞上的细胞表面标记的cd123。在优选的实施方式中，所述胞外配体结合结构域包含含有靶抗原特异性单克隆抗cd-123抗体klon43的通过柔性接头连接的轻(vl)和重(vh)可变片段的单链抗体片段(scfv)。所述vl和vh优选选自表1至2中公开的序列，更优选选自包含来自或源自klon43的vh、接头和vl(如表2中的人源化vh和vl)的scfv。它们优选通过包含序列seqidno.10的序列(ggggs)n，其中n＝1至4，更优选n＝3的柔性接头连接至一起。换句话说，所述car优选包含含有与选自由vh的seqidno:12和vl的seqidno:11以及人源化片段的seqidno:18至seqidno:30(见表2)组成的组中的氨基酸序列具有100％的一致性的多肽序列的胞外配体结合域。本文使用的术语“重组抗体”是指使用重组dna技术产生的抗体或抗体片段，如例如由噬菌体、酵母表达系统或哺乳动物细胞表达系统表达的抗体或抗体片段。该术语也应解释为是指通过合成编码抗体或抗体片段的dna分子产生的抗体或抗体片段，并且该dna分子表达抗体或抗体片段蛋白，或指定抗体或抗体片段的氨基酸序列，其中dna或氨基酸序列已经使用本领域可用和熟知的重组或合成dna或氨基酸序列技术获得。正如本文所用的术语“保守序列改造”或“人源化”或“人源化抗体”或“人源化抗体片段”，“人源化vh或人源化vl”旨在是指不会显著影响或改变car的结合特性和/或不显著影响含有改造的氨基酸序列的car的活性和降低或消除人抗鼠抗体(hama)响应的氨基酸改造。在优选的实施方式中，氨基酸改造显著改善car的结合特性和/或显著改善含有改造的氨基酸序列的car的活性，并降低或消除人抗鼠抗体(hama)响应。这种保守改造包括在所述car和/或所述car分子的任何其它部分中的抗体片段内的氨基酸取代、添加和缺失。通过本领域已知的标准技术，如定向诱变，pcr介导诱变或通过使用优化的种系序列，可以将改造引入抗体，引入抗体片段或本发明的car分子的任何其它部分中。保守氨基酸取代是其中氨基酸残基被具有相似侧链的氨基酸残基取代的一种。具有相似侧链的氨基酸残基家族已经在本领域中定义。这些家族包括以下的氨基酸：具有碱性侧链(例如赖氨酸、精氨酸、组氨酸)、酸性侧链(例如天冬氨酸、谷氨酸)、不带电荷的极性侧链(例如甘氨酸、天冬酰胺、谷氨酰胺、丝氨酸、苏氨酸、酪氨酸、半胱氨酸、色氨酸)、非极性侧链(例如丙氨酸、缬氨酸、亮氨酸、异亮氨酸、脯氨酸、苯丙氨酸、甲硫氨酸)、β-支链侧链(例如、苏氨酸、缬氨酸、异亮氨酸)和芳族侧链(例如、酪氨酸、苯丙氨酸、色氨酸、组氨酸)。因此，本发明的car内的一个或多个氨基酸残基可以被来自相同侧链家族的其它氨基酸残基取代，并且改变的car可以使用本文描述的功能性试验对结合cd123的能力测试。在一个实施方式中，所述scfv包含结合至单克隆抗体的至少一个，优选两个表位。这种表位的实例在表7中公开。根据本发明的car的信号转导结构域或胞内信令结构域负责胞外配体结合结构域结合至靶标后的胞内信号传导，导致免疫细胞的活化和免疫响应。换言之，信号转导结构域负责活化其中表达car的免疫细胞的至少一种正常效应功能。例如，t细胞的效应功能可以是细胞溶解活性或辅助活性，包括细胞因子的分泌。因此，术语“信号转导结构域”是指转导效应信号功能信号并引导细胞执行专门功能的蛋白部分。用于car的信号转导结构域的优选实例可以是t细胞受体和抗原受体衔接之后共同作用以引发信号转导的共受体的细胞质序列，以及这些序列的任何衍生物或变体和任何具有相同功能性能力的合成序列。信号转导结构域包含两种不同类型的细胞质信令序列，引发抗原依赖性初级活化的那些，以及以抗原非依赖性方式作用而提供次级或共刺激信号的那些。初级细胞质信令序列可以包含被称为itam的免疫受体酪氨酸类活化基序的信令基序。itam是在用作syk/zap70类酪氨酸激酶的结合位点的各种受体的胞质内尾区中发现的明确定义的信令基序。本发明中使用的itam的实例可以包括作为非限制性实例的源自tcrζ、fcrγ、fcrβ、fcrε、cd3γ、cd3δ、cd3ε、cd5、cd22、cd79a、cd79b和cd66d的那些。在优选的实施方式中，car的信令转导结构域可以包含具有与选自由seqidno:9组成的组中的氨基酸序列至少70％、优选至少80％、更优选至少90％、95％、97％或99％的序列一致性的氨基酸序列的cd3ζ信令结构域。在具体的实施方式中，本发明的car的信号转导结构域包含共刺激信号分子。共刺激分子是除抗原受体外的细胞表面分子或其有效免疫响应所需的配体。“共刺激配体”是指特异性结合t细胞上的同源共刺激分子的抗原呈递细胞上的分子，从而提供除了通过例如tcr/cd3复合物与加载有肽的mhc分子的结合提供的初级信号之外介导t细胞响应，包括但不限于增殖活化，分化等的信号。共刺激配体可以包括但不限于cd7、b7-1(cd80)、b7-2(cd86)、pd-l1、pd-l2、4-1bbl、ox40l、诱导型共刺激配体(icos-l)、胞间粘附分子(icam、cd30l、cd40、cd70、cd83、hla-g、mica、m1cb、hvem、淋巴毒素β受体、3/tr6、ilt3、ilt4、结合toll配体受体的激动剂或抗体、和特异性地结合b7-h3的配体。共刺激配体除此之外还涵盖与t细胞上存在的共刺激分子特异性结合的抗体，如但不限于cd27、cd28、4-1bb、ox40、cd30、cd40、pd-1、icos、淋巴细胞功能相关抗原-1(lfa-1)、cd2、cd7、ltght、nkg2c、b7-h3、与cd83特异性结合的配体。“共刺激分子”是指t细胞上与共刺激配体特异性结合的同源结合配偶体，从而由细胞介导共刺激响应，例如但不限于增殖。共刺激分子包括但不限于mhci类分子，btla和toll配体受体。共刺激分子的实例包括cd27、cd28、cd8、4-1bb(cd137)、ox40、cd30、cd40、pd-1、icos、淋巴细胞功能相关抗原-1(lfa-1)、cd2、cd7、light、nkg2c、b7-h3和与cd83特异性结合的配体。在一个实施方式中，本发明的car的信号转导结构域，特别是共刺激分子，并不包括cd28(np_006130.1)。在一个优选的实施方式中，本发明的car不包括人cd28(np_006130.1)的序列和/或来自任何其它cd28的序列。在另一优选的实施方式中，本发明的car的信号转导结构域包含选自由4-1bb(genbank：aaa53133)的片段组成的组中的共刺激信号分子的部分。具体地，本发明的car的信号转导结构域包含含有与选自由seqidno:8组成的组中的氨基酸序列具有至少70％、优选至少80％、更优选至少90％、95％、97％或99％的序列一致性的氨基酸序列。根据本发明的car表达于细胞的表面膜上。因此，这样的car进一步包含跨膜结构域。合适的跨膜结构域的区别特征包括在细胞，在本发明中优选免疫细胞，特别是淋巴细胞或天然杀手(nk)细胞的表面上表达和一起相互作用用于引导免疫细胞对抗预定义的靶细胞的细胞响应的能力。跨膜结构域可以源自天然的或合成的来源。跨膜结构域可以源自任何膜结合蛋白或跨膜蛋白。作为非限制性实例，跨膜多肽可以是t细胞受体的亚单位，如α，β，γ或δ，构成cd3复合物的多肽，il2受体p55(α链)，p75(β链)或γ链，fc受体的亚单位链，特别是fcγ受体iii或cd蛋白。另外，跨膜结构域可以是合成的，并可以主要包含疏水性残基如亮氨酸和缬氨酸。在优选的实施方式中，所述跨膜结构域(tm)源自人cd8α链(例如，np_001139345.1)、igg1、igg4、fcγriiiα。在更优选的实施方式中，所述tm结构域包含seqidno6的序列或部分。根据本发明的cd123car通常进一步包含来自cd8α的跨膜结构域(tm)，显示出与seqidno.6的多肽至少90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或100％的序列一致性。在一个实施方式中，本发明的cd123car不包含来自4-1bb，优选序列iisfflaltstlfllffltlrfsvv(seqidno.7)的tm结构域。在更优选的实施方式中，所述铰链是seqidno.171。根据本发明的car包括在所述胞外配体结合结构域和所述跨膜结构域之间的铰链区。本文使用的术语“铰链区”通常是指作用为将跨膜结构域连接到胞外配体结合结构域的任何寡肽或多肽。具体地，铰链区用于为胞外配体结合结构域提供更多的柔性和可接近性。铰链区可以包含多达300个氨基酸，优选10至100个氨基酸而最优选25至50个氨基酸。铰链区可以源自天然存在的分子的全部或部分，如来自cd8、cd4的胞外区的全部或部分，或来自抗体恒定区的全部或部分。在一个实施方式中，所述铰链区域包含至少一个由单克隆抗体识别的表位，如表7所公开。在一个实施方式中，所述铰链区包含seqidn°161的，优选seqidn°171的至少两个序列。在一个实施方式中，本发明的所述cd123car包括scfv中的seqidn°161的至少一个序列。在一个实施方式中，本发明的所述cd123car包括scfv中，优选在scfv的n端的seqidn°161的两个序列和seqidno169的序列。另外，铰链区可以是对应于天然存在的铰链序列的合成序列，或可以是完全合成的铰链序列。在优选的实施方式中，所述铰链结构域包含在本说明书中分别称为seqidno.3，seqidno.4和seqidno.5的人cd8α链、fcγriiiα受体或igg1的一部分，或优选显示出与这些多肽至少80％、更优选至少90％、95％、97％或99％的序列一致性的铰链多肽。在更优选的实施方式中，所述铰链结构域包含人cd8α链或fcγriiiα受体的一部分，更优选铰链结构域包含序列seqidno.3或seqidno.4的序列，或与seqidno.3或seqidno.4具有至少80％、更优选至少90％、95％、97％或99％的序列一致性。其他另外的scfv通常在癌细胞中观察到靶抗原的下调或突变，产生抗原缺失逃逸变体。因此，为了抵消肿瘤逃逸并使免疫细胞对靶标更具特异性，根据本发明的cd123特异性car可以包含另一胞外配体结合结构域，以同时结合靶中的不同元件，从而增强免疫细胞活化和功能。在一个实施方式中，胞外配体结合域可以串联置于同一跨膜多肽上，并可选地可以通过接头分开。在另一实施方式中，所述不同的胞外配体结合结构域可以置于构成car的不同跨膜多肽上。在另一实施方式中，本发明涉及各自包含不同胞外配体结合域的car群体。具体地，本发明涉及工程化免疫细胞的方法，包括提供免疫细胞，并在所述细胞的表面表达各自包含不同胞外配体结合结构域的car群体。在另一具体实施方式中，本发明涉及工程化免疫细胞的方法，包括提供免疫细胞，并将编码构成各自包含不同胞外配体结合结构域的car群体的多肽引入所述细胞中。对于car群体，其是指至少两个、三个、四个、五个、六个或更多个car，每个car包含不同的胞外配体结合域。根据本发明的不同胞外配体结合结构域可以优选同时结合靶中的不同元件，从而增加免疫细胞的活化和功能。本发明还涉及包含各自含有不同胞外配体结合结构域的car群体的分离的免疫细胞。在优选的实施方式中，根据本发明的cd123car包含seqidno.31的多肽或seqidno.32的多肽，更优选根据本发明的cd123car包含与seqidno.31具有至少80％一致性，优选80％至99％一致性的多肽或与seqidno.32具有80％至99％一致性的多肽。更加优选地，根据本发明的car包含与seqidno.31的多肽或与seqidno.32具有85％至99％一致性的多肽。在优选的实施方式中，根据本发明的cd123car包含具有以下序列seqidno.31的多肽。在优选的实施方式中，根据本发明的cd123car包含具有选自以下序列seqidno.32，seqidno.31和seqidno.160的多肽。在一个优选的实施方式中，根据本发明的car包含至少一种选自以下序列的多肽：evklvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsksilylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvss，(seqidno.24)evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsksilylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvss，(seqidno.25)evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsksiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvss，(seqidno.26)evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvgfirskadgytteysasvkgrftisrddsksiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvss，(seqidno.27)evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvgfirskadgytteyaasvkgrftisrddsksiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvss，(seqidno.28)evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteyaasvkgrftisrddsksiaylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvss(seqidno.29)和evqlvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvgfirskadgytteyaasvkgrftisrddsksiaylqmnslktedtavyyctrdaayysyyspegamdywgqgtlvtvss(seqidno.30)和至少一种选自以下序列的序列madykdivmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgrgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr，(seqidno.18)madykdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgrgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr，(seqidno.19)madykdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr，(seqidno.20)madykdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapklliysasyrysgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr，(seqidno.21)madykdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapklliysasyrqsgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr(seqidno.22)和madykdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapklliysasygqsgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikr(seqidno.23)。在一个实施方式中，根据本发明的cd123car包含一种选自以下序列的多肽：seqidno.24、seqidno.25、seqidno.26、seqidno.27、seqidno.28、seqidno.29和seqidno.30，和选自以下序列的肽：seqidno.18、seqidno.19、seqidno.20、seqidno.21、seqidno.22和seqidno.23。在一个实施方式中，根据本发明的cd123car包含与seqidno.11的多肽具有80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％的一致性，或与seqidno.12的多肽具有至少80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％的一致性的多肽。在更优选的实施方式中，根据本发明的cd123car包含含有与seqidno.11+seqidno.10+seqidno.12的80％、81％、82％、83％、84％、85％、86％、87％、88％、89％、90％、91％、92％、93％、94％、95％、96％、97％、98％、或99％一致性的多肽。根据本发明，表达本发明的抗cd123car的免疫细胞，即使在flag治疗的嘌呤类似物存在下，也会引发抗癌免疫响应，没有或降低gvhd和增殖。在优选的实施方式中，表达赋予本发明的抗-cd123car的本发明的car的免疫细胞确实触发了不包含人抗鼠抗体(hama)响应的免疫响应。根据本发明，有效量的本发明的工程化免疫细胞可以单独或与其他治疗组合向对其需要的患者给予至少一次。多核苷酸，载体本发明还涉及多核苷酸，编码根据本发明的上述car的载体。多核苷酸可以包括在表达组件或表达载体(例如，用于引入到细菌宿主细胞中的质粒，或用于转染昆虫宿主细胞的病毒载体如杆状病毒载体，或用于转染哺乳动物宿主细胞的质粒或病毒载体如慢病毒)中。在具体的实施方式中，不同核酸序列可以包括于一个包含编码核糖体跳过序列，如编码2a肽的序列的核酸序列的多核苷酸或载体中。在小核糖核酸病毒的口蹄疫病毒亚型中识别的2a肽导致核糖体从一个密码子“跳过”至下一密码子，而不在密码子编码的两个氨基酸之间形成肽键(参见(donnellyandelliott2001；atkins，willsetal.2007；doronina，wuetal.2008))。“密码子”是指由核糖体转译成一个氨基酸残基的mrna(或dna分子的有义链)上的三个核苷酸。因此，当多肽被框内的2a寡肽序列分离时，两个多肽可以由mrna内的单个连续的开放阅读框合成。这种核糖体跳过机制是本领域公知的，并已知由几个载体用于表达由单个信使rna编码的几种蛋白。为了将跨膜多肽导入宿主细胞的分泌路径，在多核苷酸序列或载体序列中提供了分泌信号序列(也称为先导序列(leadersequence)，前导序列(preprosequence)或前序列(presequence))。分泌信号序列可操作地连接到跨膜核酸序列，即两个序列在正确的阅读框内连接并定位为将新合成的多肽导入宿主细胞的分泌路径中。分泌信号序列通常位于编码所感兴趣的多肽的核酸序列的5'，尽管某些分泌信号序列可以位于所感兴趣的核酸序列的其他位置(参见例如，welch等的美国专利no.5，037，743；holland等的美国专利no.5，143，830)。在优选的实施方式中，信号肽包含氨基酸序列seqidno:1和2或与seqidno:1或2，优选seqidno:1至少90％，95％，97％或99％的序列一致性。本领域技术人员将认识到，考虑到遗传密码的简并性，这些多核苷酸分子之中相当大的序列变化是可能的。优选地，本发明的核酸序列对于哺乳动物细胞中的表达，优选人细胞中的表达是密码子优化的。密码子优化是指在给定物种中高度表达的基因中通常罕见的密码子的感兴趣的序列由该物种中高度表达的基因中通常常见的密码子替换，这种密码子编码如被替换的密码子的氨基酸。在一个实施方式中，编码本发明的cd123car的不同核酸序列可以包括于一个多核苷酸或载体中。在更优选的实施方式中，要求保护的本发明涉及允许本发明的car稳定表达的载体。此处稳定是指本发明的car在注射后至少1年内在工程化细胞的细胞表面上被检测到。在另一实施方式中，要求保护的本发明涉及允许本发明的cd123car，优选seqidno.31，seqidno32或seqidno160稳定表达的载体。在优选的实施方式中，本发明提供了包含编码本发明的任一种cd123car，优选seqidno31、seqidno32或seqidno.160的cd123car的序列的pcls27333载体。细胞根据本发明的细胞是指功能上参与先天和/或适应性免疫响应的引发和/或执行的造血源的细胞。根据本发明的细胞优选是从供体获得的t细胞。根据本发明的所述t细胞可以源自干细胞。干细胞可以是成体干细胞，胚胎干细胞，更具体地非人类干细胞、脐带血干细胞、祖细胞、骨髓干细胞、全能干细胞或造血干细胞。在优选的实施方式中，细胞是人类细胞、具体地人类干细胞。在更优选的实施方式中，细胞是人类t细胞，具体地人类工程化t细胞。代表性的人类干细胞是cd34+细胞。所述分离的细胞也可以是树突细胞、杀手树突细胞、肥大细胞、nk细胞、b细胞或选自由炎性t淋巴细胞、细胞毒性t淋巴细胞、调节性t淋巴细胞或辅助t淋巴细胞组成的组的t细胞。在另一实施方式中，所述细胞可以源自由cd4+t淋巴细胞和cd8+t淋巴细胞组成的组。在优选的实施方式中，所述细胞可以源自由工程化cd4+t淋巴细胞和工程化cd8+t淋巴细胞组成的组。在本发明的细胞的扩增和遗传改造之前，可以通过各种非限制性方法从受试者获得细胞源。细胞可以获得自许多非限制性来源，包括外周血单核细胞、骨髓、淋巴结组织、脐带血、胸腺组织、来自感染部位的组织、腹水、胸腔积液、脾组织和肿瘤。在本发明的某些实施方式中，可以使用本领域技术人员可用的和已知的任何数量的t细胞系。在另一实施方式中，所述细胞优选源自健康供体。在另一实施方式中，所述细胞是具有不同表型特性的混合细胞群体的部分。优选地，干细胞的分离和制备不需要破坏至少一个人类胚胎。考虑操作自体治疗法，免疫细胞可以源自患者，或考虑产生同种异体细胞，可以源自一个或多个供体，其可以用于同种异体治疗。更优选地，本发明的工程化免疫细胞在细胞表面上表达对应于seqidno31，seqidno32或seqidno33的抗cd123car，更加优选地，本发明的工程化免疫细胞表达相应于人源化seqidno31，seqidno32或seqidno32的人源化抗cd123car。在一个实施方式中，本发明的工程化免疫细胞表达对应于seqidno.34至seqidno.159，优选seqidno.34至seqidno.117，更优选seqidno.76至seqidno.117的抗cd123car。在这些抗cd123car之中，包含vh1/vl1，vh1/vl3；vh1/vl4；vh2/vl2，vh2/vl3，vh2/vl4；vh3/vl1，vh3/vl2，vh3/vl3，vh3/vl4vh4/vl1，vh4/vl2，vh4/vl3，vh4/vl4的那些是优选的；包含vh1/vl1，vh1/vl3；vh2/vl4；vh3/vl1，vh3/vl2，vh3/vl3，vh4/vl1，vh4/vl2，vh4/vl3，vh4/vl4的那些是更优选的，并且包含vh3/vl2，vh4/vl1，vh4/vl2，vh4/vl3，vh4/vl4的那些是更加优选的。最优选的是具有人源化klone43(huk43)和vh10a/vl1avh9a/vl6avh10a/vl3avh9a/vl8avh2a/vl3avh10a/vl9avh9a/vl3avh2a/vl1a的那些。在一个实施方式中，本发明的工程化免疫细胞表达对应于seqidno.160和seqidno.172至seqidno.187的抗cd123car。工程化赋予car的免疫细胞的方法：本发明包括制备用于免疫疗法的免疫细胞的方法，包括将编码先前描述于wo2014/130635，wo2013/176916，wo2013/176915(通过引证并入本文)中的cd123car的多核苷酸或载体体外引入免疫细胞中。在优选的实施方式中，考虑到在免疫细胞中稳定表达，所述多核苷酸包括于慢病毒载体中。在更优选的实施方式中，考虑到在免疫细胞中稳定表达，所述多核苷酸包括在慢病毒载体中。根据进一步的实施方式，所述方法进一步包括遗传改造所述细胞而使其更适合同种异体移植并降低gvhd响应的步骤。通过灭活至少一种编码t细胞受体(tcr)组件的基因来改造t-细胞。根据第一方面，例如，如wo2013/176915中所述，通过使至少一个表达t细胞受体(tcr)的一个或多个组件的基因失活，可以使免疫细胞较不同种异体，这可以与编码或调节hla或β2m蛋白表达的基因的灭活组合。因此，移植物抗宿主综合征和移植排异的风险会显著降低。因此，当免疫细胞是t-细胞时，本发明还提供了工程化较不同种异体的t细胞的方法。使细胞较不同种异体的方法可以包括使至少一个编码t细胞受体(tcr)组件的基因，特别是tcrα，tcrβ基因失活的步骤。wo2013/176915中公开的通过灭活t细胞受体(tcr)的一个或多个组件来制备适于同种异体移植的表达car的免疫细胞的方法通过引证结合于本文中。本发明包括表达抗cd123car的免疫细胞，其中表达一个或多个t细胞受体(tcr)的组件的至少一个基因已被灭活。因此，本发明提供了表达抗cd123car的t细胞，其中car源自klon43，特别是与seqidn°31具有至少80％的一致性，并且其中至少一个表达t细胞受体(tcr)的一个或多个组件的基因被灭活。本发明包括表达抗cd123car的免疫细胞，其中至少一个表达t细胞受体(tcr)的一个或多个组件的基因已被灭活。因此，本发明提供了表达抗cd123car的t细胞，其中car源自klon43，特别是具有与seqidn°32至少80％的一致性，并且其中至少一个表达t细胞受体(tcr)的一个或多个组件的基因已被灭活。本发明包括表达抗cd123car的免疫细胞，其中至少一个表达t细胞受体(tcr)的一个或多个组件的基因已被灭活。因此，本发明提供了表达抗cd123car的t细胞，其中car源自klon43，特别是具有与seqidn°160至少80％的一致性并且其中至少一个表达t细胞受体(tcr)的一个或多个组件的基因已被灭活。根据本发明，其中t细胞受体(tcr)的一个或多个组件灭活的抗cd123car免疫细胞旨在用作药物。通过灭活tcr基因，旨在使所感兴趣的基因不以功能性蛋白形式表达。在具体的实施方式中，该方法的遗传改造依赖于所提供的待工程化的细胞中一种稀切内切核酸酶的表达，使得所述稀切内切核酸酶特异性催化一种靶基因中的切割，从而使所述靶基因失活。由稀切内切核酸酶引起的核酸链断裂通常通过同源重组或非同源末端连接(nhej)的独特机制修复。然而，nhej是不完美的修复过程，通常会导致在切割位点上dna序列的变化。机制涉及通过直接再连接(critchlowandjackson1998)或经由所谓的微生物学介导的末端连接(betts，brenchleyetal.2003；ma，kimetal.2003)重新连接两个dna端的剩余部分。经由非同源末端连接(nhej)的修复通常导致小的插入或缺失，并可以用于产生特异性基因敲除。所述改造可以是至少一个核苷酸的取代，缺失或添加。其中已经发生裂解诱导的诱变事件，即，与nhej事件连续的诱变事件的细胞，可以通过本领域公知的方法识别和/或选择。在具体实施方式中，灭活至少一个编码t细胞受体(tcr)的组件的基因到每个个体样品的细胞中的步骤包括向细胞中引入可以破坏至少一个编码t细胞受体(tcr)的组件的基因的稀切内切核酸酶。在更具体的实施方式中，每个个体样品的所述细胞用编码能够破坏编码t细胞受体(tcr)的组件的至少一个基因的稀切内切核酸酶的核酸转化，且将所述稀切内切核酸酶表达至所述细胞中。所述稀切内切核酸酶可以是大范围核酸酶，锌指核酸酶，crispr/cas9核酸酶，argonaute核酸酶，tale-核酸酶或mbbbd-核酸酶。在优选的实施方式中，所述稀切内切核酸酶是tale-核酸酶。tale核酸酶旨在是由源自转录激活子样效应因子(tale)的dna结合结构域和一个切割核酸靶序列的核酸酶催化性结构域组成的融合蛋白(boch，scholzeetal.2009；moscouandbogdanove2009；christian，cermaketal.2010；cermak，doyleetal.2011；geissler，scholzeetal.2011；huang，xiaoetal.2011；li，huangetal.2011；mahfouz，lietal.2011；miller，tanetal.2011；morbitzer，romeretal.2011；mussolino，morbitzeretal.2011；sander，cadeetal.2011；tesson，usaletal.2011；weber，gruetzneretal.2011；zhang，congetal.2011；deng，yanetal.2012；li，piateketal.2012；mahfouz，lietal.2012；mak，bradleyetal.2012)。在本发明中，新的tale-核酸酶设计用于精确靶向过继性免疫治疗策略的相关基因。识别和切割靶序列的优选tale核酸酶描述于pct/ep2014/075317中。具体地，可以将其它催化性结构域进一步引入到具有所述稀切内切核酸酶的细胞中以增加诱变，以增强其灭活靶向基因的能力。更具体地，所述其它催化性结构域是dna末端加工酶。dna末端加工酶的非限制性实例包括5-3'外切核酸酶，3-5'外切核酸酶，5-3'碱性外切核酸酶，5'侧翼内切核酸酶，解旋酶，磷酸酶，水解酶和非模板依赖性dna聚合酶。这种催化性结构域的非限制性实例包括选自由hexoi(exo1_human)、酵母exoi(exo1_yeast)、大肠杆菌exoi、人trex2、小鼠trex1、人trex1、牛trex1、大鼠trex1、tdt(末端脱氧核苷酸基转移酶)、人dna2、酵母dna2(dna2_yeast)组成的组中的蛋白结构域或蛋白结构域的催化活性衍生物。在优选的实施方式中，所述其它催化性结构域具有3'-5'外切核酸酶活性，并且在更优选的实施方式中，所述其它催化性结构域是trex，更优选trex2催化性结构域(wo2012/058458)。在另一个优选的实施方式中，所述催化性结构域由单链trex2多肽编码。所述其它催化性结构域可以可选地通过肽接头融合至根据本发明的核酸酶融合蛋白或嵌合蛋白中。已知内切核酸断裂会促进同源重组的速率。因此，在另一实施方式中，该方法的遗传改造步骤进一步包括将包含至少与一部分靶核酸序列同源的序列的外源核酸导入细胞中，使得同源重组发生于靶核酸序列和外源核酸之间的步骤。在具体实施方式中，所述外源核酸包含分别与靶核酸序列的5'区域和3'区同源的第一和第二部分。这些实施方式中的所述外源核酸还包含位于第一和第二部分之间不含与靶核酸序列的5'区和3'区同源的第三部分。在靶核酸序列切割后，会在靶核酸序列和外源核酸之间刺激同源重组事件。优选地，在所述供体基质内使用至少50bp，优选大于100bp，而更优选大于200bp的同源序列。在具体的实施方式中，同源序列可以是200bp至6000bp，更优选1000bp至2000bp。实际上，共有的核酸同源性位于断裂位点的上游和下游侧接的区域内，并且要引入的核酸序列应位于两臂之间。药物抗性t-细胞本发明人寻求工程化用于免疫疗法的tcrkot细胞，特别是工程化可以与治疗药物(抗癌药物)组合使用的表达seqidno°31，seqidno°32，或seqidno160的tcrko抗cd123car的免疫细胞。如本文所用的对药剂“抗性或耐受”的细胞是指已经遗传改造使得细胞增殖并在一定量的抑制或防止没有遗传改造的细胞增殖的药物存在下活性的细胞。通过使基因失活，旨在使所感兴趣的基因不以功能性蛋白形式表达。在具体实施方式中，该方法的遗传改造依赖于提供待工程化的细胞中一种稀切内切核酸酶的表达，使得所述稀切内切核酸酶特异性催化一种靶向基因中的切割，从而使靶基因失活。在具体的实施方式中，灭活至少一个药物敏化基因的步骤包括向细胞中引入可以破坏至少一个药物敏化基因的稀切内切核酸酶。在更具体的实施方式中，所述细胞用编码能够破坏药物敏化基因的稀切内切核酸酶的核酸转化，且将所述稀释内切核酸酶被表达至细胞中。所述稀切内切核酸酶可以是大范围核酸酶，锌指核酸酶，crispr/cas9核酸酶，ambbbd核酸酶或tale-核酸酶。在优选实施方式中，稀切内切核酸酶是tale-核酸酶。在优选的实施方式中，可以灭活以赋予t细胞药物抗性的药物敏化基因是人脱氧胞苷激酶(dck)基因。该酶是脱氧核糖核苷脱氧胞苷(dc)，脱氧鸟苷(dg)和脱氧腺苷(da)的磷酸化所必需的。嘌呤核苷酸类似物(pnas)通过dck代谢成单-、二-和三-磷酸pna。它们的三磷酸酯形式，且特别是氯法拉滨三磷酸酯会与atp竞争dna合成，充当促凋亡剂，并是参与三核苷酸生产的核糖核苷酸还原酶(rnr)的强效抑制剂。优选地，t细胞中dck的失活由tale核酸酶介导。为了实现这一目标，已经设计了几对dcktale核酸酶，在多核苷酸水平下组装并通过测序验证。根据本发明可以使用的tale核酸酶对的实例描述于pct/ep2014/075317中。t细胞中的这种dck失活赋予了对嘌呤核苷类似物(pnas)，如氯法拉宾和氟达拉滨的抗性。在更优选的实施方式中，t细胞中的dck失活与trac基因的失活相结合，赋予这些双敲除(ko)t细胞对药物如氯法拉滨的耐药性，以及比具有完整tcr的相同细胞更低的同种异体性。这种双重特征尤其适用于治疗目的，允许用于免疫疗法的“现成”同种异体细胞结合化疗治疗患癌症，优选难治的复发性aml或bpdnl的患者。在seqidno°31，seqidno°32，或seqidno160的cd123car表达之前或之后，可以同时或依次实施这种双重ko灭活dck/trac。在pct/ep2014/075317中描述了本发明中成功的tale核酸酶dck/trac对的一个实例，具体地，2个位点中的靶序列(dck和trac)。根据另一方面，本发明的表达cd123car的t细胞(表达seqidno°31，seqidno°32，或seqidno160的tcrko抗cd123car的免疫细胞)可以进一步进行遗传工程化而改进其对用作治疗癌症的标准护理的免疫抑制药物或化疗治疗的耐受性。几种细胞毒性药剂(抗癌药物)如抗代谢物，烷化剂，蒽环霉素，dna甲基转移酶抑制剂，铂化合物和纺锤体抑制剂已经开发用于杀死癌细胞。然而，这些药剂与新疗法，如免疫疗法一起引入，是有问题的，因为这些药物会影响免疫t细胞的功能/存活。例如，由于药剂的非特异性毒性特征，化疗剂可能会有损于建立强健的抗肿瘤免疫活性细胞。靶向细胞增殖途径的基于小分子的疗法也可能会阻碍抗肿瘤免疫的建立。如果短时有效的化疗方案可以与新型的免疫活性细胞疗法相结合，则可以实现抗肿瘤疗法的显著改进(dasgupta，mccartyetal.2011)。为了改进癌症治疗和选择性植入seqidno31、seqidno32或seqidno160的同种异体的表达tcrkocd123car的t细胞，对所述同种异体t细胞赋予抗药性而保护其免受化疗剂的毒副作用。t细胞的药物抗性也允许其在体内或体外富集，因为表达药物抗性基因的t细胞将会相对于药敏性细胞而存活和增殖。用于工程化对化疗剂抗性的t细胞的方法公开于pct/ep2014/075317中，该专利通过引证完全引入本文中。具体地，本发明公开了工程化适用于免疫疗法的同种异体tcrko，表达seqidno31、seqidno32或seqidno160的cd123car的t细胞的方法，其中将编码t细胞受体(tcr)的组件的至少一个基因灭活，并且将至少一个基因改造而赋予药物抗性，优选灭活dck基因。一种工程化适用于与采用嘌呤类似物的组合疗法的表达seqidno31、seqidno32或seqidno160的同种异体cd123car的t细胞的方法，包括：○提供表达seqidno°31、seqidno°32、seqidno°160的抗cd123car的t细胞，○通过使至少一个编码t细胞受体(tcr)组件的基因失活来改造所述表达抗cd123car的t细胞；○改造所述表达抗cd123car的t细胞以赋予所述表达抗cd123car的t细胞抗药性；优选赋予对嘌呤类似物的抗性；○在所述药物存在下扩增所述工程化的表达-cd123car的t细胞，所述药物是选自喷司他丁、氟达拉滨2-脱氧腺苷、克拉屈滨、氯法拉滨、奈拉滨、优选喷司他丁、氟达拉滨单磷酸和2-氯脱氧腺苷(2-cda)的嘌呤类似物。可替换地，本发明涉及一种方法，包括：○提供表达seqidno°31、seqidno°32或seqidno°160的抗cd123car的t细胞，○通过缺失dck基因，改造所述表达seqidno°31、seqidno°32或seqidno160的抗cd123car的t细胞，赋予所述表达seqidno°31、seqidno°32或seqidno°160的抗cd123car的t细胞抗药性；优选地，所述药物是嘌呤类似物；○通过使至少一个编码t细胞受体(tcr)组件的基因失活而改造所述表达seqidno°31、seqidno°32或seqidno°160的抗cd123car的t细胞；○在药物存在下，扩增所述表达seqidno°31、seqidno°32或seqidno°160的抗cd123car的t细胞，所述药物是选自喷司他丁、氟达拉滨2-脱氧腺苷、克拉屈滨、氯法拉宾、奈拉滨、优选喷司他丁、氟达拉滨单磷酸酯和2-氯脱氧腺苷(2-cda)的嘌呤类似物。具体地，本发明涉及工程化适用于免疫疗法的同种异体细胞的方法，其中编码t细胞受体(tcrα)组件的基因被灭活，并且dck基因改造为赋予对嘌呤类似物的抗性，包括：○提供表达抗cd123car的t细胞；具体地表达seqidno°31、seqidno°32或seqidno°160的抗cd123car的t细胞，○通过使编码t细胞受体(tcrα)组件的基因失活而表达改造seqidno°31、seqidno°32或seqidno160的抗cd123car的t细胞；○灭活所述表达seqidno°31、seqidno°32或seqidno°160的抗cd123car的t细胞中的dck基因而赋予对嘌呤类似物的抗性；○在所述药物存在下扩增所述工程化的表达seqidno°31、seqidno°32或seqidno°160的抗cd123car的t细胞。可替换地，本发明涉及一种方法，包括：○提供表达抗cd123car的t细胞；具体地表达seqidno°31、seqidno°32或seqidno°160的抗cd123car的t细胞，○灭活表达所述seqidno°31、seqidno°32或seqidno°160的抗cd123car的t细胞中的dck基因而赋予对嘌呤类似物的抗性；○通过使至少一个编码t细胞受体(tcrα)组件的基因失活而改造所述表达seqidno°31、seqidno°32或seqidno°160的抗cd123car的t细胞；○在嘌呤类似物存在下扩增所述工程化的表达抗cd123car的t细胞。在优选的实施方式中，所提供的表达seqidno°31、seqidno°32或seqidno°160的抗cd123car的dckko，tcrkot细胞对选自喷司他丁、氟达拉滨2脱氧腺苷、克拉屈滨、氯法拉积或尼拉滨、优选对氟达拉滨单磷酸、或对2氯脱氧腺苷(2cda)的药物抗性。赋予表达抗cd123car的免疫细胞抗药性的基因表达在具体实施方式中，所述药物抗性可以通过表达至少一种药物抗性基因而赋予于本发明的t细胞。所述药物抗性基因是指编码对药剂，如化疗剂(例如，氨甲喋呤)的“抗性”的核酸序列。换言之，药物抗性基因在细胞中的表达允许细胞在药物存在下增殖的程度大于没有药物抗性基因的相应细胞的增殖或在所述药物存在下存活。药物抗性基因在细胞中的表达允许细胞在药物存在下的增殖并且不影响其活性。本发明的药物抗性基因可以编码对于抗代谢物、甲氨蝶呤、长春花碱、顺铂，烷化剂，蒽环霉素，细胞毒性抗生素，抗免疫亲和素，其类似物或衍生物的抗性。在一个实施方式中，药物抗性基因赋予对药物(或药剂)，特别是选自阿糖胞苷(aracytine)，胞嘧啶阿拉伯糖苷(cytosinearabinoside)、安吖啶(amsacrine)、柔红霉素(daunorubicine)、伊达比星(idarubicine)、诺安托(novantrone)、米托蒽醌(mitoxantrone)、足叶乙苷(vepeside)、依托泊苷(etoposide)(vp16)、三氧化二砷(arsenictrioxyde)、反式维甲酸(transretinoicacid)，三氧化三砷、全反式维甲酸的组合、氮芥(mechlorethamine)、甲基苄肼(procarbazine)、苯丁酸氮芥(chlorambucil)、阿糖胞苷(cytarabine)、蒽环霉素、6-硫鸟嘌呤(thioguanine)、羟基脲、泼尼松及其组合的抗性。几种已经确定的药物抗性基因可以潜在地用于赋予本发明的表达cd123cart细胞抗药性(takebe，zhaoetal.2001；sugimoto，tsukaharaetal.2003；zielske，reeseetal.2003；nivens，felderetal.2004；bardenheuer，lehmbergetal.2005；kushman，kableretal.2007)。抗药性基因的一个实例也可以是二氢叶酸还原酶(dhfr)编码基因的突变或改造形式。dhfr是参与调节细胞中四氢叶酸的量的酶，并是dna合成所必需的。叶酸类似物如甲氨蝶呤(mtx)会抑制dhfr，并因此在临床上用作抗肿瘤剂。已经描述了具有对通过疗法中所用的抗叶酸盐的抑制增加的抗性的dhfr的不同突变体形式。在具体的实施方式中，根据本发明的抗药性基因可以是编码包含赋予对抗叶酸治疗如甲氨蝶呤的抗性的至少一个突变的人野生型dhfr(genbank：aah71996.1)的突变形式的核酸序列。在具体的实施方式中，dhfr的突变形式在位置g15，l22，f31或f34，优选在位置l22或f31上包含至少一个突变的氨基酸(schweitzer，dickeretal.1990；国际申请wo94/24277；美国专利us6,642,043)。在具体的实施方式中，所述dhfr突变体形式包含位置l22和f31处的两个突变的氨基酸。本文描述的氨基酸位置的对应关系通常关于genbank：aah71996.1中列出的野生型dhfr多肽形式的氨基酸的位置表示。在具体的实施方式中，位置15上的丝氨酸残基优选被色氨酸残基取代。在另一具体的实施方式中，位置22上的亮氨酸残基优选被将会破坏突变型dhfr与抗叶酸剂的结合的氨基酸，优选被不带电荷的氨基酸残基如苯丙氨酸或酪氨酸取代。在另一具体实施方式中，位置31或34上的苯丙氨酸残基优选被小的亲水性氨基酸如丙氨酸，丝氨酸或甘氨酸替代。正如本文所用，“抗叶酸剂”或“叶酸类似物”是指以某种程度干扰叶酸代谢途径的分子。抗叶酸剂的实例包括，例如，甲氨蝶呤(mtx)；氨基蝶呤(aminopterin)；曲麦克特(trimetrexate)(neutrexintm)；依达曲沙(edatrexate)；n10-炔丙基-5,8-二脱氮叶酸(cb3717)；zd1694(tumodex)，5,8-二脱氮异叶酸(iahq)；5,10-二脱氮四氢叶酸(ddathf)；5-脱氮叶酸；pt523(nα-(4-氨基-4-脱氧蝶酰基)-nδ-半邻苯二甲酰基-l-鸟氨酸)；10-乙基-10-脱氮氨基蝶呤(ddathf，lomatrexol)；吡曲克辛(piritrexim)；10-edam；zd1694；gw1843；培美曲塞(pemetrexate)和pdx(10-炔丙基-10-脱氮氨基蝶呤)。抗药性基因的另一个实例也可以是肌苷-5'-单磷酸脱氢酶ii(impdh2)，鸟苷核苷酸从头合成中的限速酶的突变或改造形式。impdh2的突变体或改造形式是impdh抑制剂抗性基因。impdh抑制剂可以是霉酚酸(mpa)或其前药霉酚酸酯(mmf)。突变体impdh2可以在野生型人impdh2(np_000875.2)的map结合位点上包含导致对impdh抑制剂的抗性显著增加的至少一个，优选两个突变。突变优选在位置t333和/或s351上(yam，jensenetal.2006；sangiolo，lesnikovaetal.2007；jonnalagadda，brownetal.2013)。在具体的实施方式中，位置333上的苏氨酸残基被异亮氨酸残基取代，且位置351上的丝氨酸残基被酪氨酸残基取代。本文描述的氨基酸位置的对应关系通常以np_000875.2中的野生型人impdh2多肽的形式的氨基酸的位置表示。另一种药物抗性基因是钙调磷酸酶的突变形式。钙调磷酸酶(pp2b)，普遍表达的丝氨酸/苏氨酸蛋白磷酸酶，涉及许多生物过程，并是t细胞活化的核心。钙调磷酸酶是由催化性亚单元(cna；三种同种型)和调节亚单元(cnb；两种同种型)组成的异源二聚体。在与t细胞受体结合后，钙调磷酸酶使转录因子nfat去磷酸化，使其转运到细胞核和活性关键靶基因如il2。与fkbp12复合的fk506，或与cypa阻断nfat复合的环胞菌素a(csa)进入钙调磷酸酶的活性位点，阻止其脱磷酸化，从而抑制t细胞活化(brewin，mancaoetal.2009)。本发明的抗药性基因可以是编码对钙调神经磷酸酶抑制剂如fk506和/或csa抗性的钙调磷酸酶的突变形式的核酸序列。在具体的实施方式中，所述突变体形式可以包含以下位置上的野生型钙调磷酸异源二聚体a的至少一个突变的氨基酸：v314、y341、m347、t351、w352、l354、k360、优选在位置t351和l354或v314和y341上双重突变。在具体的实施方式中，对应于genbank：acx34092.1的序列的位置341上的缬氨酸残基可以被赖氨酸或精氨酸残基取代，位置341上的酪氨酸残基可以被苯丙氨酸残基取代；位置347上的甲硫氨酸可以被谷氨酸、精氨酸或色氨酸残基替代；位置351上的苏氨酸可以被谷氨酸残基取代；位置352上的色氨酸残基可以被半胱氨酸，谷氨酸或丙氨酸残基取代，位置353上的丝氨酸可以被组氨酸或天冬酰胺残基取代，位置354上的亮氨酸可以被丙氨酸残基取代；位置360上的赖氨酸可以被丙氨酸或苯丙氨酸残基取代。本文描述的氨基酸位置的对应关系通常关于(genbank：acx34092.1)中描述的野生型人钙调磷酸酶异源二聚体a多肽的形式的氨基酸的位置表示。在另一具体实施方式中，所述突变体形式可以包含以下位置上的野生型钙调磷酸酶异源二聚体b的至少一个突变的氨基酸：v120，n123，l124或k125，优选在位置l124和k125上双重突变。在具体的实施方式中，对应于genbank：acx34095.1的氨基酸序列中，位置120上的缬氨酸可以被丝氨酸，天冬氨酸，苯丙氨酸或亮氨酸残基取代；位置123上的天冬酰胺可以被色氨酸，赖氨酸，苯丙氨酸，精氨酸，组氨酸或丝氨酸取代；位置124上的亮氨酸可以被苏氨酸残基取代；位置125上的赖氨酸可以被丙氨酸，谷氨酸，色氨酸取代，或两个残基如亮氨酸-精氨酸或异亮氨酸-谷氨酸可以在位置125上的赖氨酸之后加入。本文的氨基酸位置的对应关系通常关于(genbank：acx34095.1)中描述的野生型人钙调磷酸酶异源二聚体b多肽的形式的氨基酸的位置表示。另一种抗药性基因是编码人烷基鸟嘌呤转移酶(hagt)的0(6)-甲基鸟嘌呤甲基转移酶(mgmt)。agt是赋予对烷基化剂如亚硝基脲和替莫唑胺(tmz)的细胞毒性作用的抗性的dna修复蛋白。6-苄基鸟嘌呤(6-bg)是增强亚硝基脲毒性的agt抑制剂，并与tmz共同给予而增强该药剂的细胞毒性作用。编码agt变体的几种mgmt突变体形式对6-bg的灭活作用高度抗性，但保留了其修复dna损伤的能力(maze，kurpadetal.1999)。在具体的实施方式中，agt突变体形式可以包含氨基酸序列seqidno:18(uniprotkb：p16455)中的野生型agt位置p140的突变氨基酸。在优选的实施方式中，位置140上的所述脯氨酸被赖氨酸残基取代。另一种抗药性基因可以是多药物抗性蛋白1(mdr1)基因。这个基因编码膜糖蛋白，称为p-糖蛋白(p-gp)，涉及代谢副产物跨细胞膜的转运。p-gp蛋白对几种结构不相关的化疗剂显示出广泛的特异性。过表达多药物抗性蛋白质1已经描述为赋予对药物如米托蒽醌的抗性(charless.morrow，christinapeklak-scott，bimjhanabishwokarma，timothye.kute，pamelak.smitherman，andalanj.townsend.multidrugresistanceprotein1(mrp1，abcc1)mediatesresistancetomitoxantroneviaglutathione-dependentdrugeffluxmolpharmacolapril200669:1499-1505)。因此，通过编码mdr-1(np_000918)的核酸序列的表达可以将药物抗性赋予细胞。制备根据本发明的抗药性细胞的又一种方法是制备具有特异性突变，如人拓扑异构酶ii基因中的arg486和glu571上的突变的细胞，以赋予对安吖啶的抗性(s.patel，b.a.keller，andl.m.fisher.2000.molecularpharmacology.vol57：p784–791(2000)。制备根据本发明的抗药性细胞的另一种方法是制备过表达microrna-21的细胞以赋予对柔红霉素的抗性(involvementofmir-21inresistancetodaunorubicinbyregulatingptenexpressionintheleukaemiak562celllinebai，haitaoetal.febsletters，volume585，issue2，402–408)。在优选的实施方式中，本发明的细胞携带这种赋予抗药性的mrna或蛋白质，并且还包含抑制性mrna或基因，其表达由另一药物调节，允许在所述其他药物存在下，或在给予所述其他药物时选择性地破坏根据本发明的抗药性细胞。抗药性基因也可以赋予对细胞毒性抗生素的抗性，并可以是ble基因或mcra基因。当暴露于化疗剂，分别为博莱霉素或丝裂霉素c时，免疫细胞中ble基因或mcra的异位表达具有选择性优势。基因治疗最实用的方法是通过使用采用载体，优选病毒载体的有效基因递送来添加基因以工程化t细胞。因此，在具体的实施方式中，本发明提供了通过将优选由至少一种载体编码的转基因引入细胞中以赋予本发明的cd123免疫细胞抗药性的方法。将基因随机插入基因组中可能会导致插入的基因或插入位点附近的基因不适当的表达。使用包含内源序列的外源核酸向基因组中特异性位点的靶基因的同源重组的特异性基因疗法，可以允许t细胞的安全工程化。如上所述，根据本发明的方法的遗传改造步骤可以包括将包含至少一个编码抗药性基因和内源性基因的部分的序列的外源性核酸导入细胞中，使得同源重组发生于内源性基因和外源性核酸之间的步骤。在具体的实施方式中，所述内源性基因可以是野生型“抗药性”基因，使得之在同源重组后，野生型基因被赋予对药物的抗性的基因的突变形式取代。已知内切核酸水解裂解会刺激同源重组的速率。因此，在具体的实施方式中，本发明的方法进一步包括在细胞中表达能够切割内源性基因内的靶序列的稀切内切核酸酶的步骤。所述内源性基因可以编码例如dhfr、impdh2、钙调磷酸酶或agt。所述稀切内切核酸酶可以是tale核酸酶、锌指核酸酶、crispr/cas9内切核酸酶、mbbbd-核酸酶或巨型核酸酶。可以被灭活的酶的另一个实例是人类次黄嘌呤-鸟嘌呤磷酸核糖基转移酶(hprt)基因(genbank：m26434.1)。具体地，hprt可以在工程化t细胞中被灭活以赋予对细胞生长抑制代谢物6-硫鸟嘌呤(6tg)的抗性，其通过hpt转化为细胞毒性硫鸟嘌呤核苷酸并在当前用于治疗患癌症，特别是白血病的患者(hacke，tregeretal.2013)。鸟嘌呤类似物被hprt转移酶代谢，hprt转移酶催化磷酸核糖基部分的加成并使得可以形成tgmp鸟嘌呤类似物，包括6-巯基嘌呤(6mp)和6-硫鸟嘌呤(6tg)，其通常用作淋巴消除(lymphodepleting)药物治疗all。它们被hprt(次黄嘌呤磷酸核糖基转移酶，其催化磷酸核糖基部分的加成并可以形成tgmp)代谢。它们随后的磷酸化导致其最终整合到dna中的三磷酸化形式的形成。一旦引入dna中，硫代gtp通过其硫醇盐分组作用损害dna复制的保真度，并产生对细胞完整性高度有害的随机点突变。在另一实施方式中，通常在t细胞表面表达的cd3的失活可以赋予抗cd3抗体如泰瑞珠单抗的抗性。组合治疗本文所用的术语“治疗剂”，“化疗剂”或“药物”或“抗癌药物”是指可以与癌细胞相互作用，从而降低细胞的增殖状态和/或杀死细胞的药物，优选化合物或其衍生物。化疗剂或“抗癌药物”的实例包括，但不限于，烷化剂(例如，白消安(busulfan)、卡铂(carboplatine)、苯丁酸氮芥(chlorambucil)、顺铂(cisplatine)、环磷酰胺(cyclophosphamide)、异环磷酰胺(ifosfamide)、美法仑(melphalan)、氮芥(méchloréthamine)、奥沙利铂(oxaliplatine)、乌拉莫司汀(uramustine)、·替莫唑胺(temozolomide)、福莫司汀(fotemustine))，代谢拮抗剂(例如，嘌呤核苷抗代谢物，如氯法拉滨，氟达拉滨或2'-脱氧腺苷，甲氨蝶呤(mtx)，5-氟尿嘧啶或其衍生物，硫唑嘌呤(azathioprine)、卡培他滨(capecitabine)、阿糖胞苷(cytarabine)、·氟尿苷(floxuridine)、·氟尿嘧啶、·吉昔单抗(gemcitabine)、·甲氨蝶呤、培美曲塞)、抗肿瘤抗生素(例如、丝裂霉素、阿霉素、博莱霉素、·柔红霉素、·多柔比星、·表柔比星、·羟基脲、·伊达比星、·丝裂霉素c、·米托蒽醌)、植物源的抗肿瘤药物(例如长春新碱、长春地辛、紫杉酚(taxol)、长春花碱、·(长春瑞滨(vinorelbine))、·多西他赛(docetaxel)、·紫杉醇)、拓扑异构酶抑制剂(伊立替康(irinotecan)、·托泊替康(topotecan)、·依托泊苷(etoposide))。在优选的实施方式中，本文所用的治疗剂，化疗剂是指可以用于治疗癌症，具体地治疗造血液癌症细胞且更具体地aml，更加具体地难治性复发性aml，从而降低癌细胞的增殖状态和/或杀死癌细胞的化合物或其衍生物。化疗剂的其它实例包括，但不限于阿糖胞苷、胞嘧啶阿拉伯糖苷、安吖啶、柔红霉素、伊达比星、诺安托、米托蒽醌、足叶乙苷、依托泊苷(vp16)、三氧化二砷、反式维甲酸、氮芥、甲基苄肼、苯丁酸氮芥、及它们的组合。在本发明的其他实施方式中，本发明的细胞结合选自以下的药物(或药剂)给予患者：阿糖胞苷(aracytine)、胞嘧啶阿拉伯糖苷、安吖啶、柔红霉素、伊达比星、诺安托、米托蒽醌、足叶乙苷、依托泊苷(vp16)、三氧化二砷、反式维甲酸、阿糖胞苷(cytarabine)、蒽环霉素、6-硫鸟嘌呤、羟基脲、泼尼松、及它们的组合。这种药剂可以进一步包括但不限于抗癌剂trimethotrixatetm(tmtx)、temozolomidetm、raltritrexedtm、s-(4-硝基苄基)-6-硫代肌苷(nbmpr)、6-苄基鸟嘌呤(6-bg)、双氯亚硝基脲(bcnu)和camptothecintm，或其任一种的治疗性衍生物。在更优选的实施方式中，与选自阿糖胞苷、胞嘧啶阿拉伯糖苷、安吖啶、柔红霉素、伊达比星、诺安托、米托蒽醌、足叶乙苷、依托泊苷(vp16)、三氧化二砷、反式维甲酸及它们的组合中的至少一种组合向患者给予表达seqidno°31、seqidno°32或seqidno160的具有tcr和dckko基因的t细胞。表达seqidno°31、seqidno°32或seqidno160的抗cd123car的具有tcr和dckko基因的t细胞，与至少一种选自阿糖胞苷、胞嘧啶阿拉伯糖苷、安吖啶、柔红霉素、伊达比星、诺安托、米托蒽醌、足叶乙苷、依托泊苷(vp16)、三氧化二砷、反式维甲酸及它们的组合的治疗药物组合用作治疗剂。优选地，表达seqidno°31、seqidno°32或seqidno160的抗cd123car的具有tcr和dckko基因的t细胞优选与嘌呤类似物(氟达拉滨)组合用作治疗药物。优选地，表达seqidno°31、seqidno°32或seqidno160的抗cd123car的具有tcr和dckko基因的t细胞优选与flag治疗组合用作治疗药物。在一个实施方式中，所述cd123car选自seqidno76至seqidno.117且表达于双tcrdckkot细胞中，并结合至嘌呤类似物或flag作为治疗药物。在本发明中，组合治疗包括输液用于分选和/或消除目的的mab。在优选的实施方式中，mab是利妥昔单抗。优选通过静脉内途径给药的利妥昔单抗最大剂量为2,250mg/m2。其不作为静脉内推注或丸剂给药。表达抗cd123car的免疫细胞的多抗药性在另一具体实施方式中，本发明人力图寻求开发使用同种异体t细胞，特别是用不同药物治疗患者时对多种药物抗性的表达同种异体抗cd123car的t细胞而介导工程化t细胞的选择的“现成”免疫治疗策略。通过遗传工程化多种抗药性的同种异体t细胞，可以显著提高治疗效果。这样的策略可以特别有效地治疗对表现出协同作用的药物组合响应的肿瘤。此外，多重耐药性工程化的t细胞可以使用药物试剂的最小剂量的药剂来扩增和选择。因此，根据本发明的方法可以包括改造本发明的t细胞而赋予本发明的所述t细胞多重抗药性。所述多重抗药性可以通过表达多于一种抗药性基因或通过灭活多于一种药敏基因赋予。在另一具体实施方式中，通过表达至少一种抗药性基因并使至少一种药敏基因失活，可以赋予所述t细胞多重抗药性。具体地，通过表达至少一种抗药性基因，例如dhfr的突变形式，impdh2的突变形式，钙调磷酸酶的突变体形式，mgmt的突变体形式，ble基因和mcra基因并使至少一种药敏基因如hprt基因失活，可以赋予t细胞多重抗药性。在优选的实施方式中，通过使hprt基因失活并表达dhfr的突变形式；或通过灭活hprt基因并表达impdh2的突变形式；或通过使hprt基因失活并表达钙调磷酸酶的突变形式；通过灭活hprt基因并表达mgmt的突变形式；通过使hprt基因失活并表达ble基因；通过使hprt基因失活并表达mcra基因，可以赋予多重抗药性。在一个实施方式中，本发明提供了表达多于一种抗药性基因，或其中多于一种药敏基因失活的同种异体的表达抗cd123car的t细胞。本发明的表达抗cd123car的免疫细胞中的自杀基因在一些情况下，由于工程化t细胞可以在给予后扩增并持续多年，因此期望的是包括安全机制以允许选择性消除给予的t细胞。因此，在一些实施方式中，本发明的方法包括用重组自杀基因改造t细胞。所述重组自杀基因用于降低一旦给予受试者，所述t细胞的直接毒性和/或失控增殖的风险(quintarellic，veraf，blood2007；teysk，dottig.，rooneycm，boilbloodmarrowtransplant2007)。自杀基因使得可以体内选择性消除转化的细胞。具体地，自杀基因具有将无毒前药转化为细胞毒性药物或表达毒性基因表达产物的能力。换句话说，“自杀基因”是编码产物的核酸，其中该产物本身或在其它化合物存在下导致细胞死亡。这种自杀基因的代表性实例是编码单纯疱疹病毒的胸苷激酶的基因。另外的实例是可以将5-氟胞嘧啶转化为高毒性化合物5-氟尿嘧啶的水痘带状疱疹病毒胸苷激酶和细菌基因胞嘧啶脱氨酶。自杀基因还包括作为非限制性实例的半胱天冬酶-9或半胱天冬酶-8或胞嘧啶脱氨酶。可以使用特定的二聚作用的化学诱导剂(cid)活化半胱天冬酶-9。自杀基因还可以是在细胞表面上表达并可以使细胞对治疗性单克隆抗体敏感的多肽。本文所用的“前药”是指可以用于本发明的方法中的任何可转化为毒性产物的化合物。在本发明的方法中，前药被自杀基因的基因产物转化为毒性产物。这种前药的代表性实例是更昔洛韦，其通过hsv-胸苷激酶在体内转化为毒性化合物。更昔洛韦衍生物随后对肿瘤细胞是有毒的。前药的其他代表性实例包括，无环鸟苷，fiau[1-(2-脱氧-2-氟-β-d-阿拉伯呋喃糖基)-5-碘尿嘧啶]，vzv-tk的6-甲氧基阿拉伯糖苷和胞嘧啶的5-氟胞嘧啶脱氨酶。本发明的一个优选自杀基因系统使用了包含由抗cd20mab利妥昔单抗，特别是如wo2013153391中的所谓rqr8多肽中的qben10识别的抗原基序的重组抗原多肽。然后可以使用批准的抗体药物利妥昔单抗，在需要时用于细胞消除。在一个实施方式中，本发明提供了表达seqidno.31或32的抗cd123car的tcrko-dckkot细胞，其表达允许细胞选择性破坏的rqr8自杀基因。更优选地，本发明提供了表达抗cd123car的tcrko-dckkot细胞，其中所述cd123car包含允许表达cd123car的细胞选择性破坏的自杀结构域，优选地，所述自杀体结构域包含seqidno161的至少两个结构域，更优选地，所述cd123car包含seqidno171的序列。用于测试抗药性同种异体cart细胞的细胞毒性的cd123+/luc+抗药性daudi细胞本发明还包括用于生产表达cd123且对嘌呤类似物抗性的靶细胞的方法。这些靶细胞特别适用于测试本发明的cd123cart细胞的细胞毒性。这些细胞很容易抵抗临床相关剂量的氯法拉滨和港口荧光素酶(harborluciferase)活性。该特性的组合使其可以在小鼠模型中体内跟踪或在需要时将其破坏。更具体地，它们可以用于评价在氯法拉滨或其它pna存在下小鼠中的抗药性t细胞的细胞毒性性质。氯法拉滨抗性daudi细胞模拟了急性淋巴细胞白血病(all)患者复发形式诱导疗法的生理状态，其具有抗药性b细胞恶性肿瘤。因此，这些细胞对于评价抗药性cart细胞的可靠性和细胞毒性是非常感兴趣的。优选地，这些靶细胞是cd123+萤光素酶+daudi细胞。分离的细胞本发明涉及表达与cd123结合的cd123car的分离的细胞。因此，本发明涉及表达抗cd123car的细胞。在具体的实施方式中，所述表达抗cd123car的细胞对至少一种药物抗性，和/或包含至少一个破坏的编码t细胞受体成分的基因。在优选的实施方式中，本发明涉及分离的t细胞，其表达结合cd123的car并且对至少一种嘌呤类似物抗性，并且包含破坏的编码t细胞受体α组件的基因。在更优选的实施方式中，本发明涉及分离的t细胞，其表达结合至cd123的seqidno31，32或160的car，并且破坏cd123表达细胞并且对至少一种嘌呤类似物抗性，并且包含被破坏的编码t细胞受体α组分的基因。在更优选的实施方式中，本发明涉及分离的t细胞，其表达结合至cd123的seqidno160的car，并且破坏cd123表达细胞，并且对至少一种嘌呤类似物抗性，并且包含被破坏的编码t细胞受体β组分的基因。在另一具体实施方式中，所述表达抗cd123car的t细胞包含至少一个被破坏的药物致敏基因，如dck或hprt基因。在更具体的实施方式中，所述分离的抗cd123cart细胞包含破坏的hprt基因并表达dhfr突变体；所述分离的抗cd123cart细胞包含破坏的hprt基因并表达impdh2突变体；所述分离的抗cd123cart细胞包含破坏的hprt基因并表达钙调磷酸酶突变体；所述分离的抗cd123cart细胞包含破坏的hprt基因并表达agt突变体。具体地，本发明涉及分离的t细胞，特别是分离的同种异体的表达抗cd123car的t细胞，并且优选包含具有seqidno31，32或160的序列的分离的同种异体的表达抗cd123car的t细胞，所述分离的同种异体的表达抗cd123car的t细胞对嘌呤类似物更加特别抗性，且特别适用于嘌呤类似物存在下的免疫治疗。在一方面中，本发明提供了用于工程化分离的免疫细胞而使其对嘌呤类似物(嘌呤核苷酸类似物或pna)，如氯法拉滨或氟达拉滨抗性的方法，以使其可以用于用这些传统化疗法预治疗的患者中的癌症免疫疗法治疗。通过灭活负责细胞对药物的敏感性的一个或多个基因(药敏基因)，例如dck和/或hprt基因，可以对本发明的分离的t-细胞赋予对药物的抗性。免疫检查点本发明提供了表达抗cd123car的同种异体dckkot细胞，特别是seqidno°31或seqidno°32或seqidno°160的抗-cd123car，其中至少一种表达一个或多个t细胞受体(tcr)组件的基因被灭活和/或一个选自基因ctla4、ppp2ca、ppp2cb、ptpn6、ptpn22、pdcd1、lag3、havcr2、btla、cd160、tigit、cd96、crtam、lair1、siglec7、siglec9、cd244、tnfrsf10b、tnfrsf10a、casp8、casp10、casp3、casp6、casp7、fadd、fas、tgfbrii、tgfbri、smad2、smad3、smad4、smad10、ski、skil、tgif1、il10ra、il10rb、hmox2、il6r、il6st、csk、pag1、sit1、foxp3、prdm1(orblimp1)、batf、gucy1a2、gucy1a3、gucy1b2、gucy1b3的基因如wo2014/184741中提及的被灭活。根据本发明进一步的方面，通过使编码作用为“免疫检查点”，作用为t细胞活化的调节剂的蛋白的基因，如选自以下基因的基因失活，可以进一步操作免疫细胞而使其更具有活性或限制耗尽：ctla4、ppp2ca、ppp2cb、ptpn6、ptpn22、pdcd1、lag3、havcr2、btla、cd160、tigit、cd96、crtam、lair1、siglec7、siglec9、cd244、tnfrsf10b、tnfrsf10a、casp8、casp10、casp3、casp6、casp7、fadd、fas、tgfbrii、tgfbri、smad2、smad3、smad4、smad10、ski、skil、tgif1、il10ra、il10rb、hmox2、il6r、il6st、csk、pag1、sit1、foxp3、prdm1(orblimp1)、batf、gucy1a2、gucy1a3、gucy1b2、gucy1b3，优选地，所述基因是pdcd1或ctla-4。在本发明的t细胞中表达可以减少或抑制的基因的实例如表9中所示。在一个实施方式中，所述基因是编码β2微球蛋白的作用为t细胞活化的调节剂的基因。根据本发明进一步的方面，本发明的抗cd123car免疫细胞可以进一步操作而使其对药物，特别是对抗癌症，尤其是表达cd123的细胞介导的癌症，如aml的化疗法期间使用的药物是抗性的。这可以通过引入赋予对所述药物的抗性的基因而实现。通过使用如前所述的基因可诱导抑制/表达系统，可以打开和关闭该基因(garciael，millsaa(2002)gettingaroundlethalitywithinduciblecre-mediatedexcision.semincelldevbiol13:151–8，lewandoskim(2001)conditionalcontrolofgeneexpressioninthemouse.natrevgenet2:743–55；scharfenbergerl，hennericit，kirlygetal.(2014)transgenicmousetechnologyinskinbiology：generationofcompleteortissue-specificknockoutmice.jinvestdermatol134:e16；schwenkf，kuhnr，angrandpoetal.(1998)temporallyandspatiallyregulatedsomaticmutagenesisinmice.nucleicacidsres26:1427–32)。因此，本发明的目的是对应于表达seqidno31，seqidno32或seqidno160的序列的抗cd123car的pna抗性的免疫t细胞，其中(i)至少一种表达一个或多个t细胞受体(tcr)组件的基因被灭活(ii)并入至少一种赋予对药物(pna之外)的抗性的基因或使赋予对所述药物(pna之外)的敏感性的基因缺失或突变而失活(iii)选自表9中公开的基因的另一个基因被灭活。本发明包括通过本发明方法可获得的分离的抗cd123car免疫细胞或细胞系，更具体地包含本文描述的任何蛋白、多肽、等位变体、改变或缺失的基因或载体的分离的细胞。该目的提供用于癌症，特别是aml，难治性复发性aml，bpdnl的治疗。本发明的免疫细胞或细胞系可以进一步包含外源性重组多核苷酸，具体地car或自杀基因(编码seqidno.161)，或它们可以包含编码有助于它们作为治疗产品，理想地作为“现成”产品的效果的检查点蛋白或其配体的修改或缺失的基因。在另一方面中，本发明涉及用于通过给予至少一次通过上述方法可获得的工程化免疫细胞治疗或预防癌症的方法。表5：编码在本发明的工程化t细胞中改造的免疫检查点蛋白的基因的列表在本发明的工程化t细胞中改造的上述基因中的一个，优选两个等位基因，对于用于ko所述基因/等位基因的talen的每种制备验证了基因座。在优选的实施方式中，进一步工程化免疫细胞的所述方法涉及向所述t细胞中引入编码特异性稀切内切核酸酶的多核苷酸，特别是mrna，而通过dna切割选择性地灭活上述基因。在更优选的实施方式中，所述稀切内切核酸酶是tale核酸酶或cas9内切核酸酶。迄今为止，tal核酸酶已经证明比其他类型的稀切内切核酸酶具有更高的特异性和切割效率，使其成为以恒定转化数大规模生产工程化免疫细胞的内切核酸酶的选择。递送方法上述的不同方法涉及使所感兴趣的蛋白如抗药性基因，稀切内切核酸酶，嵌合抗原受体(car)，特别是抗cd123car，且更具体地，包含seqidno.31，或32或160和/包括自杀性结构域的car表达到分离的细胞中。作为非限制性实例，所述感兴趣的蛋白可以通过其作为优选由至少一个质粒载体编码的转基因的引入而表达于细胞中。由于将编码多肽的多核苷酸引入细胞中，所述多肽可以表达于细胞中。或者，在细胞外可以产生所述多肽，而随后将其引入其中。用于将多核苷酸构建体引入细胞中的方法在本领域内是已知的，并作为非限制性实例，包括其中将多核苷酸构建体整合到细胞的基因组中的稳定转化方法，其中多核苷酸构建体未整合到细胞的基因组中的瞬时转化方法，和病毒介导的方法。所述多核苷酸可以通过例如重组病毒载体(例如，逆转录病毒，腺病毒)，脂质体等引入细胞中。例如，瞬时转化方法包括，例如，显微注射法，电穿孔法或粒子轰击法，细胞融合法。考虑到细胞中表达，所述多核苷酸可以包括于载体中，更特别是质粒或病毒中。质粒载体可以包含提供识别和/或选择接收载体的细胞的选择标记。不同的转基因可以包含于一个载体中。载体可以包含编码核糖体跳跃序列的核酸序列，如编码2a肽的序列。在小核糖核酸病毒的口蹄疫病毒亚型中识别的2a肽，导致从一个密码子“跳过”到下一个密码子的核糖体，而不在密码子编码的两个氨基酸之间形成肽键(参见donnellyetal.，j.ofgeneralvirology82：1013-1025(2001)；donnellyetal.，j.ofgen.virology78：13-21(1997)；doroninaetal.，mol.and.cell.biology28(13)：4227-4239(2008)；atkinsetal.，rna13：803-810(2007))。“密码子”是指由核糖体翻译成一个氨基酸残基的mrna(或dna分子的有义链)上的三个核苷酸。因此，当多肽被框内的2a寡肽序列分离时，两个多肽可以由mrna内的单个连续的开放阅读框合成。这种核糖体跳过机制在本领域是公知的，并且已知由几个用于表达由单个信使rna编码的几个蛋白质的载体使用。在本发明的更优选的实施方式中，编码根据本发明的多肽的多核苷酸可以是，例如，通过电穿孔直接引入细胞中的mrna。本发明人确定了t细胞中的mrna电穿孔的最佳条件。本发明人使用cytopulse技术，这种技术允许通过使用脉冲电场而瞬时渗透活细胞以将材料递送到细胞中。这种技术基于pulseagile(btxhavardapparatus，holliston，may01746，usa)的电穿孔波形的使用，容许精确控制脉冲持续时间，强度以及脉冲之间的间隔(美国专利us6,010,613和国际pct申请wo2004083379)。所有这些参数都可以修改，以达到最高转染效率的最佳条件，而死亡率最低。基本上，第一高电场脉冲使得孔隙形成，而随后的低电场脉冲使得多核苷酸移动到细胞中。上述不同的方法涉及将seqidno.31、seqidno32或seqidno160的cd123car引入到细胞中。作为非限制性实例，所述car可以作为由一个质粒载体编码的转基因而引入。所述质粒载体也可以含有提供接收所述载体的细胞的识别和/或选择的选择标记。作为将编码所述多肽的多核苷酸引入细胞中的结果，在细胞中可以原位合成多肽。可替换地，可以在细胞外产生所述多肽，并随后将其引入其中。由于将多核苷酸构建体引入细胞中的方法在本领域是已知的，并作为非限制性实例，包括将多核苷酸构建体整合到细胞的基因组中的稳定转化方法，多核苷酸构建体未整合到细胞的基因组中的瞬时转化方法，和病毒介导的方法。多核苷酸可以通过，例如，重组病毒载体(例如，逆转录病毒，腺病毒)，脂质体等引入到细胞中。例如，瞬时转化方法包括，例如，显微注射法，电穿孔法或粒子轰击法。鉴于在细胞中表达，多核苷酸可以包括于载体中，更具体地质粒或病毒中。工程化免疫细胞本发明还涉及所述通过工程化细胞的方法易于获得的分离的细胞或细胞系。具体地，所述分离的细胞包含至少一种如上的car。在另一个实施方式中，所述分离的细胞包含各自含有不同胞外配体结合结构域的car群体。具体地，所述分离的细胞包含编码car的外源性多核苷酸序列。本发明的遗传改造的免疫细胞不依赖抗原结合机制活化和增殖。本发明的范围内还包括分离的免疫细胞，优选根据先前描述的任何一种方法获得的t细胞。所述免疫细胞是指功能上参与引发和/或执行先天的和/或适应性的免疫响应的造血来源的细胞。所述根据本发明的免疫细胞可以源自干细胞。干细胞可以是成体干细胞，非人胚胎干细胞，更具体地非人类干细胞，脐带血干细胞，祖细胞，骨髓干细胞，诱导多能干细胞，全能干细胞或造血干细胞。代表性的人类细胞是cd34+细胞。所述分离的细胞也可以是树突细胞、杀手树突状细胞、巨细胞、nk-细胞、b-细胞、或选自由炎性t-淋巴细胞、细胞毒性t-淋巴细胞、调节性t淋巴细胞或辅助性t淋巴细胞组成的组中的t细胞。在另一实施方式中，细胞可以源自由cd4+t淋巴细胞和cd8+t淋巴细胞组成的组。在本发明的细胞扩增和遗传改造之前，可以通过各种非限制性方法从受试者获得细胞来源。细胞可以从许多非限制性来源获得，包括外周血单核细胞，骨髓，淋巴结组织，脐带血，胸腺组织，来自感染部位的组织，腹水，胸腔积液，脾组织和肿瘤。在本发明的某些实施方式中，可以使用本领域技术人员可用的和已知的任何数量的t细胞系。在另一实施方式中，所述细胞可以来自健康供体，来自诊断患有癌症的患者或诊断患有感染的患者。在另一实施方式中，所述细胞是表现不同表型特性的混合细胞群体的部分。在本发明的范围内还包括根据前述方法由改造的t细胞获得的细胞系。对免疫抑制治疗抗性且易于通过先前方法获得的改造细胞都包括于本发明的范围内。作为优选的实施方式，本发明提供了如上所述的赋予具有对应于seqidno.31，seqidno.32或seqidno160的序列的cd123car的t细胞或t细胞群体，其不表达功能性tcr，对pna具有抗性，并且对cd123阳性细胞是反应性的，用于其过继转移到患者，优选患aml、难治性复发aml、bpdnl或淋巴组织增生性疾病的患者中，或作为骨髓移植前的治疗。作为更优选的实施方式，本发明提供了如上所述的赋予具有对应于seqidno.31，seqidno.32或seqidno160的序列的cd123car的t细胞或t细胞群体，并且对cd123阳性细胞是反应性的，不表达功能性tcr并且对选择的pna抗性，用于其向用所述选择的pna治疗的患者的同种异体移植。在更加优选的实施方式中，本发明提供了与另一种治疗组合的赋予包含具有对应于seqidno.31，seqidno.32或seqidno160的序列的cd123car的多肽的抗cd123car的trckodckkot细胞或t细胞群体。t细胞的活化和扩增无论是在t细胞的遗传改造之前或之后，即使本发明的遗传改造的免疫细胞不依赖抗原结合机制活化和增殖，免疫细胞，尤其是本发明的t细胞，可以通常使用例如描述于以下的方法进一步活化和扩增：美国专利6,352,694；6,534,055；6,905,680；6,692,964；5,858,358；6,887,466；6,905,681；7,144,575；7,067,318；7,172,869；7,232,566；7,175,843；5,883,223；6,905,874；6,797,514；6,867,041；和美国专利申请公开号no.20060121005。t细胞可以体外或体内扩增。通常，本发明的t细胞通过与刺激cd3tcr复合物和t细胞表面上的共刺激分子的试剂接触而产生t细胞的活化信号来扩增。例如，可以使用化学品如钙离子载体a23187，佛波醇(phorbol)12-肉豆蔻酸酯13-乙酸酯(pma)或如植物血凝素(pha)的有丝分裂凝集素的产生t细胞的活化信号。作为非限制性实例，t细胞群体可以，例如，通过与抗cd3抗体，或其抗原结合片段，或固定于表面上的抗cd2抗体接触，或通过与蛋白激酶c活化剂(例如，苔藓虫素)接触，结合钙离子载体而体外刺激。为了t细胞表面上辅助分子的共刺激，使用了结合辅助分子的配体。例如，在适于刺激t细胞增殖的条件下，t细胞群体可以与抗cd3抗体和抗cd28抗体接触。适合于t细胞培养的条件包括可能含有增殖和活力所必需的因子的合适培养基(例如，最低必需培养基(minimalessentialmedia)或rpmi培养基1640或x-vivo5，(lonza))，包括血清(例如、胎牛或人血清)、白细胞介素-2(il-2)、胰岛素、ifn-g、1l-4、1l-7、gm-csf、-10、-2、1l-15、tgfp和tnf或本领域技术人员已知用于细胞生长的任何其它添加剂。用于细胞生长的其它添加剂包括，但不限于，表面活性剂，人血浆蛋白粉(plasmanate)和还原剂如n-乙酰基-半胱氨酸和2-巯基乙醇。培养基可以包括rpmi1640、a1m-v、dmem、mem、a-mem、f-12、x-vivo1和x-vivo20、optimizer，具有添加的氨基酸，丙酮酸钠和维生素，不含血清或补充有适量的血清(或血浆)或一组确定的激素，和/或一定量的足以使t细胞生长和扩增的细胞因子。抗生素，例如，青霉素和链霉素，仅包括于实验培养物中，而不包括于要输注到受试者中的细胞的培养物中。靶细胞保持于支持生长所必需的条件下，例如，合适的温度(例如，37℃)和气氛(例如，空气+5％co2)。暴露于不同刺激时间的t-细胞可能会表现出不同的特性。在另一个具体实施方式中，所述细胞可以通过与组织或细胞共培养来扩增。细胞还可以体内扩增，例如，在将细胞给予受试者之后在受试者的血液中扩增。药物组合物本文提供了包含本发明的工程化免疫细胞的药物组合物，例如，具有对应于seqidno.31，seqidno.32或seqidno160的序列的工程化tcrko-dckkocd123cart细胞。本文提供了包含本发明的工程化免疫细胞，例如具有对应于选自seqidno188至seqidno197中的任一种序列的工程化tcrko-dckkocd123cart细胞的药物组合物。在另一实施方式中，提供了包含本发明的遗传工程化的免疫t细胞，例如，具有选自seqidno.34至seqidno.159，优选选自seqidno.34、seqidno.76、seqidno.36、seqidno.78；seqidno.37、seqidno.79、seqidno.41、seqidno.83、seqidno.42、seqidno.8)、seqidno.43、seqidno.85、seqidno.46、seqidno.47、seqidno.48、seqidno.49、seqidno.88、seqidno.89、seqidno.90、seqidno.91、seqidno.52、seqidno.53、seqidno.54、seqidno.55、seqidno.94、seqidno.95、seqidno.96、和seqidno.97中的任何一个序列的cd123car的工程化tcrkodckkot细胞的药物组合物。根据本公开，术语“药物组合物”涉及用于向个体给予的组合物。在优选的实施方式中，药物组合物包含用于胃肠外，经皮，管腔内，动脉内，鞘内或静脉内给药(iv)或直接注射入癌的组合物。特别设想的是，所述药物组合物经由输液或注射iv给予个体。合适的组合物的给药可以通过不同的方式，例如通过静脉内(iv)，皮下，腹膜内，肌内，局部或皮内给药实施。本公开的药物组合物可以进一步包含药用载体。合适的药物载体的实例在本领域内是公知的，并包括磷酸盐缓冲盐溶液，水，乳液，如油/水乳液，各种类型的润湿剂，无菌溶液等。包含这些载体的组合物可以通过公知的常规方法配制。这些药物组合物可以以合适的剂量给予受试者。给药方案由主治医师和临床因素决定。如在医学领域中众所周知的，任何一个患者的剂量取决于许多因素，包括患者的体型，体表面积，年龄，要给药的具体化合物，性别，给药时间和途径，一般健康和其他同时给药的药物。给予剂量的实例可以处于0.24μg至48mg的根据本发明的细胞，优选0.24μg至24mg，更优选0.24μg至2.4mg，更加优选0.24μg至1.2mg，而最优选0.24μg至240mg单位/千克体重/天的范围内。特别优选的剂量如下所述。通过定期评价可以监测进度。本公开的car细胞组合物可以局部或全身给予。给予通常是非肠道的，例如静脉内；dna也可以直接给予于靶位点，例如，通过向内部或外部靶位点的基因枪(biolistic)递送或通过导管向动脉中的位点给予。在优选的实施方式中，药物组合物经皮下给予，而在更加优选的实施方式中静脉内给予。用于肠胃外给予的制剂包括无菌水或非水溶液，悬浮液和乳液。非水溶剂的实例是丙二醇，聚乙二醇，植物油如橄榄油和可注射有机酯如油酸乙酯。水性载体包括水，醇/水溶液，乳液或悬浮液，包括盐水和缓冲介质。非肠道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。静脉内载体包括流体和营养补充剂，电解质补充剂(如基于林格氏葡萄糖的那些)等。还可以存在防腐剂和其它添加剂，如抗微生物剂，抗氧化剂，螯合剂和惰性气体等。此外，本公开的药物组合物可以包含蛋白质载体，比如，例如，血清白蛋白或免疫球蛋白，优选来源于人。可以设想的是，除了蛋白质双特异性单链抗体构建体或核酸分子或对其编码的载体(如本公开中描述的)之外，本发明的药物组合物可以包含进一步的生物活性剂，这取决于药物组合物的预期用途。本文描述的任何组合物可以包含于试剂盒中。在非限制性实例中，在试剂盒中可以包含根据本发明的用于细胞疗法的一种或多种细胞和/或用于产生用于细胞疗法的一种或多种细胞的试剂，其含有重组表达载体。试剂盒以合适的容器装置提供。试剂盒的一些组件可以在水性介质中或以冻干形式，且在冷冻包装下包装。试剂盒的容器装置通常将包括至少一个小瓶，试管，烧瓶，瓶子，注射器或其他容器装置，可以将组分，优选适当地等份置入其中。在试剂盒中有不只一种组分的情况下，试剂盒通常还将包含第二，第三或其他附加容器，可以将另外的组件单独放置于其中。然而，组分的各种组合可以包括于小瓶中。试剂盒通常还将包括用于商业销售的密封包含组分的装置。这种容器可以包括注塑或吹塑成形的塑料容器，将期望的小瓶保持于其中。当试剂盒的组分提供于一种和/或多种液体溶液中时，液体溶液是水溶液，其中无菌水溶液是特别有用的。在一些情况下，容器装置本身可以是注射器，移液管和/或其它这样的类似装置，制剂可以从该装置施加到身体的感染区域，注射到动物中，和/或甚至施加和/或与试剂盒的其他组分混合。在优选的实施方式中，一种和/或多种液体溶液是防冻的。然而，试剂盒的组分或其部分可以作为干燥粉末或片剂提供。当试剂和/或组分作为干燥粉末提供时，通过加入合适的溶剂可以重构粉末。设想的是，溶剂也可以提供于另一个容器装置中。试剂盒还可以包含用于容纳无菌的药用缓冲液和/或其它稀释剂的第二容器装置。在具体实施方式中，将待用于细胞疗法的细胞提供于试剂盒中，并在一些情况下，细胞基本上是试剂盒的唯一组分。试剂盒可以包括制备期望的细胞的试剂和材料。在具体的实施方式中，试剂和材料包括用于扩增期望的序列的引物，核苷酸，合适的缓冲液或缓冲试剂，盐等，并且在一些情况下，试剂包括编码如本文中描述的car分子的载体和/或dna和/或其调节元件。在具体的实施方式中，试剂盒中有一个或多个装置适用于从个体提取一个或多个样品。装置可以是注射器，解剖刀等。在一些情况下，试剂盒，除了细胞疗法实施方式之外，还包括，例如，如化疗，激素疗法和/或免疫疗法的第二癌症疗法。试剂盒可以针对个体的具体癌症定制，并包括针对个体的各自的第二癌症疗法。优选地，其它癌症疗法是嘌呤类似物，flag治疗。包含本发明的cd123car的工程化t细胞的治疗用途。在各个实施方式中，如本文中所设想的car构建体，核酸序列，载体，宿主细胞和/或包含其的药物组合物用于癌性疾病，如肿瘤疾病的预防、治疗或改善。在具体实施方式中，本公开的药物组合物尤其适用于，例如，预防，改善和/或治疗癌症，包括具有实体瘤的癌症。在具体实施方式中，本文中提供了治疗个体的癌症的方法，包括向个体提供治疗有效量的多种本公开的任何细胞的步骤。在某些方面中，癌症是实体肿瘤，并且肿瘤可以是任何尺寸，但在具体的实施方式中，实体肿瘤的直径约2mm或更大。在某些方面中，方法进一步包括向个体提供治疗有效量的其它癌症疗法的步骤。本文中所用的“治疗(treatment)”或“治疗(treating)”包括对疾病或病理状况的症状或病理学的任何有益或期望的影响，并可以包括所治疗的疾病或病症，例如，癌症的一个或多个可测量标志物的即使最小的降低。治疗可以涉及可选地降低或改善疾病或病症的症状，或延缓疾病或病症的进展。“治疗”不一定表示完全根除或治愈疾病或病症，或其相关症状。如本文所用，“预防(prevent)”和类似的词语如“预防(prevented)”，“预防(preventing)”等表示预防，抑制或降低疾病或病症例如癌症发生或复发的可能性的方法。其也指延迟疾病或病症的发作或复发或延迟疾病或病症症状的发生或复发。如本文所用，“预防”和类似词语还包括在疾病或病症发作或复发之前降低疾病或病症的强度，影响，症状和/或负担。在具体实施方式中，本发明部分设想了可以使用标准载体和/或基因递送系统，并且在至少某些方面中，与药用载体或赋形剂一起，单独或以任何组合给予的细胞，car构建体，核酸分子和载体。在某些实施方式中，在给予之后，核酸分子或载体可以稳定地整合到受试者的基因组中。在具体的实施方式中，可以使用对某些细胞或组织特异性，并保持于所述细胞中的病毒载体。合适的药物载体和赋形剂在本领域内是公知的。根据本公开制备的组合物可以用于预防或治疗或延缓以上指出的疾病。此外，本公开涉及用于预防，治疗或改善肿瘤疾病的方法，其包括以下步骤：向对其需要的受试者或个体给予有效量的免疫细胞，例如，t细胞或细胞毒性t淋巴细胞，其携带seqidno.31的cd123car或seqidno.32的cd123car或seqidno.160的cd123car；编码其的核酸序列；包含编码如本文所述和/或通过本文描述的方法产生的所述cd123car的核苷酸序列的载体。给予示例性cd123car细胞的组合物的可能的适应症是癌性疾病，包括肿瘤疾病，包括：本公开的组合物的给予适用于淋巴增生性疾病的所有阶段和类型，包括用于微小残留疾病，早期癌症，晚期癌症和/或复发和/或难治性癌症。本公开进一步包括与通过免疫细胞起作用的其它化合物，例如，双特异性抗体构建体，靶向毒素或其他化合物的共给予方案。共给予本发明化合物的临床方案可以包括在给予其它组分的同时，之前或之后共给予。具体的组合疗法包括化疗，放疗，手术，激素疗法，或其他类型的免疫疗法。疗法的具体剂量可以使用本领域中的常规方法确定。然而，在具体的实施方式中，本发明的工程化cd123t细胞一次性递送至对其需要的个体，但在一些情况下是多次的，包括2，3，4，5，6次或更多次。当提供多次给药，给药之间的时间间隔可以是任何合适的时间，但在具体的实施方式中，其是给药之间数天或数周或数月。剂量和t细胞供体源选择为避免任何不良副作用。给药之间的时间可以在单一方案中变化，并且可以取决于接受者(对其需要的患者)。在具体的实施方式中，给药之间的时间是2，3，4，5，6，7，8，9，10，或更多天或数周。在具体情况下，例如，其为4-8或6-8周。在具体的实施方式中，一种方案包括本发明的cd123t细胞的以下给药方案中的一种：11×104/m2，11×105/m2，11×106/m2，23×106/m2，31×107/m2，43×07/m2，51×108/m2，或104至1010个细胞/kg。在可替换的实施方式中，t细胞以以下给药方案提供至个体：给药水平cd123ctl剂量11×106/m2，21×107/m2，31×108/m2，6×104至5×108个细胞/kg，有效量的本发明的cd123car工程化免疫细胞对应于这种可以根据每个治疗的个体的状态而调整的剂量。治疗应用在另一实施方式中，通过不同方法获得的分离的细胞或源自所述本发明的分离的细胞(体外1至50传代之后)的细胞可以用作药物。可以用作药物的本发明的工程化tcrkodckkocd123cart细胞可以是具有对应于seqidno.31，seqidno.32，seqidno160，seqidno.34至seqidno.159中任一种的序列的cd123car的那些。在优选的实施方式中，具有对应于seqidno.31，seqidno.32，seqidno160的序列的工程化tcrkodckkocd123cart细胞提供用作药物。在另一个优选的实施方式中，提供具有选自以下序列中的任一种序列的遗传工程化tcrkodckkocd123cart细胞用作药物：seqidno.34、seqidno.76、seqidno.36、seqidno.78、seqidno.37、seqidno.79、seqidno.41、seqidno.83、seqidno.42、seqidno.8)、seqidno.43、seqidno.85、seqidno.46、seqidno.47、seqidno.48、seqidno.49、seqidno.88、seqidno.89、seqidno.90、seqidno.91、seqidno.52、seqidno.53、seqidno.54、seqidno.55、seqidno.94、seqidno.95、seqidno.96、seqidno.97。在另一优选实施方式中，提供具有选自seqidno.160、seqidno.188、seqidno.189、seqidno.190、seqidno.191；seqidno.192、seqidno.193、seqidno.194、seqidno.195、seqidno.196、seqidno.197中的任何一种序列的工程化tcrkodckkocd123cart细胞用作药物。在另一实施方式中，所述药物可以用于治疗癌症，特别是用于治疗对其需要的患者中的b细胞淋巴瘤和白血病。在另一实施方式中，根据本发明的所述分离的细胞或源自所述分离的细胞的细胞系可以用于生产治疗对其需要的患者中的癌症的药物。在具体实施方式中，提供表达抗cd123car的t细胞用作用于治疗aml，aml亚型，aml相关并发症，aml相关病症的药物。在优选的实施方式中，提供表达抗cd123car的t细胞作为药物，其中所述抗cd123car包含seqidno31，seqidno32或seqidno160。在另一实施方式中，所述药物可以用于治疗表达cd123的细胞介导的病理状况或特征在于表达cd123的细胞的直接或间接活性的病症。换言之，本发明涉及包含80％至100％的seqidno31，seqidno32或seqidno160的表达抗cd123car的t细胞，其用作治疗与表达cd123的细胞的有害活性相关的病症，特别是治疗选自aml，aml亚型，aml相关并发症和aml相关病症的病症的药物；另一方面，本发明依赖于用于治疗对其需要的患者的方法，所述方法包括以下步骤中的至少一个步骤：(a)提供通过任一种前述方法可获得的免疫细胞；(b)将所述转化的免疫细胞给予于患者，在一个实施方式中，本发明的所述t细胞可以经受强健的体内t细胞扩增并可以持续延长的时间。在优选实施方式中，所述t细胞通过给予选择性破坏所述t细胞的药物或抗体而破坏。在更优选的实施方式中，具有含有对应于seqidno.31，seqidno.32，seqidno160，seqidno.34至seqidno.159中的任一种的序列的cd123car的本发明的工程化tcrkodckkocd123cart细胞用作药物/治疗，而随后使用识别自杀结构域rqr8，或cd20结构域，或seqidno161的抗体，优选使用利妥昔单抗，从患者中清除。所述治疗可以是改善，治愈或预防性的。其可能是自体免疫疗法的一部分或同种异体免疫疗法的一部分。自体免疫疗法是指用于治疗患者的细胞、细胞系或细胞群源自患者或来自人白细胞抗原(hla)相容性供体。同种异体免疫疗法是指用于治疗患者的细胞或细胞群不是源自所述患者，而是来自供体。可以用于所公开的方法的本发明的细胞已经在前面的部分中描述。所述治疗可以用于治疗诊断为恶性前或恶性癌症病症，其特征在于表达cd123的细胞，特别是表达cd12的细胞过多的患者。这些病症存在于血液癌症中，如白血病或恶性淋巴增生性疾病。淋巴增生性疾病可以是淋巴瘤，特别是多发性骨髓瘤，非霍奇金淋巴瘤，伯基特淋巴瘤和滤泡性淋巴瘤(小细胞和大细胞)。使用本发明的细胞或包含所述细胞的药物组合物可以治疗的癌症可以包括非实体肿瘤(如血液肿瘤，包括但不限于前ball(儿科适应症)、成人all、套细胞淋巴瘤、弥漫性大b细胞淋巴瘤、bpdnl、aml、难治的复发性aml、或骨髓移植前。用本发明的表达car的cd123细胞治疗的癌症的类型包括，但不限于，白血病或淋巴恶性肿瘤。还包括成人肿瘤/癌症和儿科肿瘤/癌症。在一个实施方式中，本发明提供了药物组合物，用于其治疗表达cd123的细胞介导的疾病，特别是表达cd123的细胞介导的血液癌症的用途，所述组合物包含本发明的所述表达抗cd123car的t细胞，优选地，所述抗cd123car是seqidno31，seqidno32或seqidno160的抗cd123car，更优选具有选自seqidno.160、seqidno.188、seqidno.189、seqidno.190、seqidno.191；seqidno.192、seqidno.193、seqidno.194、seqidno.195、seqidno.196、seqidno.197的序列。本文公开的任何其它cd123介导的或cd123涉及的恶性淋巴增殖性疾病可以用本发明的表达抗cd123car的细胞改善。在优选的实施方式中，使用本发明的表达抗cd123car的细胞可以治疗的癌症是白血病(aml)，与白血病相关的疾病或其并发症。使用本发明的表达抗cd123car的细胞可以治疗的白血病可以是急性髓细胞白血病(aml)，慢性髓细胞白血病，骨髓增生异常综合症，急性淋巴细胞白血病，慢性淋巴细胞白血病和骨髓增生异常综合征。使用本发明的表达抗cd123car的细胞可以治疗的aml或aml亚型可以是，具体地，急性髓细胞白血病、微分化急性髓细胞白血病(minimallydifferentiatedacutemyeloblasticleukemia)、未成熟急性髓细胞性白血病、粒细胞成熟急性髓细胞性白血病、早幼粒细胞或急性早幼粒细胞白血病(apl)、急性骨髓单核细胞白血病、骨髓单核细胞与骨髓嗜酸粒细胞增多、急性原单核细胞白血病(acutemonoblasticleukemia)(m5a)或急性单核细胞白血病(acutemonocyticleukemia)(m5b)、急性红细胞白血病、包括红白血病(m6a)和非常罕见的纯红细胞性白血病(m6b)、急性巨核细胞白血病、急性嗜碱粒细胞白血病、伴有骨髓纤维化的急性全骨髓增生(acutepanmyelosiswithmyelofibrosis)，不论是否涉及cd123阳性细胞。使用本发明的表达抗cd123car的细胞可以治疗的aml亚型也包括，毛细胞白血病，费城染色体阳性急性淋巴细胞白血病。aml可以分类为具有特异性遗传异常的aml。分类是基于核型预测对诱导疗法的反应的能力，复发风险，存活率。因此，使用seqidno31，seqidno32或seqidno160的本发明的表达抗cd123car的细胞可以治疗的aml可以是在染色体8和21之间具有易位的aml，染色体16中具有易位或反转的aml，染色体9和11之间具有易位的aml，染色体15和17之间具有易位的apl(m3)，染色体6和9之间具有易位的aml，染色体3中具有易位或反转的aml，染色体1和22之间具有易位的aml(巨核细胞)。本发明特别适用于治疗与这些具体的细胞遗传学标记相关的aml。本发明还提供了用于治疗患有aml的特定细胞遗传学亚型的患者，如具有使用全反式视黄酸(atra)16-19识别的t(15；17)(q22；q22)的患者或用于治疗具有使用高剂量阿糖胞苷的重复给药识别的t(8；21)(q22；q22)或inv(16)(p13q22)/t(16；16)(p13；q22)的患者的seqidno31、seqidno32或seqidno160的表达抗cd123car的t细胞。优选地，本发明提供了结合flag用于治疗患有畸变，如-5/del(5q)、-7、3q的异常，或复杂核型(complexkaryotype)，已经显示出具有较差的完全缓解率和存活率的患者的seqidno31、seqidno32或seqidno160的表达抗cd123car的t细胞。患者分组在优选的实施方式中，本发明提供了seqidno31，seqidno32或seqidno160的表达抗cd123car的t细胞作为60岁以上患者或小于20岁的患者的aml的治疗。在更优选的实施方式中，本发明提供了seqidno31，seqidno32或seqidno160的表达抗cd123car的t细胞用作儿科治疗，特别是针对aml，或aml相关疾病或并发症的儿科治疗。在又一优选实施方式中，本发明用作具有低，差或不利状态，即具有小于5年存活率的预测存活率的aml患者的治疗。在该组中，患有具有以下细胞遗传学特性aml：-5；5q；-7；7q-；11q23；nont(9；11)；inv(3)；t(3；3)；t(6；9)；t(9；22)的患者与不良风险状态有关(byrdj.c.etal.，december15，2002；blood：100(13))，并且特别设想的是根据本发明或使用本发明的目的来治疗。在一个实施方式中，本发明的表达抗cd123car的t细胞可以用作诱导疗法，作为aml的缓解后治疗或作为患有aml的患者的巩固治疗。优选地，trcko细胞或或表达seqidno.31，seqidno.32或seqidno.160的抗cd123car的tcrko和dckkot细胞用作aml的缓解后治疗或作为患有aml的患者的巩固治疗。在一个实施方式中，在aml复发的情况下，或在难治性或耐药性aml的情况下，可以使用本发明的tcrko、dckko，表达seqidno31，seqidno32或seqidno160的抗cd123car的t细胞。优选地，本发明的所述tcrkotdckko，表达seqidno31，seqidno32或seqidno160的抗cd123car的t细胞用于患有aml复发，或难治性或耐药性aml的患者，更优选与至少一种其它抗癌药物组合。在另一优选的实施方式中，本发明的tcrko，dckko，表达seqidno31，seqidno32或seqidno160的抗cd123car的t细胞适用于防止特别是在抗癌治疗，骨髓去除期间或骨髓移植前，骨髓破坏之后发生的癌细胞发展。aml并发症在一个具体实施发生中，本发明提供了改善患者，特别是患有与aml相关的并发症的患者的健康状况的药物。更优选地，tcrko，dckko，表达seqidno31，seqidno32或seqidno160的抗cd123car的t细胞，优选与flag一起，用作治疗与aml有关的并发症的药物。与aml相关的并发症或疾病可以包括前期骨髓增生阶段(precedingmyelodysplasiaphase)，继发性白血病，特别是继发性aml，高白细胞计数，以及奥氏小体(auerrods)缺失。其中，白血病和中枢神经系统(cns)介入，高白细胞增生症(hyperleukocytosis)，残留疾病，也认为是与aml有关的并发症或疾病。aml相关的疾病在一个实施方式中，本发明还提供了tcrko，dckko，表达seqidno31，seqidno32或seqidno160的抗cd123car的t细胞用于治疗与aml相关的病理状况。优选地，本发明提供了tcrko，dckko，表达seqidno31，seqidno32或seqidno160的抗cd123car的t细胞用于治疗与aml相关的病理状况。本发明提供了一种用于aml相关的髓性肿瘤，用于急性髓细胞白血病和骨髓增生异常综合征，治疗复发或难治性急性髓细胞白血病，治疗成人的复发性或难治性急性早幼粒细胞白血病，治疗急性前随细胞白血病(acutepromyeloidleukaemia)，治疗60岁以上成人急性髓细胞白血病的疗法(tcrko，dckko，表达seqidno31，seqidno32或seqidno160的抗cd123car的t细胞，优选具有选自seqidno.160、seqidno.188、seqidno.189、seqidno.190、seqidno.191；seqidno.192、seqidno.193、seqidno.194、seqidno.195、seqidno.196、seqidno.197的序列)。根据另一方面，本发明提供了用于治疗aml相关的疾病，特别是与aml相关的血液恶性肿瘤的组合物。与aml病症相关的血液恶性肿瘤包括骨髓增生异常综合征(mds，以前称为“前白血病”)，其是通过骨髓血液细胞的无效生产(或发育异常)和转化为am的风险联合的血液病的多样集合。在另一实施方式中，本发明提供了改善患有多发性骨髓瘤的患者的健康状态的药物。与aml风险相关的其它病理状况或遗传综合征可以充分利用本发明而改进，所述遗传综合征包括唐氏综合征，三染色体性(trisomy)，范康尼贫血症(fanconianemia)，布卢姆综合征(bloomsyndrome)，共济失调毛细血管扩张症(ataxia-telangiectasia)，戴-布二氏贫血症(diamond-blackfananemia)，舒-戴二氏综合征(schwachman-diamondsyndrome)，李弗劳明综合征(li-fraumenisyndrome)，1型神经纤维瘤(neurofibromatosistype1)，重型先天性中性粒细胞减少症(severecongenitalneutropenia)(也称为kostmann综合征)。其他cd123介导的病理状况根据另一方面，本发明提供了用于治疗cd123+细胞介导的疾病的组合物。这些cd123+细胞介导的疾病包括炎症，自身免疫性疾病。具体地，本发明可以用于治疗cd123+细胞介导的疾病，如胃肠粘膜的炎症，而更具体而言，炎性肠病，鼻过敏，皮肤炎症，如青少年皮肌炎，血液病。本发明可以用作治疗cd123+细胞介导的疾病如自身免疫疾病，特别是菊池病(kikushidisease)的药物。优选地，本发明提供了复发性感染的治疗，包括由病毒引起的感染，如爱泼斯坦-巴尔(epstein-barr)病毒，单纯疱疹(herpessimplex)病毒，特别是致癌病毒，hhv-8，hhv-6，htlv或hiv，寄生虫感染如由于恶性疟原虫(plasmodiumfalciparum)，间日疟原虫(plasmodiumvivax)，卵形疟原虫(plasmodiumovale)或三日疟原虫(plasmodiummalariae)的感染。具体地，本发明提供了用于爱泼斯坦-巴尔病毒淋巴结炎(epstein-barrviruslymphadenitis)，单纯疱疹病毒淋巴结炎(herpessimplexviruslymphadenitis)的治疗。在另一方面中，本发明提供了用于治疗系统性红斑狼疮淋巴结炎，结核病，囊性纤维化，肝炎，胆道闭锁，特别是儿童中的病毒诱导肝炎或胆道闭锁，自身免疫性肝炎，原发胆汁性肝硬化的组合物。包含根据本发明的工程化t细胞的组合物用作药物和方法本发明也提供了包含具有对应于seqidno.31，seqidno.32或seqidno160的序列，或赋予选自seqidno.160、seqidno.188、seqidno.189、seqidno.190、seqidno.191；seqidno.192、seqidno.193、seqidno.194、seqidno.195、seqidno.196、seqidno.197的序列的遗传工程化免疫tcrko-dckko-cd123cart细胞，或具有任何一种选自以下的的序列的遗传工程化免疫tcrko-dckkocd123cart细胞的组合物：seqidno.34至seqidno.159、优选选自seqidno.34、seqidno.76、seqidno.36、seqidno.78；seqidno.37、seqidno.79、seqidno.41、seqidno.83、seqidno.42、seqidno.8、seqidno.43、seqidno.85、seqidno.46、seqidno.47、seqidno.48、seqidno.49、seqidno.88、seqidno.89、seqidno.90、seqidno.91、seqidno.52、seqidno.53、seqidno.54、seqidno.55、seqidno.94、seqidno.95、seqidno.96和seqidno.97。优选地，本发明提供了包含具有对应于seqidno31的序列的工程化免疫tcrko-dckko-cd123car的t细胞的组合物。优选地，本发明提供了包含具有对应于seqidno32的序列的工程化免疫tcrko-dckko-cd123car的t细胞的组合物。优选地，本发明提供了工程化免疫tcrko-dckko-cd123car的t细胞的组合物，包含具有对应于seqidno160的序列或任一种选自seqidno.160、seqidno.188、seqidno.189、seqidno.190、seqidno.191；seqidno.192、seqidno.193、seqidno.194、seqidno.195、seqidno.196、seqidno.197的序列，用于其治疗癌症如bpdnl或作为骨髓移植前的治疗的用途或方法。一方面，该疾病是血液学癌症，特别是干细胞癌，包括但不限于白血病(例如急性髓细胞白血病(aml)、慢性髓细胞白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病和骨髓增生异常综合征)和恶性淋巴增生性病症、包括淋巴瘤(例如多发性骨髓瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、小细胞和大细胞滤泡淋巴瘤)或其并发症(复发难治性aml)。本发明还提供了如上述组合物用于其抑制增殖或降低患者中表达cd12的细胞群体或活性的用途或方法。示例性方法包括使包含cd123表达细胞的细胞群体与本发明的结合至表达cd123的细胞的cd123cart细胞接触。在更具体的方面中，本发明提供了组合物，用于其抑制增殖或降低患者中表达cd123的癌细胞群体的用途和方法，该方法包括使表达cd123的癌细胞群体与本发明的与表达cd123的细胞结合的cd123cart细胞接触，本发明的cd123cart细胞与表达cd123的癌细胞的结合会导致表达cd123的癌细胞破坏在某些方面中，本发明的cd123cart细胞相对于阴性对照，在具有髓细胞白血病或与表达cd123的细胞相关的另一种癌症的受试者或动物模型中将细胞和/或癌细胞的数量，数目，量或百分比降低至少25％、至少30％、至少40％、至少50％、至少65％、至少75％、至少85％、至少95％、或至少99％(至不可检测的水平)。本发明还提供了组合物，用于其预防，治疗和/或控制与表达cd123的细胞(例如，与血液学癌症相关)的疾病或病症的用途或方法，方法包括向对其需要的受试者给予本发明的结合至表达cd123的细胞的cd123cart细胞。在一方面中，受试者是人类。与表达cd123的细胞相关的疾病的非限制性实例包括自身免疫性疾病(如狼疮)，炎症性疾病(如过敏，ibd和哮喘)和癌症(如血液癌症，特别是aml或aml并发症)。本发明还提供了组合物，用于其预防，治疗和/或控制与表达cd123的细胞相关的疾病的用途或方法，方法包括向对其需要的受试者给予本发明的结合至表达cd123的细胞的cd123cart细胞。在一方面中，受试者是人类。与表达cd123的细胞相关的疾病的非限制性实例包括急性髓细胞白血病(aml)、脊髓发育不良(myelodysplasia)、b细胞急性淋巴白血病、t细胞急性淋巴白血病、毛细胞白血病、母细胞性浆细胞样树突状细胞肿瘤(bpdcn)、慢性髓细胞白血病、霍奇金淋巴瘤。本发明提供了组合物，用于其治疗或预防与表达cd123的细胞相关的癌症复发的用途或方法，方法包括向对其需要的受试者给予本发明的结合至表达cd123的细胞的cd123cart细胞。在另一方面中，方法包括结合有效量的另一种治疗，向对其需要的受试者给予有效量的本发明的结合至表达cd123的细胞的cd123cart细胞。在一个方面中，cd123被认为是aml中的“癌干细胞”标记物。因此，本发明的cd123cart细胞可以预防aml的复发，或甚至治疗主要为cd123阴性但具有cd123+细胞(表达cd123的细胞)的“干”群体的aml。在一方面中，本发明提供用于治疗经受与cd19表达水平升高相关的疾病或病症的治疗，并表现出与升高的cd123水平相关的疾病或病症的受试者的组合物和方法。在一方面中，b细胞急性淋巴细胞白血病(all)是需要使用cart细胞进行系列治疗的疾病的实例。例如，用抗cd19cart细胞治疗有时可能导致cd19阴性复发，其可以用本发明的抗cd123cart细胞治疗。另外，本发明包括使用包含抗cd19car和抗cd123car的cart细胞的双重靶向。使用根据本发明的工程化免疫细胞的治疗可以与一种或多种抗癌治疗组合，该治疗选自抗体疗法、化学疗法、细胞因子疗法、树突细胞疗法、基因疗法、激素疗法、激光疗法和辐射疗法。优选地，根据本发明的工程化免疫细胞的治疗可以与一种或多种选自以下的抗癌疗法组合(例如，之前，同时或之后)给予：阿糖胞苷(aracytine)，胞嘧啶阿拉伯糖苷(cytosinearabinoside)，安吖啶，柔红霉素，伊达比星，诺安托，米托蒽醌，足叶乙苷，依托泊苷(vp16)，三氧化二砷，反式维甲酸，三氧化三砷、反式维甲酸、氮芥、甲基苄肼、苯丁酰氮芥的组合，及它们的组合。根据本发明的优选实施方式，所述治疗可以给予正经受免疫抑制治疗的患者。实际上，本发明优选地依赖于由于编码这种免疫抑制剂的受体的基因失活而使其对至少一种免疫抑制剂抗性的细胞或细胞群。在这方面中，免疫抑制治疗应该有助于根据本发明的t细胞在患者体内的选择和扩增。根据本发明的细胞或细胞群体的给予可以以任何方便的方式进行，包括通过气溶胶吸入、注射、摄入、输液、植入或移植。本文的组合物可以通过皮下、皮内、肿瘤内、结节内、髓内、肌肉内，通过静脉内或淋巴管内注射，或腹膜内给予于患者。在一个实施方式中，本发明的细胞组合物优选地通过静脉内注射给予。细胞或细胞群体的给予可以由给予104-109个细胞/kg体重，优选105-106个细胞/kg体重组成，包括在该范围内的所有细胞数的整数值。细胞或细胞群体可以以一此或多次给药给予。在另一实施方式中，所述有效量的细胞作为单次给药给予。在另一实施方式中，所述有效量的细胞在一段时间内以多于一次给药给予。给予的时机在主任医师的判断之内，取决于患者的临床状况。细胞或细胞群体可以获得自任何来源，例如血库或供者。尽管个体需求不同，但确定特定疾病的给定细胞类型的有效量的最佳范围或条件都在本领域的技术范围内。有效量是指提供治疗或预防益处的用量。给予的剂量将取决于接受者的年龄、健康和体重，并发治疗的种类，如果有的话，治疗频率和所需效果的性质。在另一实施方式中，将所述有效量的细胞或包含这些细胞的组合物肠胃外给予。所述给予可以是静脉内给予。所述给予可以通过肿瘤内注射直接进行。在本发明的某些实施方式中，细胞与任何数量的相关治疗方式，包括但不限于采用药物的治疗如抗病毒疗法，西多福韦和白细胞介素-2，阿糖胞苷(也称为ara-c)或用于ms患者的那他珠单抗治疗或用于牛皮癣患者的依法利珠单抗治疗或用于pml患者的其他治疗结合(例如，之前，同时或之后)给予患者。在进一步的实施方式中，本发明的t细胞可以与化学疗法、放射、免疫抑制剂如环孢菌素、硫唑嘌呤、甲氨蝶呤、霉酚酸酯和fk506、抗体或其他免疫消融剂(immunoablative)如campath、抗cd3抗体或其他抗体疗法、细胞毒素、氟达拉滨、环孢菌素、fk506、雷帕霉素(rapamycin)、霉酚酸(mycoplienolicacid)、类固醇、fr901228、细胞因子和辐照组合使用。这些药物抑制钙依赖性磷酸酶钙调磷酸酶(环孢菌素和fk506)或抑制对生长因子诱导的信号传导重要的p70s6激酶(雷帕霉素)(henderson，nayaetal.1991；liu，albersetal.1992；bierer，hollanderetal.1993)。在进一步的实施方式中，本发明的细胞组合物与骨髓移植，使用化疗药物如氟达拉滨的t细胞消融疗法，外照射治疗(xrt)，环磷酰胺，或抗体如okt3或campath结合(例如，之前，同时或之后)给予于患者。在另一实施方式中，本发明的细胞组合物在b细胞消融疗法，如与cd20反应的药物，例如利妥昔单抗(rituxan)之后给予。在这种情况下，在本发明的t细胞中表达的cd123car不包含seqid160，除非其在利妥昔单抗之前给予。例如，在一个实施方式中，受试者可以接受高剂量化疗，随后外周血干细胞移植的标准治疗。在某些实施方式中，在移植之后，受试者接受本发明的扩增的免疫细胞的输液。在其它实施方式中，扩增的细胞在手术之前或之后给予。在本发明的某些实施方式中，将粘度抗cd123car的细胞与选自阿胞嘧啶、胞嘧啶阿拉伯糖苷、安吖啶、柔红霉素、伊达比星、诺安托、米托蒽醌、足叶乙苷、依托泊苷(vp16)、三氧化二砷、反式维甲酸、氮芥、甲基苄肼、苯丁酰氮芥、及其组合的药物组合(例如，之前，同时或之后)向患者给予。在这些实施方式中，表达抗cd123car的细胞可以具有对具体药物或与表达抗cd123car的细胞联合给予的药物组合的抗性。在本发明的其他实施方式中，表达抗cd123car的细胞与选自阿糖胞苷，蒽环霉素，6-硫鸟嘌呤，羟基脲，泼尼松及其组合的药物联合给予患者。其他定义-除非另有说明，否则“一个”，“一种”，“该”和“至少一个”可以互换使用，并是指一个或多于一个。-多肽序列中的氨基酸残基在本文中根据单字母代码表示，其中，例如，q表示gln或谷氨酰胺残基，r表示arg或精氨酸残基，而d表示asp或天冬氨酸残基。-氨基酸取代是指将一个氨基酸残基用另一个氨基酸残基取代，例如，用肽序列中的谷氨酰胺残基取代精氨酸残基就是氨基酸取代。-核苷酸指定如下：单字母代码用于指定核苷的碱基：a是腺嘌呤，t是胸腺嘧啶，c是胞嘧啶，而g是鸟嘌呤。对于简并核苷酸，r表示g或a(嘌呤核苷酸)，k表示g或t，s表示g或c，w表示a或t，m表示a或c，y表示t或c(嘧啶核苷酸)，d表示g，a或t，v表示g，a或c，b表示g，t或c，h表示a，t或c，而n表示g，a，t或c。-如本文所用，“核酸”或“多核苷酸”是指核苷酸和/或多核苷酸，如脱氧核糖核酸(dna)或核糖核酸(rna)，寡核苷酸，通过聚合酶链反应(pcr)产生的片段，以及通过连接，剪切，内切核酸酶作用和外切核酸酶作用而产生的片段。核酸分子可以由天然存在的核苷酸(如dna和rna)或天然存在的核苷酸的类似物(例如，天然存在的核苷酸的对映体形式)，或两者的组合的单体构成。改造的核苷酸可以在糖部分和/或嘧啶或嘌呤碱基部分中具有改变。糖的改造包括，例如，用卤素，烷基基团，胺和叠氮基团取代一个或多个羟基基团，或糖可以官能化为醚或酯。此外，整个糖部分可以用空间和电子上相似的结构取代，如氮杂糖和碳环类似物。碱基部分中改造的实例包括烷基化嘌呤和嘧啶，酰化嘌呤或嘧啶，或其它众所周知的杂环替代物。核酸单体可以通过磷酸二酯键或这种连接键的类似物连接。核酸可以是单链或双链。-嵌合抗原受体(car)旨在是结合针对存在于靶细胞上的组件的结合结构域，例如，对期望的抗原(例如，肿瘤抗原)的基于抗体的特异性，与t细胞受体活化的胞内结构域而产生展现特异性抗靶细胞免疫活性的分子。通常，car由融合到t细胞抗原受体复合物ζ链(scfvfc：ζ)的胞内信令结构域的胞外单链抗体(scfvfc)组成，并当在t细胞中表达时具有基于单克隆抗体的特异性重定向抗原识别的能力。在本发明中使用的car的一个实例是针对cd123抗原的car，并可以包含作为非限制性实例的氨基酸序列：seqidno:23至48和160。-术语“内切核酸酶”是指可以催化dna或rna分子，优选dna分子内的核酸之间的键的水解(切割)的任何野生型或变体酶。内切核酸酶不会切割与其序列无关的dna或rna分子，而是识别和切割在特定多核苷酸序列上的dna或rna分子，进一步称为“靶序列”或“靶位点”。当通常具有多于12个碱基对(bp)长度，更优选14-55bp的多核苷酸识别位点时，内切核酸酶可以分类为稀切内切核酸酶。稀切内切核酸酶通过在定义的位点上诱导dna双链断裂(dsb)而显著提高hr(perrin，buckleetal.1993；rouet，smihetal.1994；choulika，perrinetal.1995；pingoudandsilva2007)。稀切内切核酸酶可以，例如，是归巢内切核酸酶(homingendonuclease)(paquesandduchateau2007)，由工程化的锌指结构域与限制酶如foki的催化结构域融合产生的嵌合锌指核酸酶(zfn)(porteusandcarroll2005)，来自crispr系统的cas9内切核酸酶(gasiunas，barrangouetal.2012；jinek，chylinskietal.2012；cong，ranetal.2013；mali，yangetal.2013)或化学内切核酸酶(eisenschmidt，lanioetal.2005；arimondo，thomasetal.2006)。在化学内切核酸酶中，化学或肽切割物与核酸聚合物缀合或缀合于识别特异性靶序列的另一dna，从而将切割活性靶向于特异性序列。化学内切核酸酶也包括合成的核酸酶，比如邻菲咯啉的复合物，dna切割分子，已知结合特异性dna序列的三链体形成寡核苷酸(tfo)(kalishandglazer2005)。这样的化学内切核酸酶包含于根据本发明的术语“内切核酸酶”中。-“tale核酸酶”(talen)旨在是由通常源自转录活化因子样效应子(tale)的核酸结合结构域和一个核酸酶催化结构域组成以切割核酸靶序列的融合蛋白。催化结构域优选是核酸酶结构域，而更优选具有内切核酸酶活性的结构域，如例如i-tevi，cole7，nuca和fok-i。在具体的实施方式中，tale结构域可以融合到大范围核酸酶中，如例如i-crei和i-onui或其功能变体。在更优选的实施方式中，所述核酸酶是单体tale核酸酶。单体tale核酸酶是不需要二聚用于特异性识别和切割的tale核酸酶，如wo2012138927中描述的工程化tal重复序列与i-tevi催化结构域的融合。转录活化因子样效应子(tale)是来自细菌种黄杆菌属(xanthomonas)的蛋白质，包含多个重复序列，每个重复序列包含对于核酸靶向的序列的每个核苷酸碱基特异性的12和13位上的二残基(rvd)。具有相似的模块化逐碱基核酸结合特性(mbbbd)的结合结构域也可以源自由本申请人最近在不同细菌种中发现的新模块化蛋白质。新的模块化蛋白质具有比tal重复序列显示更多序列变异性的优点。优选地，与识别不同核苷酸相关的rvd是用于识别c的hd、用于识别t的ng、用于识别a的ni、用于识别g或a的nn、用于识别a、c、g或t的ns、用于识别t的hg、用于识别t的ig、用于识别g的nk、用于识别c的ha、用于识别c的nd、用于识别c的hi、用于识别g的hn、用于识别g的na、用于识别g或a的sn和用于识别t的yg、用于识别a的tl、用于识别a或g的vt和用于识别a的sw。在另一个实施方式中，关键氨基酸12和13可以朝着其他氨基酸残基突变，以调节其对核苷酸a，t，c和g的特异性，且特别是增强这种特异性。已经描述了tale核酸酶并用于刺激基因靶向和基因改造(boch，scholzeetal.2009；moscouandbogdanove2009；christian，cermaketal.2010；li，huangetal.2011)。工程化tal核酸酶是在商品名talentm下可商购的(cellectis，8ruedelacroixjarry，75013paris，france)。根据本发明的稀切内切核酸酶也可以是cas9内切核酸酶。最近，基于rna导向的cas9核酸酶(gasiunas，barrangouetal.2012；jinek，chylinskietal.2012；cong，ranetal.2013；mali，yangetal.2013)，由ii型原核crispr(成簇规律间隔短回文重复序列(clusteredregularlyinterspacedshortpalindromicrepeats))适应性免疫系统(参见综述(sorek，lawrenceetal.2013))开发了新的基因组工程化工具。crispr相关(cas)系统首先发现于细菌中，并起到防御外来dna，或病毒或质粒的作用。crispr介导的基因组工程化首先通过选择通常侧接称为前间区序列邻近基序(pam)的短序列基序的靶序列进行。在靶序列选择后，将与该靶序列互补的特异性crrna工程化。crisprii型系统中所需要的反式活化crrna(tracrrna)与crrna配对并结合至提供的cas9蛋白。cas9起到促进tracrna与crna的碱基配对的分子锚的作用(deltcheva，chylinskietal.2011)。在这种三元复合体中，双重tracrrna:crrna结构起到将内切核酸酶cas9引导至同源靶序列的引导rna的作用。通过扫描靶序列的靶序列和crrna之间的同源性而开始通过cas9-tracrrna:crrna复合体的靶识别。除了靶序列-crrna互补性之外，dna靶向要求存在与前间区序列相邻的短基序(前间区序列邻近基序-pam)。在双-rna和靶序列之间配对后，cas9随后引入pam基序上游的钝双链断裂3碱基(garneau，dupuisetal.2010)。稀切内切核酸酶可以是归巢内切核酸酶，也称为大范围核酸酶。这种归巢内切核酸酶在本领域内是熟知的(stoddard2005)。归巢核酸内切酶会识别dna靶序列并产生单链或双链断裂。归巢内切核酸酶是高度特异性的，会识别长度为12至45碱基对(bp)范围，通常为14至40bp范围的dna靶位点。根据本发明的归巢内切核酸酶可以，例如对应于laglidadg内切核酸酶，对应于hnh内切核酸酶，或对应于giy-yig内切核酸酶。根据本发明的优选归巢内切核酸酶可以是i-crei变体。-“递送载体(deliveryvector)”或“递送载体(deliveryvectors)”旨在是可以用于本发明以使本发明中所需的试剂/化学物质和分子(蛋白质或核酸)与细胞接触(即“接触”)或递送到细胞内或亚细胞区室(即“引入”)的任何递送载体。其包括，但不限于，脂质体递送载体、病毒递送载体、药物递送载体、化学载体、聚合物载体、脂质复合体、复合载体、树枝状聚合物、微泡(超声造影剂)、纳米颗粒、乳液或其它合适的转移载体。这些递送载体允许递送分子、化学物质、大分子(基因，蛋白)或其它载体如质粒，由diatos开发的肽。在这些情况下，递送载体是分子载体。“递送载体(deliveryvector)”或“递送载体(deliveryvectors)”还旨在是用于进行转染的递送方法。-术语“载体(vector)”或“载体(vectors)”是指能够转运与其连接的另一个核酸的核酸分子。本发明中的“载体”包括，但不限于，病毒载体，质粒，rna载体或可以由染色体，非染色体，半合成或合成的核酸组成的线性或环状dna或rna分子。优选的载体是能够自主复制(附加型载体)和/或表达其连接的核酸(表达载体)的那些。大量合适的载体是本领域技术人员已知的并可商购。病毒载体包括逆转录病毒，腺病毒，细小病毒(例如，腺相关病毒)，冠状病毒，负链rna病毒如正粘病毒(例如，流感病毒)，弹状病毒(例如，狂犬病和水泡性口炎病毒)，副粘病毒(例如，麻疹和仙台病毒)，正链rna病毒如小核糖核酸病毒和甲病毒，以及双链dna病毒，包括腺病毒，疱疹病毒(例如，1型和2型单纯疱疹病毒，爱泼斯坦-巴尔病毒，巨细胞病毒)和痘病毒(例如，牛痘，禽痘和金丝雀痘)。其他病毒包括，例如，诺瓦克病毒，披膜病毒，黄病毒，呼肠弧病毒，乳多空病毒，嗜肝dna病毒和肝炎病毒。逆转录病毒的实例包括：禽白血病肉瘤(avianleukosis-sarcoma)，哺乳动物c型，b型病毒，d型病毒，htlv-blv组，慢病毒，泡沫病毒(coffin，j.m.，retroviridae：thevirusesandtheirreplication，infundamentalvirology，thirdedition，b.n.fields，etal.，eds.，lippincott-ravenpublishers，philadelphia，1996)。-“慢病毒载体”是指由于其相对较大的包装容量，降低的免疫原性以及高效率地稳定转导大范围不同细胞类型的能力，用于基因递送非常有希望的基于hiv的慢病毒载体。慢病毒载体通常在将三种(包装，包膜和转运)或更多的质粒瞬时转染到生产细胞中后产生。像hiv一样，慢病毒载体通过病毒表面糖蛋白与细胞表面受体的相互作用而进入靶细胞中。进入时，病毒rna会经历逆转录，其由病毒逆转录酶复合体介导。逆转录的产物是双链线性病毒dna，其是用于病毒整合于感染细胞dna的底物。“整合慢病毒载体(或lv)”是指作为非限制性实例，能够整合靶细胞基因组的这种载体。相反，“非整合慢病毒载体(或nilv)”是指不通过病毒整合酶的作用整合靶细胞的基因组的有效基因递送载体。-递送载体和载体可以关联或结合任何细胞透化技术，如声孔作用或电穿孔或这些技术的衍生。-细胞(cell)或细胞(cells)旨在是来自这些生物体而用于体外培养的任何真核活细胞，原代细胞和细胞系。-“原代细胞(primarycell)”或“原代细胞(primarycells)”，旨在是直接从活组织采集的细胞(即，活检材料)，并建立用于体外生长，其会经历非常少的群体倍增，而因此与连续致瘤性或人造永生化细胞系相比，更能代表其衍生自的组织的主要功能组分和特性。作为非限制性实例，细胞系可以选自由以下组成的组：cho-k1细胞；hek293细胞；caco2细胞；u2-os细胞；nih3t3细胞；nso细胞；sp2细胞；cho-s细胞；dg44细胞；k-562细胞，u-937细胞；mrc5细胞；imr90细胞；jurkat细胞；hepg2细胞；hela细胞；ht-1080细胞；hct-116细胞；hu-h7细胞；huvec细胞；molt4细胞。所有这些细胞系可以通过本发明的方法改造而提供细胞系模型以产生、表达、定量、检测、研究所感兴趣的基因或蛋白质；这些模型也可以用于在研究和生产以及各种领域，作为非限制性实例，如化学、生物燃油、治疗和农学中筛选所感兴趣的生物活性分子。-“突变”旨在是多核苷酸(cdna，基因)或多肽序列中高达一、二、三、四、五、六、七、八、九、十、十一、十三、十四、十五、二十、二十五、三十、四十、五十个或更多个核苷酸/氨基酸的取代，缺失，插入。突变可以影响基因或其调控序列的编码序列。其也可能影响基因组序列的结构或编码的mrna的结构/稳定性。-“变体(一个或多个)”旨在是指重复变体，变体，dna结合变体，tale-核酸酶变体，通过突变或取代母体分子的氨基酸序列中的至少一个残基而获得的多肽变体。-“功能性变体”旨在是蛋白或蛋白结构域的催化活性突变体；这种突变体与其母体蛋白或蛋白结构域相比，可以具有相同的活性或其它性质，或更高或更低的活性。-“一致性”是指两个核酸分子或多肽之间的序列一致性。一致性可以通过比较每个序列中为了比较目的对齐的位置来确定。当比较的序列中的位置被相同碱基占据时，则分子在该位置是相同的。核酸或氨基酸序列之间的相似性或一致性的程度是在核酸序列共有的位置上相同或匹配的核苷酸数量的函数。可以使用各种比对算法和/或程序，包括可用作gcg序列分析包的一部分的fasta或blast(universityofwisconsin，madison，wis.)计算两个序列之间的一致性，并可以以默认设置使用。例如，设想了与本文的特异性多肽具有至少70％，85％，90％，95％，98％或99％的一致性并优选显示出基本上相同功能的多肽，以及编码此类多肽的多核苷酸。-“相似性”描述了两个或多个多肽的氨基酸序列之间的关系。也可以使用blastp，采用相似性矩阵，如blosum45，blosum62或blosum80，确定具有与对照氨基酸序列至少70％、75％、80％、85％、87.5％、90％、92.5％、95％、97.5％、98％、99％的序列相似性的氨基酸序列。除非另外指出，相似性计分将基于blosum62的使用。当使用blastp时，百分比相似性基于blastp正数计分，并且百分比序列一致性基于blastp相等计分。blastp“相等”表示高分数序列对中总残基的数量和分数是相同的；而blastp“整数”表示比对分数具有正值并且彼此相似的残基数量和分数。设想到具有这些程度的一致性或相似性或与本文中公开的氨基酸序列的相似性的任何中间程度的一致性的氨基酸序列并涵盖于本公开中。相似多肽的多核苷酸序列可以使用遗传密码推导，并可以通过常规方法而获得。例如，ptα的功能变体可以与seqidno:107的氨基酸序列具有70％、75％、80％、85％、87.5％、90％、92.5％、95％、97.5％、98％、99％的序列相似性。编码这种功能性变体的多核苷酸将通过使用遗传密码反向翻译其氨基酸序列而产生。-“信号转导结构域”或“共刺激配体”是指抗原呈递细胞上特异性结合t细胞上的同源共刺激分子的分子，从而提供除了例如通过tcr/cd3复合体与负载有肽的mhc分子的结合而提供的主要信号之外的介导t细胞响应，包括但不限于增殖活化，分化等的信号。共刺激配体可以包括但不限于cd7、b7-1(cd80)、b7-2(cd86)、pd-l1、pd-l2、4-1bbl、ox40l、诱导型共刺激配体(icos-l)、细胞间粘附分子(icam、cd30l、cd40、cd70、cd83、hla-g、mica、m1cb、hvem、淋巴毒素β受体、3/tr6、ilt3、ilt4、结合toll配体受体的激动剂或抗体、和特异性地与b7-h3结合的配体。共刺激分子除此之外还涵盖特异性结合t细胞上存在的共刺激分子的抗体，例如，但不限于cd27、cd28、4-ibb、ox40、cd30、cd40、pd-1、icos、淋巴细胞功能相关的抗原-1(lfa-1)、cd2、cd7、ltght、nkg2c、b7-h3、与cd83特异性结合的配体。“共刺激分子”是指t细胞上与共刺激配体特异性结合从而介导通过细胞的共刺激响应，如但不限于增殖作用的同源结合配偶体。共刺激分子包括，但不限于mhci类分子，btla和toll配体受体。本文所用的“共刺激信号”是指与如tcr/cd3连接的主要信号组合，导致t细胞增殖和/或关键分子的上调或下调的信号。本文所用的术语“胞外配体结合结构域”定义为能够结合配体的寡肽或多肽。优选地，结构域能够与细胞表面分子相互作用。例如，胞外配体结合结构域可以选择为识别充当与特定疾病状态相关的靶细胞上的细胞表面标志物的配体。因此，细胞表面标志物可以充当配体的实例包括与病毒、细菌和寄生虫感染，自身免疫疾病和癌细胞相关的那些。本文所用的术语“受试者”或“患者”包括动物界的所有成员，包括非人类灵长类和人类。术语“复发性”是指具有在治疗后已经缓解的癌症的受试者或哺乳动物具有癌细胞回归的情况。术语“难治性或耐受性”是指受试者或哺乳动物即使在强烈治疗后在其体内也具有残留癌细胞的情况。术语“抗药性”是指当疾病对一种或多种药物的治疗没有响应的情况。抗药性可以是内在的(或原发性抗性)，这意味着疾病从未对一种或多种药物响应，或其可以是获得性的，这意味着疾病停止对疾病以前响应的一种或多种药物的响应(继发性抗性)。在某些实施方式中，抗药性是固有的。在某些实施方式中，抗药性是获得性的。术语“血液恶性肿瘤”或“血液癌症”是指身体的血液、骨髓和/或淋巴组织的癌症。血液恶性肿瘤的实例包括，例如，骨髓增生异常、白血病、淋巴瘤、如皮肤淋巴瘤、非霍奇金淋巴瘤、霍奇金氏症(也称为霍奇金淋巴瘤)和骨髓瘤，如急性淋巴细胞白血病(all)、急性髓细胞白血病(aml)、急性早幼粒细胞白血病(apl)、慢性淋巴细胞性白血病(cll)、慢性髓细胞白血病(cml)、慢性嗜中性白血病(cnl)、急性未分化白血病(aul)、间变性大细胞淋巴瘤(alcl)、前淋巴细胞白血病(pml)、青少年骨髓单核细胞白血病(jmml)、成人t细胞all、具有三系骨髓造血异常(trilineagemyelodysplasia)的aml(aml/tmds)、混合谱系白血病(mll)、骨髓增生异常综合征(mds)、骨髓增生性疾病(mpd)和多发性骨髓瘤(mm)。术语“白血病”是指血液形成组织的恶性肿瘤，包括但不限于慢性淋巴细胞白血病或慢性淋巴白血病，慢性髓细胞白血病，或慢性髓性白血病，急性淋巴细胞白血病，急性髓细胞白血病或急性髓性白血病(aml)和急性成髓细胞白血病。通常，原代细胞是从血液样品或活检中分离，而随后可选地在体外进一步培养的细胞。细胞系是改造的癌细胞的细胞培养物，优选改造的癌细胞的同源细胞培养物(其中标记物由高斯曲线表示)。本发明的以上书面描述提供了制备和使用其的方式和方法，使得本领域技术人员可以制备和使用其，特别是针对所附权利要求的主题提供了该实现，其构成了原始描述的一部分。在本文中列出了数字限制或范围的情况下，包括端点。此外，数值限制或范围内的所有值和子范围都将明确包含在内，如同明显写出一样。呈现以上描述而使本领域技术人员可以制备和使用本发明，并在具体应用及其要求的上下文中提供。对优选的实施方式的各种修改对于本领域技术人员将是显而易见的，并且在不脱离本发明的精神和范围的情况下，本文中定义的通用原理可以应用于其他实施方式和应用。因此，本发明预想并不限于所示的实施方式，而应该符合与本文公开的原理和特征相一致的最宽范围。一般性地描述本发明，通过参考某些具体实施例可以获得进一步的理解，这些具体实施例仅为了说明的目的而提供于本文中，除非另有说明，否则并不旨在是限制的。一般方法通常，本发明的cd123cart细胞使用从来自不同供体的血沉棕黄层(buffycoat)样品纯化的t细胞制备。方法和产品满足“良好生产规范(goodmanufacturingpractices)”(fda21cfr和eugmp)的要求。临床试验根据“良好临床实践惯例(goodclinicalpractices)”(ukgcp或usagcp)blood2014；124(21):4689进行。临床前研究-原代t-细胞培养t细胞使用ficoll梯度密度培养基由efs(etablissementdusang，paris，france)提供的血沉棕黄层样品纯化。回收pbmc层，并使用可商购的t细胞富集试剂盒纯化t细胞。纯化的t细胞在补充有20ng/ml人il-2，5％人和dynabeads人t活化剂cd3/cd28的x-vivotm-15培养基(lonza)中以珠:细胞比率＝1:1(lifetechnologies)活化。-carmrna转染在t细胞纯化和活化后第4天或第11天进行转染。用15μg编码不同car构建体的mrna转染5百万个细胞。使用t7mrna聚合酶转染产生carmrna，其使用细胞脉冲cytopulse技术，通过在3000v/cm下施加两个0.1ms脉冲，然后在0.4cm间隙比色杯中以325v/cm施加四个0.2ms脉冲，在最终体积为200μl的“细胞穿孔(cytoporation)缓冲液t”(btxharvardapparatus)中完成。将细胞立即在x-vivotm-15培养基中稀释，并在37℃下用5％co2培养。以20ng/ml电穿孔后2h加入il-2。t-细胞转导在t细胞纯化/活化后3天，进行用重组慢病毒载体表达car转导t细胞。慢病毒载体由vectalyssa(toulouse，france)通过在hek-293细胞中转染基因组和辅助质粒而产生。以5的感染倍率进行转导，每次转导使用106个细胞。使用由人cd123蛋白的胞外结构域与鼠igg1fc片段(由lakepharma生产)融合构成的重组蛋白，在t细胞表面上完成car检测。用靶向蛋白质的小鼠fc部分的pe结合的第二抗体(jacksonimmunoresearch)检测这种蛋白与car分子的结合，并通过流式细胞术分析。-脱粒试验(cd107a迁移)将t细胞连同等量的表达各种水平的cd123蛋白的细胞一起细胞培养于96孔板(40,000个细胞/孔)中。在37℃下以5％co2将共培养物在最终体积100μl的x-vivotm-15培养基(lonza)中维持6小时。在细胞刺激期间，通过在共培养开始时加入荧光抗cd107a抗体，连同1μg/ml抗-cd49d、1μg/ml抗-cd28和1×莫能菌素(monensin)溶液一起，完成cd107a染色。在6h培养期后，用可固定活性染料(fixableviabilitydye)和荧光染料结合的抗cd8染色细胞，并通过流式细胞术分析。作为cd8+/cd107a+细胞的％，并通过测定cd8+细胞中cd107a染色的平均荧光强度信号(mfi)，测定脱粒活性。mrna转染后24h进行脱粒试验。-ifnγ释放试验将t细胞与表达各种水平的cd123蛋白的细胞系一起培养于96孔板(40,000个细胞/孔)中。在37℃下用5％co2将共培养物在最终体积100μl的x-vivotm-15培养基(lonza)中维持24小时。在此培养期后，将板以1500rpm离心5分钟，并将上清液回收于新的板中。通过elisa试验进行细胞培养物上清液中的ifnγ检测。通过在mrna转染后24小时开始细胞的共培养进行ifnγ释放试验。-细胞毒性试验将t细胞与10,000个靶细胞(表达cd123)和10,000对照(cd123阴性)细胞一起在同一孔中培养于96孔板中(100,000个细胞/孔)。在将其与car+t细胞共培养前，用荧光胞内染料(cfse或细胞示踪紫(celltraceviolet))标记靶细胞和对照细胞。将共培养物在37℃下用5％co2培养4小时。在这个培养期后，用可固定活性染料标记细胞，并通过流式细胞术分析。测定每个细胞群体(靶细胞或cd123阴性对照细胞)的存活率，并计算特异性细胞溶解的％。细胞毒性分析测定在mrna转染后48小时进行。-t细胞转导在t细胞纯化/活化后3天，进行用表达car的重组慢病毒载体转染转导t细胞。使用由人cd123蛋白的胞外结构域与鼠igg1fc片段的融合构成的重组蛋白质，在t细胞表面进行car检测。用靶向蛋白质的鼠fc部分的荧光染料结合的第二抗体检测该蛋白对car分子的结合，并通过流式细胞术分析。-抗肿瘤小鼠模型用表达cd123表达的molm13-萤光素酶细胞静脉内(iv)注射免疫缺陷型nog小鼠作为aml异种移植小鼠模型。可选地，小鼠接受pna或flag的抗癌治疗。然后小鼠iv注射(注射肿瘤细胞系后2或7天)不同剂量的待测试的car+t细胞，或未用car慢病毒载体转导的t细胞。在t细胞注射当天(d0)，t细胞注射后d7，14，21，28和40时测定生物发光信号，以跟踪不同动物上的肿瘤进展。临床研究i期剂量递增试验设计为评价遗传改造为表达靶向cd123分子(cd123car)的人造t细胞受体(car)的同种异体tcrko特异性细胞毒性t淋巴细胞(ctl)在具有复发/难治性急性髓细胞白血病(aml)、原发性浆细胞样树突细胞肿瘤、移植过渡的患者中的安全性和生物学效力。每个患者将接受至少一次给药的供体衍生的遗传改造的ctl，并将对毒性和转导的ctl的检测以及疾病特异性标记物进行监测。以下任何一种在医疗指示时可能会各自变化。研究类型：介入研究设计：终点分类：安全/功效研究介入模型：单组分配掩蔽：开放标签主要目的：治疗官方标题：移植过渡期间使用遗传靶向b细胞特异性抗原cd123阳性残留或复发性急性髓细胞白血病，母细胞性浆细胞样树突细胞肿瘤的体外扩增的同种异体细胞毒性t淋巴细胞(ctl)的i期剂量递增试验。关键词急性髓细胞白血病，母细胞性浆细胞样树突细胞瘤，移植过渡主要测量指标：评价提供用于aml的持续性或复发，用于母细胞性浆细胞样树突细胞肿瘤或在移植过渡中的改造为表达靶向cd123分子的同种异体特异性ctl的递增剂量的安全性/持续性。次要测量指标：·评价过继转移的cd123特异性t细胞对aml进展的影响。·定量输液之后在定义的间隔下血液中cd123嵌合抗原受体(cd123car)阳性的t细胞的数量以确定其在宿主中的存活和增殖在输液利妥昔单抗(375mg/m2)之后在定义的间隔下定量测定血液中cd123嵌合抗原受体(cd123car)阳性t-细胞的数量合格性适合研究的性别：两者接受健康志愿者：不标准包括标准：·cd123+白血病史，有骨髓复发或持续的证据。·持续性微量残留病必须通过形态学，fish，流式细胞术或rt-pcr以至少2次间隔至少1周的顺序测试证实。·患者无年龄限制·kps或lansky得分>或＝至40·肾功能(在调理化疗前测定)·肝功能(在调理化疗前测定)：·继发于白血病介入的ast≤5×惯常uln升高不是排除标准。白血病介入将由前一个月内升高的骨髓或外周血白血病急变以及不存在开始已知的肝毒性药物(例如，唑类)所定义的进行性复发的存在确定。·总胆红素≤2.5×惯常uln·足够的心脏功能(例如，lvef≥40％)，如由在注册的1个月内进行echo或muga，或的其他类似心脏影像评价的。·肺功能(调理化疗前测定)：·室内空气的氧饱和度≥90％供体合格性：·供体，包括第三方供体，必须同意以一次或多次放血获得的白细胞分离或全血献血，这总体上将是成人共计约250毫升，而对于儿科供体每次抽取不超过5ml/kg。·<18岁的年龄的相关供体需要放置白细胞分离术导管，将捐献通过放血采集的外周血(如果体重允许，会包括血液单位)，并且白细胞分离术不得进行导管置换，因为认为其高出供体的最小风险。·供体没有上限年龄。然而，相关供体的最低年龄是7岁，因为这是一个人被认为有能力同意参与研究的最年轻的年龄。·供体的高分辨率hla分型必须可用于审查·捐献一周内的cbc。测试结果必须处于不阻止献血或进行白细胞分离术的范围内。·传染性疾病的血清学测试将按照现有nmdp和fact指南中所采用的惯常准则进行。基于这些准则，供体应该认为有资格捐献白细胞分离或血液(献血准则)排除标准：·具有活性hiv、b型肝炎或c型肝炎感染的患者。·患有任何由需要除预期观察之外的任何治疗的恶性肿瘤定义的并发活性恶性肿瘤的患者。·怀孕的女性·如果他们患有all的隔离性髓外复发，患者将被排除。·具有活动性(2至4级)急性移植抗宿主病(gvhd)、慢性gvhd或需要糖皮质激素治疗(>0.5mg/kg/天泼尼松或其等效物)作为治疗的明显自身免疫性疾病(例如，溶血性贫血)的患者·在28天治疗内的活动性中枢神经系统(cns)白血病，由脑脊髓液(csf)或症状性cns白血病(即，颅神经麻痹或其他显著神经功能障碍)中的淋巴母细胞的明确形态学证据定义。预防性鞘内药物不是排除的原因。·患有以下心脏病症的成年患者(≥18岁)将被排除：·纽约心脏协会(nyha)iii期或iv期充血性心力衰竭·心肌梗死，注册之前≤6个月·临床上显著的室性心律失常或不明原因性晕厥的病史，不被认为是天性的或由于脱水所致的血管迷走神经性的。·严重非缺血性心肌病病史，ef≤20％第一数据表明，本发明的工程化t-细胞可以以107个细胞/kg的剂量iv输注于复发难治性aml患者，并选择性地清除cd123-表达癌细胞长达至少11个月。实施例实施例1：表达cd123-car的tcrα灭活细胞的增殖。设计并制备了靶向以t细胞受体α恒定链区(trac)基因内的15bp间隔子隔开的两个17bp长的序列(称为半靶)的异源二聚tale核酸酶。每个半靶通过表10中列出的半tale核酸酶的复制体识别。表10：靶向tcrα基因的tal核酸酶在t7启动子的控制下，使用哺乳动物表达载体中的限制酶消化来亚克隆每个tale核酸酶构建体。从携带t7启动子下游的编码序列的质粒合成编码切割trac基因组序列的tale核酸酶的mrna。用编码两半trac_t01tale-核酸酶的两个mrna的每个转染用抗cd3/cd28涂覆的珠在72小时内预活化的纯化的t细胞。转染后48小时，分别用编码前述的cd-123car(seqidno：23至48)之一的慢病毒载体转导来自同一供体的不同组的t细胞。转导后2天，使用抗cd3磁珠纯化cd3neg细胞，且转导后5天，用可溶性抗cd28(5μg/ml)再活化细胞。在再活化之后通过每周2次计数细胞，细胞增殖最高达30天。与未转导细胞相比，特别是在用抗cd28再活化时，观察到表达cd-123car的tcrα灭活细胞中的增殖增加。为了研究表达cd123-car的人t细胞是否显示出活化状态，在转导后7天通过facs分析活化标记物cd25的表达。用编码cd-123car的慢病毒载体转导的纯化细胞分析其表面上的cd25表达，以与未转导细胞比较而评价其活化。在cd28再活化或无再活化条件下都会预期cd25表达增加。实施例2：使用源自klon43的抗cd123scfv抗体片段构建cd123car，tcrko和dckkotcrcd123表达细胞中的功能分析使用vh(seqidno12，l(seqidno10)，vlseqidno11的组合，或选自seqidno24至seqidno.30的vh，接头l和选自seqidno.18至seqidno.23的vl的组合制备来自klon43的scfv或人源化scfv，分别用于产生cd123嵌合抗原受体(本发明的cd123car)并筛选它们以选择高性能(具有较少副作用的抗肿瘤活性)。使用结构v1或v3，优选v3(图2和图3)，并且在人t细胞中表达时测定活性(图4，图5，图6和图7)。图4中所示的结果显示了在car+t细胞与表达cd123的细胞(rpmi8226)，或不表达cd123的细胞(k562)共培养6小时时的根据本发明的不同scfv对于一种结构(v3：cd8-铰链/cd8-跨膜)的脱粒活性。白色条对应于单独培养的t细胞中观察到的脱粒信号，黑色条表示当与rpmi8226细胞共培养t细胞时观察到的信号，而灰色条显示了与k562细胞共培养的t细胞的脱粒信号。图5显示了用表达不同水平的cd123的细胞(kg1a或rpmi8226)，或用不表达cd123的细胞(k562)共培养24小时时由t细胞释放的ifnγ的量。也显示了在与共培养物相同的条件下单独培养的t细胞的ifnγ释放。对三个独立供体进行了实验，并且此处显示了代表性供体的结果。图6和7显示了在用pna(20mg/kg)ip处理的小鼠体内的cart细胞的特异性溶胞活性的剂量响应。在注射未转导的人t细胞，或用不同剂量的抗cd123car+t细胞注射前2天，对免疫缺陷小鼠注射molm13-荧光素酶细胞。结果表示在t细胞注射后的不同时间点观察到的生物发光信号。实施例3：临床研究临床研究提供了证明本文描述的临床研究的可行性的数据。至少有一名患有难治性/复发性aml的患者接受了根据本发明的治疗，这显著提高了其预期寿命超过16个月，并将癌细胞降低至检测水平之下长达至少6个月。在输液后至少3个月检测到表达cd123的工程化免疫细胞。利妥昔单抗(美罗华(rituxan)(r))的给予。在初始利妥昔单抗给药375mg/m2后4天内静脉注射给予的利妥昔单抗的总剂量为2,250mg/m2。在每次输液之前用乙酰氨基酚和抗组胺药进行预治疗。在另一个实施方式中，第一次输液以50mg/小时的速度开始。在没有输液毒性的情况下，每30分钟将输液速率提高50mg/小时，直至最大的400mg/小时。对于随后的输液，以100mg/小时的速率进行。在没有输液毒性的情况下，增加到最大400mg/小时而达到2,250mg/m2。结果表明，患者血液中cd123car细胞水平在最后一次输液后24h时处于低于检测之下。klo43-1(seqidno.31)在一个实施方式中，klon43-1是klo43-3(seqidno.32)在一个实施方式中，klon43-3是klo43-5(seqidno.33)在一个实施方式中，klon43-5是本发明的人源化cd123包含以下序列之一：版本1vh1vl1malpvtalllplalllhaarpevklvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsksilylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvssggggsggggsggggsmadykdivmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgrgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikrglavstissffppgyqiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapayqqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalpprvl2malpvtalllplalllhaarpevklvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsksilylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvssggggsggggsggggsmadykdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgrgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikrglavstissffppgyqiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapayqqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalpprvl3malpvtalllplalllhaarpevklvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsksilylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvssggggsggggsggggsmadykdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapkaliysasyrysgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikrglavstissffppgyqiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapayqqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalpprvl4malpvtalllplalllhaarpevklvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsksilylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvssggggsggggsggggsmadykdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapklliysasyrysgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikrglavstissffppgyqiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapayqqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalpprvl5malpvtalllplalllhaarpevklvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsksilylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvssggggsggggsggggsmadykdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapklliysasyrqsgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikrglavstissffppgyqiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapayqqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalpprvl6malpvtalllplalllhaarpevklvesggglvqpgrslrlsctasgftftdyymswvrqapgkglewvglirskadgytteysasvkgrftisrddsksilylqmnslktedtavyycardaayysyyspegamdywgqgtlvtvssggggsggggsggggsmadykdiqmtqspssvsasvgdrvtitcrasqnvdsavawyqqkpgkapklliysasygqsgvpsrfsgsgsgtdftltisslqpedfatyycqqyystpwtfgqgtkveikrglavstissffppgyqiyiwaplagtcgvlllslvitlyckrgrkkllyifkqpfmrpvqttqeedgcscrfpeeeeggcelrvkfsrsadapayqqgqnqlynelnlgrreeydvldkrrgrdpemggkprrknpqeglynelqkdkmaeayseigmkgerrrgkghdglyqglstatkdtydalhmqalppr版本1vh2vl1malpvtalllplalllhaarpevq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