免疫治疗在胰腺癌中是否有一席之地?

2017-04-15 Dr. GHL 肿瘤资讯

免疫治疗是肿瘤治疗中异军突起的一员,在肺癌、黑色素瘤等实体肿瘤的临床试验中都取得了很好的结果。正是因为其疗效惊人,各研究机制正努力将免疫治疗推广到更多实体瘤中。在“癌中之王”胰腺癌中,由于晚期胰腺癌的化疗药物种类十分有限,仅有吉西他滨、FOLFIRINOX(亚叶酸,5-氟尿嘧啶,伊立替康,奥沙利铂)、白蛋白紫杉醇等几种药物的疗效在临床中得到证实。因此研究者们不约而同的开始探索免疫治疗在胰腺癌中的效


胰腺癌免疫微环境

胰腺癌的免疫抑制微环境是高度异质性的。巨噬细胞,骨髓来源的抑制性细胞(Myeloid-derived suppressor cells,MDSCs)和调节性T细胞(Treg)是早期胰腺上皮内瘤变(PanIN)阶段的三种主要白细胞亚型,主要表现为Treg数量增加、效应T细胞功能失活。动物模型显示,这些免疫抑制细胞也在外周血和基质中增加,并在阻碍正常效应T细胞增殖和应答的胰腺癌组织中积累。同时,操纵这些免疫细胞可能抑制或限制肿瘤生长。此外,NK细胞免疫、FoxP3+T细胞和CD8+T细胞与胰腺癌患者的生存呈正相关。这些是免疫治疗在PDAC中应用的理论基础。

免疫检查点抑制剂(Immune checkpoint inhibitors)

主要组织相容性复合物(MHC)向T细胞受体(TCR)呈递肿瘤肽抗原,引起抗体免疫应答。 这种应答受到T细胞上表达的“免疫检查点”的调节。 这些共刺激或共抑制分子与TCR信号协同作用,促进或抑制生理或病理条件下的免疫活性。 共调节分子作为免疫治疗靶标,可以修饰MHC-TCR信号优化针对肿瘤细胞的免疫应答。用于临床的免疫检查点受体包括CTLA-4和PD-1/PD-L1。

抗CTLA-4

属于CD28受体家族,在CD8+和CD4+ T细胞表面都有表达。 CTLA-4与抗原呈递细胞(APC)上的配体B7-1(CD80)和B7-2(CD86)结合。由于 CTLA-4亲合力高,能够替代共刺激受体CD28。因此,通过阻断CD28配体的刺激作用,抑制白细胞介素-2的产生,激活抑制T细胞作用来减弱免疫反应。胰腺癌中的肿瘤微环境中的Tregs 含量增加,同时负向共刺激分子的表达增加。这些因素被认为是限制包括自身抗原在内的免疫应答。

ipilimumab

Ipilimumab是抗CTLA-4的完全人源化的IgG1单克隆抗体(mAb)。 II期试验[Royal et al  2010]评估了ipilimumab对晚期胰腺癌的疗效。结果显示27例受试者中没有患者达到符合RECIST标准的肿瘤缓解,但一个受试者达得肿瘤延迟退缩。鉴于RECIST或WHO标准可能不能科学评估对免疫治疗的肿瘤疗效。另一1b期单臂试验[ClinicalTrials.gov:NCT00836407]用于明确ipilimumab 单药或与粒细胞巨噬细胞集落刺激因子(GM-CSF)疫苗GVAX联合应用时对既往治疗过的胰腺癌患者的疗效和安全性。在单药组的有2例患者达到疾病稳定(SD),联合治疗组有3个病人达到SD,联合治疗组中7个患者出现CA19-9水平下降。此外,联合治疗组的生存预后更好,中位OS(3.6对5.7个月),1年OS率(7%对27%)[Le et al。 2013]。

Tremeimumab

Tremelimumab是抗CTLA-4的人源IgG2单抗。 每3个月以15mg / kg的剂量治疗的晚期黑素瘤患者的II期/ III期临床试验未能产生任何显着的生存获益[Kirkwood et al。 2010; Ribas等人 2013]。 恶性间皮瘤患者的II期单臂研究产生6.2个月的PFS,中位OS为10.7个月[Calabròet al。 2013]。 胰腺癌中tremelimumab的临床试验正在进行中。

抗PD1和抗PD-L1

程序性细胞死亡蛋白-1(PD-1)/ CD279是CD28家族的共抑制分子。它主要在Tregs 、活化的CD4+T细胞、CD8+T细胞、B细胞,NK细胞,单核细胞和某些树突状细胞(DC)上表达。PD-1与B7族的PD-L1(B7-H1)和PD-L2(B7-DC)配体结合。 PD-L1在几种实体肿瘤细胞和肿瘤浸润性淋巴细胞(TILs)上表达,PD-L2在DC、巨噬细胞和B细胞亚群,及淋巴造血恶性肿瘤中表达上调。 PD-L1与PD-1和B7-1(CD80)结合引起负反馈信号,导致T细胞增殖降低,细胞因子释放和细胞溶解活性的PD-1+T细胞的水平下降,抑制免疫活性。慢性抗原暴露如癌症和病毒感染可导致持续的PD-1表达,诱导抗原特异性T细胞疲劳,并帮助肿瘤细胞逃脱宿主免疫攻击。封锁这些靶点可抑制其对肿瘤的保护,为肿瘤治疗提供有效方法。肿瘤的PD-L1和PD-L2表达增加与胰腺癌预后差显着相关。敲减B7-H1(PD-L1)可抑制胰腺癌细胞的增殖。

Nivolumab和pembrolizumab是抗PD-1抗体,在恶性黑色素瘤,肾细胞癌及其他肿瘤的研究中已有阳性结果。在实体瘤I期研究中没有观察到抗PD-L1抗体在胰腺癌和结肠直肠癌中的反应。目前各种PD-1和PD-L1抑制剂在胰腺肿瘤中均处于临床试验阶段。

原始出处:


[2] Clark, C., Hingorani, S., Mick, R.,et al.Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res.

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    2017-04-24 ylzr123

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  2. [GetPortalCommentsPageByObjectIdResponse(id=190056, encodeId=50891900565e, content=感谢小编为我们精心准备了如此精辟的精神大餐,小编辛苦了,点个赞吧!, beContent=null, objectType=article, channel=null, level=null, likeNumber=70, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo7s7ZCKOmmbBTD6nE7gcd5OZpvyGEzkxBP3S275k5ZJVrsPkotZhBglRHM9rKvcj1OgkssqhcnoPw8zIaMZTF8c/0, createdBy=4c441942088, createdName=ylzr123, createdTime=Mon Apr 24 07:25:02 CST 2017, time=2017-04-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=188489, encodeId=233618848995, content=这篇文章有点拼拼凑凑嫌疑哦~, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20170803/IMG5982F7A3DBB3C1061.jpg, createdBy=0ba51605600, createdName=Jianghuiqin, createdTime=Tue Apr 18 09:18:35 CST 2017, time=2017-04-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=188362, encodeId=22e618836205, content=学习了谢谢分享!!, beContent=null, objectType=article, channel=null, level=null, likeNumber=63, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20200816/e4675a86ea694f12b82202b320dc2654/12f6b900498349e994ce8f516a584d6a.jpg, createdBy=09431951290, createdName=大爰, createdTime=Tue Apr 18 06:41:05 CST 2017, time=2017-04-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=188220, encodeId=dd2e18822005, content=收藏, beContent=null, objectType=article, channel=null, level=null, likeNumber=66, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mONcle9pic3xjZ9qh3bhXrJtUlmycKGfQKPuADVZQsdNAQj5IrHHlzbGsDwScictBgogYRk8KhicpgEKwTEfOHgqw/0, createdBy=bc931611963, createdName=jin321, createdTime=Mon Apr 17 11:38:49 CST 2017, time=2017-04-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=187918, encodeId=c8ce18e91892, content=学习!!!!, beContent=null, objectType=article, channel=null, level=null, likeNumber=54, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=078f1661649, createdName=wei834766788, createdTime=Sun Apr 16 14:38:02 CST 2017, time=2017-04-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=187858, encodeId=9f5618e858ef, content=巨噬细胞,骨髓来源的抑制性细胞(Myeloid-derivedsuppressorcells,MDSCs)和调节性T细胞(Treg)是早期胰腺上皮内瘤变(PanIN)阶段的三种主要白细胞亚型,主要表现为Treg数量增加、效应T细胞功能失活, beContent=null, objectType=article, channel=null, level=null, likeNumber=20, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/Pw2csslt7CukWiabqiblnQAXaDEiaxhu025c3P0XshccTrbvGWBjKvnHIxbK3vqa80P7WGIFuicCFet97TicrNKpgB3TdabxP1vMh/0, createdBy=28851960965, createdName=榄枷檬, createdTime=Sun Apr 16 08:37:46 CST 2017, time=2017-04-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=187847, encodeId=bce418e8476d, content=谢谢分享,学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=14, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6Nx0VGA4QMDzOP8oAgnV4h51EjSfehJ9QxyiaSmw8PB56BhY8KXFSxHCibXrzcy4abrzSibXQPxJ9kzrLcJyhhB8a/0, createdBy=1d3b1672603, createdName=明月清辉, createdTime=Sun Apr 16 08:13:05 CST 2017, time=2017-04-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=187835, encodeId=f46a18e8353c, content=学习了谢谢分享。有帮助。, beContent=null, objectType=article, channel=null, level=null, likeNumber=21, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cdnapi.center.medsci.cn/medsci/head/2017/04/21/72142930668371951a41ef4ea4b233e6.jpg, createdBy=dcbc1715228, createdName=刘煜, createdTime=Sun Apr 16 07:51:35 CST 2017, time=2017-04-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=187801, encodeId=495518e801e5, content=学习了很有用, beContent=null, objectType=article, channel=null, level=null, likeNumber=15, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/oLAjfB7s1ib3IzoRn621JdKCFUI4XvNELcibocrAVU6aUzEVDSaf3rYH08PUYUiagGqxAEhj8g9WqqNvD1CupIpCrmnR2OrqHZh/0, createdBy=7f181365728, createdName=飛歌, createdTime=Sun Apr 16 05:02:08 CST 2017, time=2017-04-16, status=1, ipAttribution=)]
    2017-04-18 Jianghuiqin

    这篇文章有点拼拼凑凑嫌疑哦~

    0

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    2017-04-18 大爰

    学习了谢谢分享!!

    0

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    2017-04-17 jin321

    收藏

    0

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    2017-04-16 wei834766788

    学习!!!!

    0

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    2017-04-16 榄枷檬

    巨噬细胞,骨髓来源的抑制性细胞(Myeloid-derivedsuppressorcells,MDSCs)和调节性T细胞(Treg)是早期胰腺上皮内瘤变(PanIN)阶段的三种主要白细胞亚型,主要表现为Treg数量增加、效应T细胞功能失活

    0

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    2017-04-16 明月清辉

    谢谢分享,学习了

    0

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    2017-04-16 刘煜

    学习了谢谢分享。有帮助。

    0

  9. [GetPortalCommentsPageByObjectIdResponse(id=190056, encodeId=50891900565e, content=感谢小编为我们精心准备了如此精辟的精神大餐,小编辛苦了,点个赞吧!, beContent=null, objectType=article, channel=null, level=null, likeNumber=70, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo7s7ZCKOmmbBTD6nE7gcd5OZpvyGEzkxBP3S275k5ZJVrsPkotZhBglRHM9rKvcj1OgkssqhcnoPw8zIaMZTF8c/0, createdBy=4c441942088, createdName=ylzr123, createdTime=Mon Apr 24 07:25:02 CST 2017, time=2017-04-24, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=188489, encodeId=233618848995, content=这篇文章有点拼拼凑凑嫌疑哦~, beContent=null, objectType=article, channel=null, level=null, likeNumber=0, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cacheapi.medsci.cn/resource/upload/20170803/IMG5982F7A3DBB3C1061.jpg, createdBy=0ba51605600, createdName=Jianghuiqin, createdTime=Tue Apr 18 09:18:35 CST 2017, time=2017-04-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=188362, encodeId=22e618836205, content=学习了谢谢分享!!, beContent=null, objectType=article, channel=null, level=null, likeNumber=63, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://img.medsci.cn/20200816/e4675a86ea694f12b82202b320dc2654/12f6b900498349e994ce8f516a584d6a.jpg, createdBy=09431951290, createdName=大爰, createdTime=Tue Apr 18 06:41:05 CST 2017, time=2017-04-18, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=188220, encodeId=dd2e18822005, content=收藏, beContent=null, objectType=article, channel=null, level=null, likeNumber=66, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/mONcle9pic3xjZ9qh3bhXrJtUlmycKGfQKPuADVZQsdNAQj5IrHHlzbGsDwScictBgogYRk8KhicpgEKwTEfOHgqw/0, createdBy=bc931611963, createdName=jin321, createdTime=Mon Apr 17 11:38:49 CST 2017, time=2017-04-17, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=187918, encodeId=c8ce18e91892, content=学习!!!!, beContent=null, objectType=article, channel=null, level=null, likeNumber=54, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=078f1661649, createdName=wei834766788, createdTime=Sun Apr 16 14:38:02 CST 2017, time=2017-04-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=187858, encodeId=9f5618e858ef, content=巨噬细胞,骨髓来源的抑制性细胞(Myeloid-derivedsuppressorcells,MDSCs)和调节性T细胞(Treg)是早期胰腺上皮内瘤变(PanIN)阶段的三种主要白细胞亚型,主要表现为Treg数量增加、效应T细胞功能失活, beContent=null, objectType=article, channel=null, level=null, likeNumber=20, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/Pw2csslt7CukWiabqiblnQAXaDEiaxhu025c3P0XshccTrbvGWBjKvnHIxbK3vqa80P7WGIFuicCFet97TicrNKpgB3TdabxP1vMh/0, createdBy=28851960965, createdName=榄枷檬, createdTime=Sun Apr 16 08:37:46 CST 2017, time=2017-04-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=187847, encodeId=bce418e8476d, content=谢谢分享,学习了, beContent=null, objectType=article, channel=null, level=null, likeNumber=14, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/NUyjXTCJjo6Nx0VGA4QMDzOP8oAgnV4h51EjSfehJ9QxyiaSmw8PB56BhY8KXFSxHCibXrzcy4abrzSibXQPxJ9kzrLcJyhhB8a/0, createdBy=1d3b1672603, createdName=明月清辉, createdTime=Sun Apr 16 08:13:05 CST 2017, time=2017-04-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=187835, encodeId=f46a18e8353c, content=学习了谢谢分享。有帮助。, beContent=null, objectType=article, channel=null, level=null, likeNumber=21, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=http://cdnapi.center.medsci.cn/medsci/head/2017/04/21/72142930668371951a41ef4ea4b233e6.jpg, createdBy=dcbc1715228, createdName=刘煜, createdTime=Sun Apr 16 07:51:35 CST 2017, time=2017-04-16, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=187801, encodeId=495518e801e5, content=学习了很有用, beContent=null, objectType=article, channel=null, level=null, likeNumber=15, replyNumber=0, topicName=null, topicId=null, topicList=[], attachment=null, authenticateStatus=null, createdAvatar=https://wx.qlogo.cn/mmopen/oLAjfB7s1ib3IzoRn621JdKCFUI4XvNELcibocrAVU6aUzEVDSaf3rYH08PUYUiagGqxAEhj8g9WqqNvD1CupIpCrmnR2OrqHZh/0, createdBy=7f181365728, createdName=飛歌, createdTime=Sun Apr 16 05:02:08 CST 2017, time=2017-04-16, status=1, ipAttribution=)]
    2017-04-16 飛歌

    学习了很有用

    0

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