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NEJM综述：CAR-T治疗成就和展望

2018-07-23 黄河，张鸿声 NEJM医学前沿

CAR-TNEJM
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编者按 嵌合抗原受体治疗（chimeric antigenreceptor T cell，CAR-T）已于2017年被美国FDA批准，针对CD19靶标治疗复发、难治性急淋和弥漫大B淋巴瘤。因其常规治疗无法比拟的疗效和临床前景，CAR-T疗法近5年成为目前全球肿瘤治疗研发和转化的热点。2018年7月5日《新英格兰医学杂志》发表了这一领域的最新综述[1]。该综述罕见地由两位在美国不同

编者按 嵌合抗原受体治疗（chimeric antigenreceptor T cell，CAR-T）已于2017年被美国FDA批准，针对CD19靶标治疗复发、难治性急淋和弥漫大B淋巴瘤。因其常规治疗无法比拟的疗效和临床前景，CAR-T疗法近5年成为目前全球肿瘤治疗研发和转化的热点。2018年7月5日《新英格兰医学杂志》发表了这一领域的最新综述[1]。该综述罕见地由两位在美国不同研究机构的CAR-T治疗研发和临床转化先驱联合撰写。其中纪念斯隆·凯特琳癌症研究中心的Michel Sadelain对CAR-T治疗的早期研发做出过重要贡献，是首位发展出携带CD28共刺激信号第二代CAR的科学家[2]，并一直引导着这一领域的科研前沿。最近，Sadelain实验室又发现了CAR-T治疗中发生细胞因子释放综合征(cytokine release syndrome, CRS)的新机制[3]。虽然Carl June团队发展出携带4-1BB共刺激信号第二代CAR的早期技术来源于另外一个研究机构[4,5]，但他们针对B细胞白血病的治疗最早在临床上获得成功[6]，经他们治疗的女孩Emily已成为CAR-T治

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  1. 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createdAvatar=https://img.medsci.cn/20200816/e4675a86ea694f12b82202b320dc2654/12f6b900498349e994ce8f516a584d6a.jpg, createdBy=09431951290, createdName=大爰, createdTime=Mon Jul 30 09:56:44 CST 2018, time=2018-07-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=333834, encodeId=e4c233383464, content=学习了谢谢, beContent=null, objectType=article, channel=null, level=null, likeNumber=24, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTLbTp9nZtjwVrSZNxAXbAicnKQWnic2eBdJUQYhxO36XdkstSicr7FVF8p5ReH4omtmsbnLdvZLiaJJ1A/132, createdBy=8bff2327056, createdName=kafei, createdTime=Tue Jul 24 10:12:00 CST 2018, time=2018-07-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=333575, encodeId=7f163335e560, content=阅, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/fhZdOu27e88Voqh19n8eF8cLplo8L4nicKtH0WnE3KFELXns5XDu8rsiceK2HHDZc2SEStia5VV3Pia2QLMVqlWbHw/0, createdBy=6e012139475, createdName=神功盖世, createdTime=Mon Jul 23 11:28:13 CST 2018, time=2018-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=333551, encodeId=29753335510b, content=学习了，谢谢, beContent=null, objectType=article, channel=null, level=null, likeNumber=28, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfNLvzZhgPxRvvXNvY0kOJqn4liar3Q6V6yPuEIawCVUyP3jVADh5icIz0ibrsxia6fKAqKsDr33jPWrjqM3D7wcRNu/0, createdBy=5a881701729, createdName=小树熊, createdTime=Mon Jul 23 09:34:36 CST 2018, time=2018-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=333534, encodeId=0558333534e1, content=学习了！！！！！！, beContent=null, objectType=article, 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    2018-10-27 仁心济世

    #CAR-#

    0

  2. 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topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/fhZdOu27e88Voqh19n8eF8cLplo8L4nicKtH0WnE3KFELXns5XDu8rsiceK2HHDZc2SEStia5VV3Pia2QLMVqlWbHw/0, createdBy=6e012139475, createdName=神功盖世, createdTime=Mon Jul 23 11:28:13 CST 2018, time=2018-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=333551, encodeId=29753335510b, content=学习了，谢谢, beContent=null, objectType=article, channel=null, level=null, likeNumber=28, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfNLvzZhgPxRvvXNvY0kOJqn4liar3Q6V6yPuEIawCVUyP3jVADh5icIz0ibrsxia6fKAqKsDr33jPWrjqM3D7wcRNu/0, createdBy=5a881701729, createdName=小树熊, createdTime=Mon Jul 23 09:34:36 CST 2018, time=2018-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=333534, encodeId=0558333534e1, content=学习了！！！！！！, beContent=null, objectType=article, 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    2018-09-21 大爰

    学习了谢谢分享！！

    0

  3. 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topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/fhZdOu27e88Voqh19n8eF8cLplo8L4nicKtH0WnE3KFELXns5XDu8rsiceK2HHDZc2SEStia5VV3Pia2QLMVqlWbHw/0, createdBy=6e012139475, createdName=神功盖世, createdTime=Mon Jul 23 11:28:13 CST 2018, time=2018-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=333551, encodeId=29753335510b, content=学习了，谢谢, beContent=null, objectType=article, channel=null, level=null, likeNumber=28, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfNLvzZhgPxRvvXNvY0kOJqn4liar3Q6V6yPuEIawCVUyP3jVADh5icIz0ibrsxia6fKAqKsDr33jPWrjqM3D7wcRNu/0, createdBy=5a881701729, createdName=小树熊, createdTime=Mon Jul 23 09:34:36 CST 2018, time=2018-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=333534, encodeId=0558333534e1, content=学习了！！！！！！, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=59321624668, createdName=zb1235672, createdTime=Mon Jul 23 08:29:34 CST 2018, time=2018-07-23, status=1, ipAttribution=)]
    2018-08-29 大爰

    学习了谢谢分享！！

    0

  4. 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createdAvatar=https://img.medsci.cn/20200816/e4675a86ea694f12b82202b320dc2654/12f6b900498349e994ce8f516a584d6a.jpg, createdBy=09431951290, createdName=大爰, createdTime=Mon Jul 30 09:56:44 CST 2018, time=2018-07-30, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=333834, encodeId=e4c233383464, content=学习了谢谢, beContent=null, objectType=article, channel=null, level=null, likeNumber=24, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://thirdwx.qlogo.cn/mmopen/vi_32/Q0j4TwGTfTLbTp9nZtjwVrSZNxAXbAicnKQWnic2eBdJUQYhxO36XdkstSicr7FVF8p5ReH4omtmsbnLdvZLiaJJ1A/132, createdBy=8bff2327056, createdName=kafei, createdTime=Tue Jul 24 10:12:00 CST 2018, time=2018-07-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=333575, encodeId=7f163335e560, content=阅, beContent=null, objectType=article, channel=null, level=null, likeNumber=33, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/fhZdOu27e88Voqh19n8eF8cLplo8L4nicKtH0WnE3KFELXns5XDu8rsiceK2HHDZc2SEStia5VV3Pia2QLMVqlWbHw/0, createdBy=6e012139475, createdName=神功盖世, createdTime=Mon Jul 23 11:28:13 CST 2018, time=2018-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=333551, encodeId=29753335510b, content=学习了，谢谢, beContent=null, objectType=article, channel=null, level=null, likeNumber=28, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfNLvzZhgPxRvvXNvY0kOJqn4liar3Q6V6yPuEIawCVUyP3jVADh5icIz0ibrsxia6fKAqKsDr33jPWrjqM3D7wcRNu/0, createdBy=5a881701729, createdName=小树熊, createdTime=Mon Jul 23 09:34:36 CST 2018, time=2018-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=333534, encodeId=0558333534e1, content=学习了！！！！！！, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=59321624668, createdName=zb1235672, createdTime=Mon Jul 23 08:29:34 CST 2018, time=2018-07-23, status=1, ipAttribution=)]
    2018-08-19 大爰

    学习并分享！！

    0

  5. 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topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/fhZdOu27e88Voqh19n8eF8cLplo8L4nicKtH0WnE3KFELXns5XDu8rsiceK2HHDZc2SEStia5VV3Pia2QLMVqlWbHw/0, createdBy=6e012139475, createdName=神功盖世, createdTime=Mon Jul 23 11:28:13 CST 2018, time=2018-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=333551, encodeId=29753335510b, content=学习了，谢谢, beContent=null, objectType=article, channel=null, level=null, likeNumber=28, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfNLvzZhgPxRvvXNvY0kOJqn4liar3Q6V6yPuEIawCVUyP3jVADh5icIz0ibrsxia6fKAqKsDr33jPWrjqM3D7wcRNu/0, createdBy=5a881701729, createdName=小树熊, createdTime=Mon Jul 23 09:34:36 CST 2018, time=2018-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=333534, encodeId=0558333534e1, content=学习了！！！！！！, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=59321624668, createdName=zb1235672, createdTime=Mon Jul 23 08:29:34 CST 2018, time=2018-07-23, status=1, ipAttribution=)]
    2018-08-18 owlhealth

    学习了，不错哟

    0

  6. 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topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/fhZdOu27e88Voqh19n8eF8cLplo8L4nicKtH0WnE3KFELXns5XDu8rsiceK2HHDZc2SEStia5VV3Pia2QLMVqlWbHw/0, createdBy=6e012139475, createdName=神功盖世, createdTime=Mon Jul 23 11:28:13 CST 2018, time=2018-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=333551, encodeId=29753335510b, content=学习了，谢谢, beContent=null, objectType=article, channel=null, level=null, likeNumber=28, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfNLvzZhgPxRvvXNvY0kOJqn4liar3Q6V6yPuEIawCVUyP3jVADh5icIz0ibrsxia6fKAqKsDr33jPWrjqM3D7wcRNu/0, createdBy=5a881701729, createdName=小树熊, createdTime=Mon Jul 23 09:34:36 CST 2018, time=2018-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=333534, encodeId=0558333534e1, content=学习了！！！！！！, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=59321624668, createdName=zb1235672, createdTime=Mon Jul 23 08:29:34 CST 2018, time=2018-07-23, status=1, ipAttribution=)]
    2018-07-30 大爰

    学习并分享！！

    0

  7. 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topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/fhZdOu27e88Voqh19n8eF8cLplo8L4nicKtH0WnE3KFELXns5XDu8rsiceK2HHDZc2SEStia5VV3Pia2QLMVqlWbHw/0, createdBy=6e012139475, createdName=神功盖世, createdTime=Mon Jul 23 11:28:13 CST 2018, time=2018-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=333551, encodeId=29753335510b, content=学习了，谢谢, beContent=null, objectType=article, channel=null, level=null, likeNumber=28, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfNLvzZhgPxRvvXNvY0kOJqn4liar3Q6V6yPuEIawCVUyP3jVADh5icIz0ibrsxia6fKAqKsDr33jPWrjqM3D7wcRNu/0, createdBy=5a881701729, createdName=小树熊, createdTime=Mon Jul 23 09:34:36 CST 2018, time=2018-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=333534, encodeId=0558333534e1, content=学习了！！！！！！, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=59321624668, createdName=zb1235672, createdTime=Mon Jul 23 08:29:34 CST 2018, time=2018-07-23, status=1, ipAttribution=)]
    2018-07-24 kafei

    学习了谢谢

    0

  8. 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topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/vi_32/fhZdOu27e88Voqh19n8eF8cLplo8L4nicKtH0WnE3KFELXns5XDu8rsiceK2HHDZc2SEStia5VV3Pia2QLMVqlWbHw/0, createdBy=6e012139475, createdName=神功盖世, createdTime=Mon Jul 23 11:28:13 CST 2018, time=2018-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=333551, encodeId=29753335510b, content=学习了，谢谢, beContent=null, objectType=article, channel=null, level=null, likeNumber=28, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mStl88fu4NfNLvzZhgPxRvvXNvY0kOJqn4liar3Q6V6yPuEIawCVUyP3jVADh5icIz0ibrsxia6fKAqKsDr33jPWrjqM3D7wcRNu/0, createdBy=5a881701729, createdName=小树熊, createdTime=Mon Jul 23 09:34:36 CST 2018, time=2018-07-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=333534, encodeId=0558333534e1, content=学习了！！！！！！, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=59321624668, createdName=zb1235672, createdTime=Mon Jul 23 08:29:34 CST 2018, time=2018-07-23, status=1, ipAttribution=)]
    2018-07-23 神功盖世

    阅

    0

  9. 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channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=59321624668, createdName=zb1235672, createdTime=Mon Jul 23 08:29:34 CST 2018, time=2018-07-23, status=1, ipAttribution=)]
    2018-07-23 小树熊

    学习了，谢谢

    0

  10. 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channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=59321624668, createdName=zb1235672, createdTime=Mon Jul 23 08:29:34 CST 2018, time=2018-07-23, status=1, ipAttribution=)]
    2018-07-23 zb1235672

    学习了！！！！！！

    0

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2017年，美国FDA先后批准两款CAR-T细胞疗法，推进了这一代表性免疫疗法的快速发展。除了“小车”CAR（嵌合抗原受体）的选择之外，科学家们开始思考免疫细胞的获得。最新一项研究提出一种可能：利用人类诱导性多能干细胞（iPSCs）获得的自然杀伤细胞（NK）经过类似的修饰之后，同样可以呈现出高效的抗癌活性。

Cancer Discov：贝勒医学院公布三靶点CAR-T治疗“癌中之王”全新结果，实体瘤CAR-T研究值得借鉴

T细胞疗法，特别是嵌合抗原受体(CAR)修饰的T细胞的出现和进步已经证明了针对难治性肿瘤的治疗潜力。但CAR-T靶向的抗原很少是绝对肿瘤特异性的，这很可能会导致非常严重的on-target/off-tumor毒性。

NEJM：CAR-T治疗的前世、今生和未来

6年前6岁的急性淋巴细胞白血病小女孩Emily在无药可医的情况下，尝试了研究性CAR-T细胞治疗，奇迹至此发生，治疗后她一直健康的生存至今。CD19 CAR T细胞治疗自此以百米速度进入公众视野和临床实践。其中CAR，即嵌合抗原受体，是该治疗的核心要素。美国June教授在NEJM杂志撰文论述了CAR-T细胞的发展简史，着重于现有CAR-T治疗的有效性和毒性作用，并展望了CAR-T治疗的未来发展与挑

对抗恶性淋巴瘤 CAR-T技术表现不俗

52岁的王女士，2015年7月中旬因腋窝肿物来到我院外科就诊，自述2个月前无意中发现双侧腋窝肿块，约花生米大小，无疼痛及不适感，也没有发热，但近来肿块逐渐增大至蛋黄一般。医生给予淋巴结穿刺活检检测，病理结果显示“弥漫大B细胞淋巴瘤”（非生发中心免疫表型），患者恐惧外科手术，遂出院回家调养。