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现在位置不用本金就能赚钱的方法>技术资料不用本金就能赚钱的方法>行业动态>技术动态>Nature Medicine综述 | CAR-T疗法:万里长征第一步

Nature Medicine综述 | CAR-T疗法:万里长征第一步

BioArt2019年11月4日 9:05 点击:507

嵌合抗原受体T细胞免疫疗法(Chimeric antigen receptor T cell therapy,简称CAR T疗法)在B细胞恶性肿瘤治疗中取得了极为鼓舞人心的效果,也因此加速了CAR T疗法的临床应用,并且成为美国食品和药物管理局(FDA)首个认证的用于治疗癌症的细胞疗法。


2019年9月9日,来自斯坦福大学的Robbie G. Majzner和Crystal L. Mackall在Nature Medicine上发表题为 Clinical lessons learned from the first leg of the CAR T cell journey 的综述文章,详细解析了时至今日CAR T疗法的现状未来,主要探讨了影响CAR T疗法的因素以及如何改善疗效。

「珍藏版」Nature Medicine综述 | CAR-T疗法:万里长征第一步





一、CAR T疗法是什么?

不用本金就能赚钱的方法QIANHEKANGYUANSHOUTITXIBAO(Chimeric antigen receptor T cell,JIANCHENGCAR T cell)SHIYIZHONGJINGGUOJIYINGAIZAO,JIYUANLAIDETXIBAOGONGNENGYUXINDEKANGYUANSHIBIEGONGNENGYUYISHENDE“CHAOJI”TXIBAO。ERCAR TLIAOFAZESHILIYONGCAR TXIBAOSHIBIEHEGONGJIAIXIBAO,CONGERZHILIAOAIZHENGDEXIBAOLIAOFA。

不用本金就能赚钱的方法RUXIATUSUOSHI,KEXUEJIACONGRENTIZHONGHUODETXIBAO,LIYONGJIYINGONGCHENG,RANGZHEIXIETXIBAOTEYIXINGBIAODAYILEISHOUTI,ZAIJIANGGAIZAOHOUDETXIBAOZHONGXINSHURURENTI。YINWEIZHEIXIESHOUTIKEYITEYISHIBIEAIXIBAODEBIAOMIANKANGYUAN,SUOYI,ZHUANSHUHUIRENTIDETXIBAOKEYIZHENDUIXINGGONGJIAIXIBAO,DUIZHENGCHANGXIBAOBUHUICHANSHENGYINGXIANG。

「珍藏版」Nature Medicine综述 | CAR-T疗法:万里长征第一步



二、 影响CAR T疗法临床效果的因素有哪些?

MUQIANXUEJIEPUBIANRENWEI,CAR TLIAOFACHENGGONGYUFOUDESANDAYINSUFENBIEWEIZHONGLIUDELEIXING(disease histology)、TXIBAOZISHENZENGZHIXIAOLVHETXIBAODEHUOXING。

2.1 肿瘤类型

CAR TLIAOFAZUIXIANYONGYUZHILIAOBXIBAOEXINGZHONGLIU,BAOKUOBXIBAOJIXINGLINBAXINGBAIXUEBING(B-cell acute lymphoblastic leukemia,JIANCHENGB-ALL),MANXINGLINBAXINGBAIXUEBING(Chronic lymphocytic leukemia,JIANCHENGCLL)HEDABXIBAOLINBALIU(large B cell lymphoma,JIANCHENGLBCL)。QIZHONG,B-ALLHECLLDOUSHIGUSUILAIYUANDEEXINGZHONGLIU。CD19SHIBXIBAODEBIAOMIANZUIWEITEYIDEBIAOZHIFENZI,ERGAIZAOTXIBAOCD19SHOUTIDECD19.28z-CAR THECD19.BBz-CAR TLIANGZHONGLIAOFADUIZHEISANZHONGBXIBAOEXINGZHONGLIUDOUJUYOUYIDINGCHENGDUDEZHILIAOXIAOGUO。

不用本金就能赚钱的方法XIAMIANZHEIFUTUBIAOXINGXIANGDEBIAOSHILEBUTONGLEIXINGDEZHONGLIU,DUIBUTONGCAR TLIAOFADEXIANGYING。MEIYIXINGDAIBIAOYILEIZHONGLIUDEZHILIAOXIAOGUOHEKENENGSHISHIBAIYUANYIN。MEIYIGEXIAORENDAIBIAO10%DEHUANZHE,FANGKUANGZHONGDEXIAORENSHUMUDAIBIAOZHEIYILEISHIBAIHUOSHICHENGGONGYUANYINDEHUANZHEZHANQUANBUHUANZHE(100%)DEBILI。

「珍藏版」Nature Medicine综述 | CAR-T疗法:万里长征第一步



SHOUXIAN,DUIYUMEIZHONGZHONGLIU,JISHUSHIWU(Manufacturing failure)DOUDAGAIDAOZHILE10%DESHIBAILV。SUIZHEJISHUDEZHUJIANJINBUCHENGSHU,SHIBAILVYOUWANGKONGZHIZAI10%YIXIA。

不用本金就能赚钱的方法QICI,BUTONGZHONGLIUDUICAR TLIAOFADECHUJIKANGYAOXING(Primary resistance)QUBIEHENDA,CHUCISHIYONGCAR TLIAOFA,80%ZUOYOUDEB-ALLHUANZHEDOUYOUBUTONGCHENGDUDECHUBUZHILIAOXIAOGUO,JINYOU10%ZUOYOUDEHUANZHECHUXIANKANGYAOXING。ERJINJIN30%ZUOYOUDECLLHUANZHEJUYOUCHUBUZHILIAOXIAOGUO,60%DEHUANZHEDOUCHUXIANKANGYAOXING。LBCLHUANZHEDEXIANGYINGZAIERZHEZHIJIAN。

ZAICI,ZAIZHEIXIEJUYOUCHUBUZHILIAOXIAOGUODEHUANZHEZHONG,YOUYOUYIDABUFENBINGQINGFUFA。DUIYUCAR TSUOZHENDUIDEBABIAOCD19,YIBUFENGAOBIAODACD19(JIKANGYUANYANGXING,TUZHONGBIAOSHIWEIAntigen+),LINGYIBUFENDIBIAODASHENZHISHIBUBIAODA,JIWEIKANGYUANYINXING(Antigen-)。DUIYUB-ALLHUANZHE,KANGYUANYANGXINGHUANZHEZAICD19.28z-CAR TZHILIAOHOUGENGRONGYIFUFA,KENENGYINWEIZHEIYILIAOFAZHUYAOJINXINGDUANSHICHENGZUOYONG,ERKANGYUANYINXINGHUANZHEZEZAICD19.BBz-CAR TZHILIAOHOUGENGJIARONGYIFUFA,ZHEIYEXUJIYUZHEIYILIAOFAZHUYAOJIEDAOCHIXUDEMIANYIFANYING。DUIYULBCLHUANZHE,QIKANGYUANBIAODAYUFOUDUILIAOXIAODEYINGXIANGJIQIYUANYINRENGRANWEIZHI,DANYIBANZUOYOUDEFUFAHUANZHEKANGYUANCHENGYINXING。

2.2 CAR T细胞增殖效率

临床研究证实,转输回人体的CAR T细胞要想迅速而有效地增殖,从而发挥作用,需要首先清除人体自身的淋巴细胞不用本金就能赚钱的方法。这样做有两点好处,一是可以增加IL-7,IL-15等细胞因子的表达,而这些细胞因子,在T细胞增殖上起促进作用。二是可以在一定程度上减弱调节性T细胞的作用,这类细胞通常认为可以抑制T细胞的增殖和活化。另外,虽然没有大批量成体系的研究支持,环磷酰胺(cyclophosphamide)和氟达拉滨(fludarabine)联合用药,可以显著提高T细胞的增殖效率和作用时间。对于LBCL患者,单独使用环磷酰胺,CD19.BBz-CAR T疗法的治愈率低于10%,而环磷酰胺-氟达拉滨联合用药,治愈率可以提高到50%。究其原因,是因为氟达拉滨有助于清除淋巴细胞,并提高IL-15的水平,从而减弱机体对CAR T细胞的排异反应。

2.3 CAR T细胞的活性

不用本金就能赚钱的方法JICAR TXIBAOSHANGLIANYOUGONGCIJIFENZIKEYIXIANZHUTIGAOQIHUOXING,CD28HE4-1BBJIUSHILIANGZHONGTXIBAODEGONGCIJIFENZI,YEYOUCIDINGYILESHANGWENTIDAODELIANGZHONGCAR TZHILIAOFANGFA:CD19.28z-CAR THECD19.BBz-CAR T。BIJIAOERZHEFAXIAN,CD19.28z-CAR TZENGZHISULVKUAI,SHUIPINGGAO,DANSHICHIXUSHICHENGJIAODUAN,JINJINYIDAOLIANGGEYUE。ERCD19.BBz-CAR TZENGZHIXIANGDUIJIAOSHAOJIAOMAN,DANCHIXUSHIJIANQUEHENZHANG,SHENZHISHIZHANGDASHUNIAN。DANGRAN,ZAOCHENGERZHEQUBIEDEYUANYINMUQIANRENGBUSHENQINGCHU,DANHENYOUKENENGYUXIAYOUXIANLITIBIANHUAXIANGGUAN。

CAR-TXIBAODEZENGZHITONGYANGHUIJIRENTIDAILAIDUFUZUOYONG,MUQIANYIZHIDELIANGDADUFUZUOYONGFENBIEWEIXIBAOYINZISHIFANGZONGHEZHENG(cytokine-release syndrome,JIANXIEWEICRS)HESHENJINGDUXING(CAR-associate neurotoxicity)。CRSBIAOXIANWEIJIESHOUCAR TZHILIAODEHUANZHETINEIGAOSHUIPINGDEYANXINGYINZI,BAOKUOIL-1HEIL-6,CONGERDAOZHIHUANZHEYOULEISINONGDUXUEZHENGDEZHENGZHUANG。ERSHENJINGDUXINGDEYUANYINSHANGBUQINGCHU,HENKENENGYUZHONGSHUSHENJINGXITONGDENEIPIXIBAOBIANHUAYOUGUAN。

不用本金就能赚钱的方法BUTONGDEZHONGLIUZHONGLEI,CD19.28z-CAR THECD19.BBz-CAR TLIANGZHONGLIAOFADEDUFUZUOYONGBIAOXIANYEBUSHENXIANGTONG。DUIYUB-ALLDEHUANZHELAISHUO,DUFUZUOYONGZHUYAOLAIZIYUTXIBAOZENGZHI,ERGONGCIJIFENZISHICD28HAISHI4-1BB,ZEYINGXIANGBUDA,SUOYI,LIANGZHONGLIAOFADEDUFUZUOYONGYEPOWEIXIANGSI。DANSHI,DUIYULBCLDEHUANZHELAISHUO,CAIYONGCD19.BBz-CAR TLIAOFA,DUFUZUOYONGJIAOQING。

三、如何改善CAR T疗法的临床效果?

不用本金就能赚钱的方法SUIRANYONGCAR TXIBAOLIAOFAZHILIAOEXINGZHONGLIUYIJINGQUDELEJIEDUANXINGCHENGGUO,DANSHI,RUHETIGAOZHIYULV,JIANGDIDUFUZUOYONG,BINGTUIGUANGZHIQITASHITILIUZHILIAO,RENGJIUSHIXUEJIEJIDAIJIEJUEDEWENTI。XIATUZHENDUIBUTONGWENTIJICHULEJIZHONGJIEJUEFANGAN:

第一、克服T细胞运输问题

不用本金就能赚钱的方法CAR TXIBAOTONGCHANGSHITONGGUOJINGMAIZHUSHEZHUANSHUHUIRENTI,JIEXIALAI,YOUZOUQUANSHEN,XUNZHAOZHONGLIU。DANSHI,CAR TXIBAOHENNANJINRUSHITILIUNEIBU,YEBUNENGTONGGUOXUENAOPINGZHANGGONGJINAOBUZHONGLIU。JIYUZHEIYIWENTIYOULIANGZHONGJIEJUEFANGAN,YISHIZAICAR TXIBAOSHANGTONGSHIBIAODAQUHUAYINZISHOUTI,ZHEIYANG,CAR TXIBAOJIUKEYIGENSUIQUHUAYINZIDAODABINGZAO;ERSHIKEYITONGGUOSHOUSHUHEXIANWEIZHUSHESHOUDUAN,JIANGCAR TXIBAOZHIJIEZHUSHEDAOBINGZAOWEIZHI。

第二、克服肿瘤异质性问题

YIZHIXINGSHIEXINGZHONGLIUDEJIBENTEZHENGZHIYI。LINCHUANGBAODAOZHICHU,ZHONGLIUFUFAHENDACHENGDUSHANGYUCAR TZHILIAOSUODAOZHIDECD19BADIANDIUSHIYOUGUAN。ZUOZHETONGYANGTICHULELIANGZHONGJIEJUEFANGAN,YISHIJINLIANGDUOJIARUGONGJIBADIAN,ERSHIXUNZHAOFANGFAJIHUOJITIZISHENDEKANGZHONGLIUMIANYIFANYING。

第三、提高T细胞活性

DAOZHITXIBAOHUOXINGJIANGDIDEYINSUSHIDUOFANGMIANDE,NEIYINZHUYAOWEITXIBAOYUKANGYUANJIEHEHUOYANZHENGFANYINGERXIAOHAODAIJIN。WAIYINZHUYAOSHINEIHUANJINGZHONGYOULIDEXIBAOYINZIHEPEIJI,LIRUTGF-betaHEPD-L1,ZHEIKEYITONGGUOJIARUBUHUOFENZILAIZHONGHEQIZUOYONG,BIRUZHENDUIPD-L1DEPD-L1KANGTI。

第四、提高T细胞增殖效率

CAR-TXIBAOLIAOFACHENGBAIYUFOU,ZHUYAOYILAIYUCAR TXIBAOSHIFOUKEYIZAITINEIZENGZHI,CONGERSHASHANGZHONGLIUXIBAO。ZHEIXIEXIBAOYAOMEXIAOHAODAIJIN,YAOMECHENGWEIJIYIXINGTXIBAO,YONGYUDUIKANGKENENGDEZHONGLIUFUFA,4-1BBZHEIYANGDEGONGCIJIFENZIDUICAR TXIBAOCHIXUZUOYONGQIDAOLESHIFENJIJIDEZUOYONG。LINGWAI,YIXIEXIBAOYINZI,BIRUIL-12,YEKEYICUJINTXIBAODEZENGZHIHECHIXUZUOYONG。

「珍藏版」Nature Medicine综述 | CAR-T疗法:万里长征第一步



四、结论与展望

CAR T细胞疗法在B细胞相关恶性肿瘤的治疗上取得了显著的成果,而且,部分研究指出,这一疗法对于一些实质瘤患者也有帮助。随着生物基因工程技术的逐渐发展成熟,对于T细胞的特异性改造完全可行,这也为学界带来一个问题,也就是如何慎重挑选作用靶点进行人体测试。时至今日,CAR T细胞疗法在B细胞相关恶性肿瘤主要挑战有二,一是基于肿瘤异质性的靶点丢失,二是T细胞自身的局限性。接下来学者们应致力于如何解决这些问题,从而提高CAR T细胞疗法治愈率,并推广至其它实体瘤。革命尚未成功,同志仍需努力。

YUANWENLIANJIE:

不用本金就能赚钱的方法http://doi.org/10.1038/s41591-019-0564-6


(来源: BioArt )


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