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Article(id=1200147893832217407, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1200147892095779072, articleNumber=1001-2494(2024)11-0961-09, orderNo=null, doi=10.11669/cpj.2024.11.002, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1647273600000, receivedDateStr=2022-03-15, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1764067155559, onlineDateStr=2025-11-25, pubDate=1717776000000, pubDateStr=2024-06-08, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764067155559, onlineIssueDateStr=2025-11-25, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764067155559, creator=13701087609, updateTime=1764067155559, updator=13701087609, issue=Issue{id=1200147892095779072, tenantId=1146029695717560320, journalId=1190317699101192196, year='2024', volume='59', issue='11', pageStart='953', pageEnd='1064', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1764067155144, creator=13701087609, updateTime=1764067375019, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1200148814364508515, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1200147892095779072, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1200148814364508516, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1200147892095779072, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=961, endPage=969, ext={EN=ArticleExt(id=1200147894058709827, articleId=1200147893832217407, tenantId=1146029695717560320, journalId=1190317699101192196, language=EN, title=Progress in CAR-T Cell therapy Combined with PD-1 Blockade Therapy for Solid Tumors, columnId=null, journalTitle=Chinese Pharmaceutical Journal, columnName=null, runingTitle=null, highlight=null, articleAbstract=

Recently, chimeric antigen receptor (CAR)-T cell therapy has made remarkable success in hematological malignancies but faces a series of challenges in solid tumors. One of the major problems is that CAR-T cells overexpress programmed death-1 (PD-1) in tumor microenvironment. Therefore, blocking PD-1 can rescue the effector functions of CAR-T cells and reduce tumor burden significantly. Herein, it is aimed to summarize the progress in preclinical and clinical research on immunotherapy of combining CAR-T cells with PD-1 blockade for solid tumors.

, correspAuthors=Liyan MIAO, authorNote=null, correspAuthorsNote=null, copyrightStatement=null, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Meng ZHENG, Yan WANG, Liyan MIAO), CN=ArticleExt(id=1200147896009061245, articleId=1200147893832217407, tenantId=1146029695717560320, journalId=1190317699101192196, language=CN, title=CAR-T与阻断PD-1联合治疗在实体瘤中的研究进展, columnId=1190352408384471863, journalTitle=中国药学杂志, columnName=综述, runingTitle=null, highlight=null, articleAbstract=

近年来,嵌合抗原受体修饰T细胞(chimeric antigen receptor-modified T cells,CAR-T)在血液系统肿瘤中的临床疗效显著,但在实体瘤的治疗中面临诸多挑战。在实体肿瘤微环境中,CAR-T细胞表面高表达的程序性细胞死亡蛋白-1 (programmed cell death-1,PD-1)是限制发挥疗效的主要因素。故而,阻断PD-1可以提高CAR-T细胞的效应功能,并显著降低肿瘤负荷。本文总结了CAR-T与PD-1阻断联合治疗在实体瘤中临床前及临床中的研究现状。

, correspAuthors=缪丽燕, authorNote=null, correspAuthorsNote=
*缪丽燕,女,博士,主任药师,教授,博士生导师 研究方向:分子影像与临床药理 Tel:(0512) 67972988
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郑梦,女,博士研究生 研究方向:分子影像与临床药学

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DOI: 10.1016/j.cellimm.2020.104112., articleTitle=Combined antitumor effects of anti-EGFR variant Ⅲ CAR-T cell therapy and PD-1 checkpoint blockade on glioblastoma in mouse model, refAbstract=null), Reference(id=1200147908998820145, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147893832217407, doi=null, pmid=null, pmcid=null, year=2020, volume=17, issue=null, pageStart=571, pageEnd=585, url=null, language=null, rfNumber=[77], rfOrder=76, authorNames=YANG C Y, FAN M H, MIAO C H, journalName=Mol Ther Oncolytics, refType=null, unstructuredReference=YANG C Y, FAN M H, MIAO C H, et al. Engineering chimeric antigen receptor T cells against immune checkpoint inhibitors PD-1/PD-L1 for treating pancreatic cancer[J]. 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Invest New Drugs, 2021, 39(1): 34-51., articleTitle=Dual-function chimeric antigen receptor T cells targeting c-Met and PD-1 exhibit potent anti-tumor efficacy in solid tumors, refAbstract=null), Reference(id=1200147909179175223, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147893832217407, doi=null, pmid=null, pmcid=null, year=2020, volume=26, issue=4, pageStart=2135, pageEnd=2141, url=null, language=null, rfNumber=[79], rfOrder=78, authorNames=ZHU H, YOU Y, SHEN Z, journalName=Pathol Oncol Res, refType=null, unstructuredReference=ZHU H, YOU Y, SHEN Z, et al. EGFRvIII-CAR-T cells with PD-1 knockout have improved anti-glioma activity[J]. 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DNR-显性阴性受体;CAR-嵌合抗原受体;CSR-嵌合开关受体。

, figureFileSmall=6dVuTCeiJ0LpMKOKzfiRBg==, figureFileBig=JuM/Sc46IuJ5wOxuSTknCg==, tableContent=null), ArticleFig(id=1200147899079290914, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147893832217407, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
序号 PD-1
干扰方法		 CAR-T
靶点		 肿瘤
模型		 CAR-T
给药方案		 动物
模型		 参考
文献
1 PD-1 单抗 (EH122H7) PLAP 结直肠癌 每只小鼠在第1、7和13天尾静脉注射1×107 CAR-T细胞 每只小鼠皮下注射2×106个结肠癌细胞 [64]
2 PD-1/CD28嵌合开关 c-Met 胃癌 小鼠于第0、7天分别瘤内注射5×106 CAR-T细胞 将1×106个MKN5-Luc细胞用100 μL PBS混
悬后,皮下注射		 [54]
3 分泌与TGF-β融合的
抗PD-1双特异性蛋白		 CD19 前列腺癌 通过尾静脉注射给药的方式,CAR-T细胞分别按
2× 106(短期研究)或4× 106(长期研究)方式给药		 NSG小鼠皮下接种3× 106个PC3-CD19细胞 [65]
4 CRISPR/Cas9干扰
PD-1		 EGFRvIII 脑胶质瘤 经尾静脉输注总容积为100 μL的效应细胞或经脑室内输注总容积为30 μL的效应细胞。脑室内注射位置在脑后膜左侧2 mm,前0.3 mm,距颅骨表面3 mm处。对所有实验的效应细胞群进行标准化,使其每次输入包含1×106个细胞 将肿瘤细胞植入脑后膜右侧2 mm处,距颅骨
表面4 mm处,共5 μL		 [66]
5 干扰PD-1 GPC3 肝癌 分别静脉注射5×106野生型CAR-T细胞与5×106 PD-1缺陷型CAR-T细胞 将3×106 PLC/PRF/5细胞用PBS混悬后,并
建立皮下移植瘤模型		 [67]
6 原位分泌抗PD-1 scFv ROR1 三阴性乳腺癌 小鼠接受单次静脉注射4× 106 CAR-T细胞或相同未经处理的T细胞 NSG小鼠皮下移植2×106 MDA-MB-231细胞 [68]
7 CRISPR/Cas9干扰
PD-1		 CD133 脑胶质瘤 在肿瘤细胞注射后的第7、11和15天,通过原始颅内注射通道注射2×106 PD-1-缺陷或正常CD133-CAR-T细胞或未转染的T细胞 NPG小鼠颅内注射2×105荧光素酶表达的
U251 CD133 OE luc细胞		 [69]
8 CRISPR/Cas9干扰PD-1 Mesothelin 三阴性乳腺癌 第25天时,每只小鼠尾静脉给予1×105个Meso CAR-T细胞 将2×106个表达荧光素酶的BT549细胞注射
到NSG小鼠的第4乳腺		 [51]
9 PD-1 诱骗受体 B7-H3 肺巨细胞癌 当肿瘤平均直径达到约4 mm时,每组小鼠分别在第5、10和15天静脉注射PBS或5×106个CAR-T细胞(Control CAR-T、H3 CAR-T、H3/DS CAR-T、H3/PD28 CAR-T或H3/PDmut7R CAR-T) NCG小鼠腰背部皮下注射0.5×106个肺巨细
胞癌(PG)细胞		 [70]
10 PD-1显性阴性受体(PD-1 DNR) MSLN 胸膜间皮瘤 4×104~1×105转导T细胞(200 μl无血清培养液)通过直接胸膜内注射转入荷瘤小鼠胸腔 经右胸切口直接胸腔内注射含200 μl无血清培养基的1×105~1×106个肿瘤细胞建立原位MPM肿瘤模型 [33]
11 PD-1-CSR NKG2D 结直肠癌和
卵巢癌腹
膜转移		 为了研究CAR-T细胞在体内的抗肿瘤作用,将表达1×107的CAR-T细胞腹腔注射到荷瘤小鼠体内 在NSG小鼠腹腔注射HCT116-Luc细胞(2×106)或SKOV3-Luc细胞(5×106)建立肿瘤模型 [71]
12 PD-1 单抗 GPC1 人食管鳞癌
和人肺鳞
状癌		 第2~3天,小鼠接受5 Gy全身照射(TBI)后,通过静脉输注培养的mCAR-T细胞或小鼠对照T细胞(mCont-T)(每支2×106个) 将3×106个TE14细胞接种于小鼠背部皮下,建立异种小鼠模型。对于同基因小鼠模型,将5×105个MC38-mGPC1或MCA205-mGPC1细胞皮下接种C57BL/6小鼠的腹部 [72]
13 PD-1显性阴性受体(PD-1 DNR) PD-L1 肺癌,胃癌和
肝癌		 肿瘤细胞移植后10 d,经小鼠尾静脉注射5×106个CAR-T细胞 在NSI小鼠右侧皮下注射5×105 H460GL细胞(含200 μL PBS)建立肺癌细胞系异种移植模型。为了开发第一代PDXs,将包括肺癌、胃癌和肝癌在内的外科肿瘤样本移植到3~6只NSI小鼠的皮下 [47]
14 分泌PD-1 CD19 肺癌 小鼠进行1×106或3×106 CAR-T细胞进行过继转移 小鼠皮下接种3×106个H292-CD19细胞 [62]
15 原位分泌抗PD-1 scFv CD20 肺癌 小鼠在第6天接受亚致死剂量的照射(3 Gy),然后在第7天静脉注射1×106个conv CAR-T细胞,scFv CAR-T细胞,或无基因转导的活化T细胞,其中总细胞数量调整为与CAR-T细胞组相当 C57BL/6小鼠在第0天注射2.5×106个3LL-hCD20 [73]
16 分泌可溶性PD1-CH3
融合蛋白		 Glypican-3
(GPC3)		 肝癌 经环磷酰胺(200 mg·kg-1)清除淋巴细胞后,在SK-HEP-1-GPC3模型中,每只小鼠尾静脉注射8×106 CAR-T细胞,而在Huh7模型中,每只小鼠注射7×106 CAR-T细胞 建立Huh7和SK-HEP-1-GPC3模型,将2×106个肿瘤细胞接种于小鼠右侧皮下 [74]
17 原位分泌抗PD-1 scFv Meso 肺癌 尾静脉输注5×106 CAR-meso 细胞和CAR-meso-α-PD-1 细胞。 皮下移植模型:每只SCID-Beige小鼠皮下接种
1×106个H322细胞;原位瘤模型:每只SCID-Beige小鼠尾静脉注射5×105个H322细胞		 [34]
18 抗hPD-1 单抗 PSMA 前列腺癌 CAR-T细胞的数量从每只老鼠20×106个减少到10×106个 在NSG小鼠右侧皮下注射1× 106个Myc-CaP:hPSMA(+)或Myc-CaP:hPSMA(-)。将
1×106个Myc-CaP野生型细胞注射到FVB/
N小鼠体内		 [75]
19 抗PD1 单抗 EGFR 脑胶质瘤 将1×107 EGFRvIII CAR+T细胞或等量地模拟T细胞(与总T细胞剂量相匹配)或1×107带有PD1阻断的EGFRvIII CAR+T细胞在接种肿瘤2~3周后尾静脉注射 皮下模型:1×106 U87-ELUC肿瘤细胞植入
NPI小皮下		 [76]
20 抗PD-1 单抗 PD-L1 胰腺癌 每只小鼠尾静脉注射1×107个PD-L1 CAR-T细胞 皮下模型: 1×107或 1.5×107 CFPAC1 细胞植
入NPI小皮下左侧;原位瘤模型:7.5×106
CFPAC1细胞于第0天注射入小鼠胰腺		 [77]
21 原位分泌抗PD-1 scFv c-Met and
PD-1		 肝癌 每只小鼠瘤内注射1×106 CAR-T细胞 小鼠右侧皮下注射5×106个MKN45或A549
细胞建立异种移植瘤		 [78]
22 敲除PD-1 EGFRvIII 脑胶质瘤 在模型建立第10天,尾静脉注射PD-1 WT EGFRvIII-CAR-T 细胞和 PD-1 KD EGFRvIII-CAR-T 细胞 原位脑胶质瘤模型:将培养的EGFRvIII+ U373
细胞立体定向注入balb/c裸鼠大脑		 [79]
), ArticleFig(id=1200147899167371299, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147893832217407, language=CN, label=表1, caption=

CAR-T细胞和阻断程序性细胞死亡蛋白-1(PD-1)联用在临床前研究现状

, figureFileSmall=null, figureFileBig=null, tableContent=
序号 PD-1
干扰方法		 CAR-T
靶点		 肿瘤
模型		 CAR-T
给药方案		 动物
模型		 参考
文献
1 PD-1 单抗 (EH122H7) PLAP 结直肠癌 每只小鼠在第1、7和13天尾静脉注射1×107 CAR-T细胞 每只小鼠皮下注射2×106个结肠癌细胞 [64]
2 PD-1/CD28嵌合开关 c-Met 胃癌 小鼠于第0、7天分别瘤内注射5×106 CAR-T细胞 将1×106个MKN5-Luc细胞用100 μL PBS混
悬后,皮下注射		 [54]
3 分泌与TGF-β融合的
抗PD-1双特异性蛋白		 CD19 前列腺癌 通过尾静脉注射给药的方式,CAR-T细胞分别按
2× 106(短期研究)或4× 106(长期研究)方式给药		 NSG小鼠皮下接种3× 106个PC3-CD19细胞 [65]
4 CRISPR/Cas9干扰
PD-1		 EGFRvIII 脑胶质瘤 经尾静脉输注总容积为100 μL的效应细胞或经脑室内输注总容积为30 μL的效应细胞。脑室内注射位置在脑后膜左侧2 mm,前0.3 mm,距颅骨表面3 mm处。对所有实验的效应细胞群进行标准化,使其每次输入包含1×106个细胞 将肿瘤细胞植入脑后膜右侧2 mm处,距颅骨
表面4 mm处,共5 μL		 [66]
5 干扰PD-1 GPC3 肝癌 分别静脉注射5×106野生型CAR-T细胞与5×106 PD-1缺陷型CAR-T细胞 将3×106 PLC/PRF/5细胞用PBS混悬后,并
建立皮下移植瘤模型		 [67]
6 原位分泌抗PD-1 scFv ROR1 三阴性乳腺癌 小鼠接受单次静脉注射4× 106 CAR-T细胞或相同未经处理的T细胞 NSG小鼠皮下移植2×106 MDA-MB-231细胞 [68]
7 CRISPR/Cas9干扰
PD-1		 CD133 脑胶质瘤 在肿瘤细胞注射后的第7、11和15天,通过原始颅内注射通道注射2×106 PD-1-缺陷或正常CD133-CAR-T细胞或未转染的T细胞 NPG小鼠颅内注射2×105荧光素酶表达的
U251 CD133 OE luc细胞		 [69]
8 CRISPR/Cas9干扰PD-1 Mesothelin 三阴性乳腺癌 第25天时,每只小鼠尾静脉给予1×105个Meso CAR-T细胞 将2×106个表达荧光素酶的BT549细胞注射
到NSG小鼠的第4乳腺		 [51]
9 PD-1 诱骗受体 B7-H3 肺巨细胞癌 当肿瘤平均直径达到约4 mm时,每组小鼠分别在第5、10和15天静脉注射PBS或5×106个CAR-T细胞(Control CAR-T、H3 CAR-T、H3/DS CAR-T、H3/PD28 CAR-T或H3/PDmut7R CAR-T) NCG小鼠腰背部皮下注射0.5×106个肺巨细
胞癌(PG)细胞		 [70]
10 PD-1显性阴性受体(PD-1 DNR) MSLN 胸膜间皮瘤 4×104~1×105转导T细胞(200 μl无血清培养液)通过直接胸膜内注射转入荷瘤小鼠胸腔 经右胸切口直接胸腔内注射含200 μl无血清培养基的1×105~1×106个肿瘤细胞建立原位MPM肿瘤模型 [33]
11 PD-1-CSR NKG2D 结直肠癌和
卵巢癌腹
膜转移		 为了研究CAR-T细胞在体内的抗肿瘤作用,将表达1×107的CAR-T细胞腹腔注射到荷瘤小鼠体内 在NSG小鼠腹腔注射HCT116-Luc细胞(2×106)或SKOV3-Luc细胞(5×106)建立肿瘤模型 [71]
12 PD-1 单抗 GPC1 人食管鳞癌
和人肺鳞
状癌		 第2~3天,小鼠接受5 Gy全身照射(TBI)后,通过静脉输注培养的mCAR-T细胞或小鼠对照T细胞(mCont-T)(每支2×106个) 将3×106个TE14细胞接种于小鼠背部皮下,建立异种小鼠模型。对于同基因小鼠模型,将5×105个MC38-mGPC1或MCA205-mGPC1细胞皮下接种C57BL/6小鼠的腹部 [72]
13 PD-1显性阴性受体(PD-1 DNR) PD-L1 肺癌,胃癌和
肝癌		 肿瘤细胞移植后10 d,经小鼠尾静脉注射5×106个CAR-T细胞 在NSI小鼠右侧皮下注射5×105 H460GL细胞(含200 μL PBS)建立肺癌细胞系异种移植模型。为了开发第一代PDXs,将包括肺癌、胃癌和肝癌在内的外科肿瘤样本移植到3~6只NSI小鼠的皮下 [47]
14 分泌PD-1 CD19 肺癌 小鼠进行1×106或3×106 CAR-T细胞进行过继转移 小鼠皮下接种3×106个H292-CD19细胞 [62]
15 原位分泌抗PD-1 scFv CD20 肺癌 小鼠在第6天接受亚致死剂量的照射(3 Gy),然后在第7天静脉注射1×106个conv CAR-T细胞,scFv CAR-T细胞,或无基因转导的活化T细胞,其中总细胞数量调整为与CAR-T细胞组相当 C57BL/6小鼠在第0天注射2.5×106个3LL-hCD20 [73]
16 分泌可溶性PD1-CH3
融合蛋白		 Glypican-3
(GPC3)		 肝癌 经环磷酰胺(200 mg·kg-1)清除淋巴细胞后,在SK-HEP-1-GPC3模型中,每只小鼠尾静脉注射8×106 CAR-T细胞,而在Huh7模型中,每只小鼠注射7×106 CAR-T细胞 建立Huh7和SK-HEP-1-GPC3模型,将2×106个肿瘤细胞接种于小鼠右侧皮下 [74]
17 原位分泌抗PD-1 scFv Meso 肺癌 尾静脉输注5×106 CAR-meso 细胞和CAR-meso-α-PD-1 细胞。 皮下移植模型:每只SCID-Beige小鼠皮下接种
1×106个H322细胞;原位瘤模型:每只SCID-Beige小鼠尾静脉注射5×105个H322细胞		 [34]
18 抗hPD-1 单抗 PSMA 前列腺癌 CAR-T细胞的数量从每只老鼠20×106个减少到10×106个 在NSG小鼠右侧皮下注射1× 106个Myc-CaP:hPSMA(+)或Myc-CaP:hPSMA(-)。将
1×106个Myc-CaP野生型细胞注射到FVB/
N小鼠体内		 [75]
19 抗PD1 单抗 EGFR 脑胶质瘤 将1×107 EGFRvIII CAR+T细胞或等量地模拟T细胞(与总T细胞剂量相匹配)或1×107带有PD1阻断的EGFRvIII CAR+T细胞在接种肿瘤2~3周后尾静脉注射 皮下模型:1×106 U87-ELUC肿瘤细胞植入
NPI小皮下		 [76]
20 抗PD-1 单抗 PD-L1 胰腺癌 每只小鼠尾静脉注射1×107个PD-L1 CAR-T细胞 皮下模型: 1×107或 1.5×107 CFPAC1 细胞植
入NPI小皮下左侧;原位瘤模型:7.5×106
CFPAC1细胞于第0天注射入小鼠胰腺		 [77]
21 原位分泌抗PD-1 scFv c-Met and
PD-1		 肝癌 每只小鼠瘤内注射1×106 CAR-T细胞 小鼠右侧皮下注射5×106个MKN45或A549
细胞建立异种移植瘤		 [78]
22 敲除PD-1 EGFRvIII 脑胶质瘤 在模型建立第10天,尾静脉注射PD-1 WT EGFRvIII-CAR-T 细胞和 PD-1 KD EGFRvIII-CAR-T 细胞 原位脑胶质瘤模型:将培养的EGFRvIII+ U373
细胞立体定向注入balb/c裸鼠大脑		 [79]
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序号 试验号 项目名称 靶点 癌症类型及条件 阶段
1 NCT03179007 CTLA-4 and PD-1 antibodies expressing MUC1-CAR-T cells for MUC1 positive advanced solid tumor MUC1 Advanced solid tumor Phase Ⅰ Phase Ⅱ
2 NCT03182816 CTLA-4 and PD-1 antibodies expressing EGFR-CAR-T cells for EGFR positive advanced solid tumor EGFR Advanced solid tumor Phase Ⅰ Phase Ⅱ
3 NCT03030001 PD-1 antibody expressing CAR T cells for mesothelin positive advanced malignancies Mesothelin Solid tumor, adult advanced cancer Phase Ⅰ Phase Ⅱ
4 NCT03182803 CTLA-4 and PD-1 antibodies expressing mesothelin-CAR-T cells for mesothelin positive advanced solid tumor Mesothelin Advanced solid tumor Phase Ⅰ Phase Ⅱ
5 NCT03706326 CAR T and PD-1 knockout engineered T cells for esophageal cancer MUC1 Advanced esophageal cancer Phase Ⅰ Phase Ⅱ
6 NCT03525782 Anti-MUC1 CAR T cells and PD-1 knockout engineered T cells for NSCLC MUC1 Lung neoplasm malignant;non-small cell lung cancer Phase Ⅰ Phase Ⅱ
7 NCT02873390 PD-1 antibody expressing CAR-T cells for EGFR family member positive advanced solid tumor EGFR Advanced malignancies Phase Ⅰ Phase Ⅱ
8 NCT03545815 Study of CRISPR-Cas9 mediated PD-1 and TCR gene-knocked out mesothelin-directed CAR-T cells in patients with mesothelin positive multiple solid tumors Mesothelin Solid tumor, adult Phase Ⅰ
9 NCT03747965 Study of PD-1 gene-knocked out mesothelin-directed CAR-T cells with the conditioning of PC in mesothelin positive multiple solid tumors Mesothelin Solid tumor, adult Phase Ⅰ
10 NCT04489862 αPD1-MSLN-CAR T cells for the treatment of MSLN-positive advanced solid tumors Mesothelin Non-small-cell lung cancer mesothelioma Early Phase Ⅰ
11 NCT04503980 αPD1-MSLN-CAR T cells for the treatment of MSLN-positive advanced solid tumors Mesothelin Colorectal cancer ovarian cancer Early Phase Ⅰ
12 NCT03615313 PD-1 antibody expressing mesoCAR-T cells for mesothelin positive advanced solid tumor (PAEMCMPAST) Mesothelin Advanced solid tumor Phase Ⅰ
Phase Ⅱ
13 NCT04768608 PD1 integrated anti-PSMA CART in treating patients with castrate-resistant prostate cancer PSMA Castrate-Resistant Prostate Cancer Phase Ⅰ
14 NCT04995003 HER2 chimeric antigen receptor (CAR) T cells in combination with checkpoint blockade in patients with advanced sarcoma HER2 Sarcoma
HER-2 protein overexpression		 Phase Ⅰ
15 NCT03874897 Chimeric antigen receptor T cells targeting claudin 18.2 in solid tumors Claudin18.2 Advanced solid tumor Phase Ⅰ
16 NCT05089266 Study of αPD1-MSLN-CAR T cells to evaluate the safety, tolerability, and effectiveness for patients with MSLN-positive advanced solid tumors Mesothelin Colorectal cancer Phase Ⅰ
17 NCT03726515 CART-EGFRvIII + pembrolizumab in GBM EGFRvIII Glioblastoma Phase Ⅰ
18 NCT03198546 GPC3-CAR-T cells for immunotherapy of cancer with GPC3 expression GPC3/TGFβ Hepatocellular carcinoma squamous cell lung cancer Phase Ⅰ
19 NCT04577326 Mesothelin-targeted CAR T-cell therapy in patients with mesothelioma Mesothelin Malignant pleural mesothelioma (MPM) Phase Ⅰ
20 NCT03980288 4th generation chimeric antigen receptor T cells targeting glypican-3 GPC3 Advanced hepatocellular carcinoma Phase Ⅰ
21 NCT01822652 3rd generation GD-2 chimeric antigen receptor and iCaspase suicide safety switch, neuroblastoma, GRAIN GD2 Neuroblastoma Phase Ⅰ
22 NCT04162119 Safety and efficiency study of BCMA-PD1-CART cells in relapsed/refractory multiple myeloma BCMA Multiple myeloma Phase Ⅱ
23 NCT03916679 MESO-CAR T Cells Therapy for Relapsed and Refractory Epithelial Ovarian Cancer MESO Ovarian Cancer Phase Ⅰ
Phase Ⅱ
24 NCT03799913 MESO-CAR T cells therapy for relapsed and refractory ovarian cancer MESO Ovarian cancer Early Phase Ⅰ
25 NCT03356782 Safety and efficacy evaluation of 4th generation safety-engineered CAR T cells targeting sarcomas Sarcoma;osteoid sarcoma
ewing sarcoma		 Phase Ⅰ
Phase Ⅱ
26 NCT02862028 PD-1 antibody expressing CAR-T cells for EGFR family member positive advanced solid tumor (lung, liver and stomach) EGFR Advanced solid tumor Phase Ⅰ
Phase Ⅱ
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CAR-T细胞和阻断PD-1联用正在实体瘤中进行的临床研究

, figureFileSmall=null, figureFileBig=null, tableContent=
序号 试验号 项目名称 靶点 癌症类型及条件 阶段
1 NCT03179007 CTLA-4 and PD-1 antibodies expressing MUC1-CAR-T cells for MUC1 positive advanced solid tumor MUC1 Advanced solid tumor Phase Ⅰ Phase Ⅱ
2 NCT03182816 CTLA-4 and PD-1 antibodies expressing EGFR-CAR-T cells for EGFR positive advanced solid tumor EGFR Advanced solid tumor Phase Ⅰ Phase Ⅱ
3 NCT03030001 PD-1 antibody expressing CAR T cells for mesothelin positive advanced malignancies Mesothelin Solid tumor, adult advanced cancer Phase Ⅰ Phase Ⅱ
4 NCT03182803 CTLA-4 and PD-1 antibodies expressing mesothelin-CAR-T cells for mesothelin positive advanced solid tumor Mesothelin Advanced solid tumor Phase Ⅰ Phase Ⅱ
5 NCT03706326 CAR T and PD-1 knockout engineered T cells for esophageal cancer MUC1 Advanced esophageal cancer Phase Ⅰ Phase Ⅱ
6 NCT03525782 Anti-MUC1 CAR T cells and PD-1 knockout engineered T cells for NSCLC MUC1 Lung neoplasm malignant;non-small cell lung cancer Phase Ⅰ Phase Ⅱ
7 NCT02873390 PD-1 antibody expressing CAR-T cells for EGFR family member positive advanced solid tumor EGFR Advanced malignancies Phase Ⅰ Phase Ⅱ
8 NCT03545815 Study of CRISPR-Cas9 mediated PD-1 and TCR gene-knocked out mesothelin-directed CAR-T cells in patients with mesothelin positive multiple solid tumors Mesothelin Solid tumor, adult Phase Ⅰ
9 NCT03747965 Study of PD-1 gene-knocked out mesothelin-directed CAR-T cells with the conditioning of PC in mesothelin positive multiple solid tumors Mesothelin Solid tumor, adult Phase Ⅰ
10 NCT04489862 αPD1-MSLN-CAR T cells for the treatment of MSLN-positive advanced solid tumors Mesothelin Non-small-cell lung cancer mesothelioma Early Phase Ⅰ
11 NCT04503980 αPD1-MSLN-CAR T cells for the treatment of MSLN-positive advanced solid tumors Mesothelin Colorectal cancer ovarian cancer Early Phase Ⅰ
12 NCT03615313 PD-1 antibody expressing mesoCAR-T cells for mesothelin positive advanced solid tumor (PAEMCMPAST) Mesothelin Advanced solid tumor Phase Ⅰ
Phase Ⅱ
13 NCT04768608 PD1 integrated anti-PSMA CART in treating patients with castrate-resistant prostate cancer PSMA Castrate-Resistant Prostate Cancer Phase Ⅰ
14 NCT04995003 HER2 chimeric antigen receptor (CAR) T cells in combination with checkpoint blockade in patients with advanced sarcoma HER2 Sarcoma
HER-2 protein overexpression		 Phase Ⅰ
15 NCT03874897 Chimeric antigen receptor T cells targeting claudin 18.2 in solid tumors Claudin18.2 Advanced solid tumor Phase Ⅰ
16 NCT05089266 Study of αPD1-MSLN-CAR T cells to evaluate the safety, tolerability, and effectiveness for patients with MSLN-positive advanced solid tumors Mesothelin Colorectal cancer Phase Ⅰ
17 NCT03726515 CART-EGFRvIII + pembrolizumab in GBM EGFRvIII Glioblastoma Phase Ⅰ
18 NCT03198546 GPC3-CAR-T cells for immunotherapy of cancer with GPC3 expression GPC3/TGFβ Hepatocellular carcinoma squamous cell lung cancer Phase Ⅰ
19 NCT04577326 Mesothelin-targeted CAR T-cell therapy in patients with mesothelioma Mesothelin Malignant pleural mesothelioma (MPM) Phase Ⅰ
20 NCT03980288 4th generation chimeric antigen receptor T cells targeting glypican-3 GPC3 Advanced hepatocellular carcinoma Phase Ⅰ
21 NCT01822652 3rd generation GD-2 chimeric antigen receptor and iCaspase suicide safety switch, neuroblastoma, GRAIN GD2 Neuroblastoma Phase Ⅰ
22 NCT04162119 Safety and efficiency study of BCMA-PD1-CART cells in relapsed/refractory multiple myeloma BCMA Multiple myeloma Phase Ⅱ
23 NCT03916679 MESO-CAR T Cells Therapy for Relapsed and Refractory Epithelial Ovarian Cancer MESO Ovarian Cancer Phase Ⅰ
Phase Ⅱ
24 NCT03799913 MESO-CAR T cells therapy for relapsed and refractory ovarian cancer MESO Ovarian cancer Early Phase Ⅰ
25 NCT03356782 Safety and efficacy evaluation of 4th generation safety-engineered CAR T cells targeting sarcomas Sarcoma;osteoid sarcoma
ewing sarcoma		 Phase Ⅰ
Phase Ⅱ
26 NCT02862028 PD-1 antibody expressing CAR-T cells for EGFR family member positive advanced solid tumor (lung, liver and stomach) EGFR Advanced solid tumor Phase Ⅰ
Phase Ⅱ
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CAR-T与阻断PD-1联合治疗在实体瘤中的研究进展
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郑梦 1, 2 , 王燕 1 , 缪丽燕 1, 2, *
中国药学杂志 | 综述 2024,59(11): 961-969
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中国药学杂志 | 综述 2024, 59(11): 961-969
CAR-T与阻断PD-1联合治疗在实体瘤中的研究进展
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郑梦1, 2, 王燕1, 缪丽燕1, 2, *
作者信息
  • 1 苏州大学附属第一医院临床药理实验室,江苏 苏州 215006
  • 2 苏州大学药物研究与转化交叉研究所, 江苏 苏州 215123

    • 郑梦,女,博士研究生 研究方向:分子影像与临床药学

通讯作者:

*缪丽燕,女,博士,主任药师,教授,博士生导师 研究方向:分子影像与临床药理 Tel:(0512) 67972988
Progress in CAR-T Cell therapy Combined with PD-1 Blockade Therapy for Solid Tumors
Meng ZHENG1, 2, Yan WANG1, Liyan MIAO1, 2, *
Affiliations
  • 1 Department of Clinical Pharmacology Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
  • 2 Institute for Interdisciplinary Drug Research and Translational Sciences, Soochow University, Suzhou 215123, China
出版时间: 2024-06-08 doi: 10.11669/cpj.2024.11.002
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摘要
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近年来,嵌合抗原受体修饰T细胞(chimeric antigen receptor-modified T cells,CAR-T)在血液系统肿瘤中的临床疗效显著,但在实体瘤的治疗中面临诸多挑战。在实体肿瘤微环境中,CAR-T细胞表面高表达的程序性细胞死亡蛋白-1 (programmed cell death-1,PD-1)是限制发挥疗效的主要因素。故而,阻断PD-1可以提高CAR-T细胞的效应功能,并显著降低肿瘤负荷。本文总结了CAR-T与PD-1阻断联合治疗在实体瘤中临床前及临床中的研究现状。

嵌合抗原受体T细胞免疫疗法  /  程序性细胞死亡蛋白-1  /  实体瘤  /  免疫疗法

Recently, chimeric antigen receptor (CAR)-T cell therapy has made remarkable success in hematological malignancies but faces a series of challenges in solid tumors. One of the major problems is that CAR-T cells overexpress programmed death-1 (PD-1) in tumor microenvironment. Therefore, blocking PD-1 can rescue the effector functions of CAR-T cells and reduce tumor burden significantly. Herein, it is aimed to summarize the progress in preclinical and clinical research on immunotherapy of combining CAR-T cells with PD-1 blockade for solid tumors.

CAR-T  /  PD-1  /  solid tumor  /  immunotherapy
郑梦, 王燕, 缪丽燕. CAR-T与阻断PD-1联合治疗在实体瘤中的研究进展. 中国药学杂志, 2024 , 59 (11) : 961 -969 . DOI: 10.11669/cpj.2024.11.002
Meng ZHENG, Yan WANG, Liyan MIAO. Progress in CAR-T Cell therapy Combined with PD-1 Blockade Therapy for Solid Tumors[J]. Chinese Pharmaceutical Journal, 2024 , 59 (11) : 961 -969 . DOI: 10.11669/cpj.2024.11.002
正文
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嵌合抗原受体修饰T细胞(chimeric antigen receptor-modified T cells,CAR-T)细胞疗法是利用基因工程手段将特异性靶向肿瘤抗原的嵌合抗原受体(chimeric antigen receptor,CARs)引入到人的T细胞,经体外扩增后,回输患者体内,从而发挥肿瘤细胞杀伤作用。与传统过继免疫疗法相比,CAR-T细胞疗法不需要抗原呈递,以非MHC限制性的方式识别并精准靶向肿瘤抗原而发挥作用[1]。因此,CAR-T细胞疗法在血液恶性肿瘤中发展迅速。截止到2023年12月,美国食品药品监督管理局已先后批准4种CD19 CAR-T活细胞药物(tisagenlecleucel,axicabtagene ciloleucel,brexucabtagene autoleucel,lisocabtagene maraleucel)用于复发或难治弥漫大B细胞瘤治疗,2种BCMA-CAR-T(idecabtagene vicleucel,ciltacabtagene autoleucel)用于复发或难治性多发性骨髓瘤[2-4]。国内上市2种CD19-CAR-T活细胞药物(阿基伦塞注射液和瑞基奥仑塞注射液)[5]用于成人复发难治性大B细胞淋巴瘤;还有一些其他的CAR-T细胞正在进行临床试验测试,如CD22-CAR-T细胞用于治疗B细胞淋巴瘤(NCT02315612)[6],BCMA CAR-T细胞用于治疗多发性骨髓瘤(NCT02658929)[7]。
然而,CAR-T治疗实体瘤的疗效却面临诸多挑战,比如,实体肿瘤异质性、免疫抑制肿瘤微环境等。在肿瘤免疫抑制性微环境中,CAR-T细胞表面过表达PD-1,从而引起细胞毒性和功能持久性下降[8-9]。因此,通过阻断PD-1来挽救CAR-T的效应功能是一个很有前途的策略[8]。为了提升CAR-T细胞功能,增强抗肿瘤疗效,目前已开展了多种方法来抵抗CAR-T细胞疗法中PD-1的抑制性作用,如抗PD-1抗体与CAR-T联合应用、CAR-T细胞中表达PD-1显性阴性受体、PD-1/CD28嵌合开关受体,或分泌PD-1阻断单链可变片段(single-chain variable fragment,scFv),以及在CAR-T细胞上PD-1基因敲除等。本文主要就CAR-T与PD-1阻断在实体瘤中临床前及临床中的研究现状进行综述。
1 CAR-T细胞结构与特点
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CAR-T细胞最早构建方案由Gross等[10]提出,他们发现VHCα或VHCβ嵌合链可以与受体T细胞的β或α链形成异源二聚体,从而以非 MHC 限制性的方式激活 T 细胞。随着技术的发展和成熟,CAR-T的结构和功能不断优化,已经发展到第五代,但其主要结构依旧由胞外scFv,跨膜结构域和胞内信号域(CD3ζ,CD28或TNFRSF9)3部分组成[11](图1)。
第1代CAR-T细胞只有单一的CD3ζ ITAM(基于免疫受体酪氨酸的激活基序)活性结构域;第2代CAR-T细胞包含一个共刺激域,来自CD28或4-1BB;第3代CAR-T细胞在第二代的基础上,增加了一个共刺激结构域,具有更强的增殖能力和更长的持久性;第4代CAR-T细胞可以产生IL-2,IL-12,IL-15,能够激活固有免疫,对病毒感染、自身免疫性疾病和代谢紊乱均有效。第5代CAR-T细胞,在CD28和CD247之间添加IL-2RB的JAK-STAT激活域。该结构域可刺激CAR-T细胞增殖,防止CAR-T终末端分化,具有更好的持久性,使CAR-T具有更好的安全性和疗效。
2 CAR-T细胞疗法在实体瘤研究中面临的挑战及现状
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CAR-T细胞结构的优化促进了其在实体肿瘤治疗中的应用。现在越来越多的CAR-T细胞疗法在靶向实体肿瘤的临床试验中进行评估,如胶质母细胞瘤[14]、肺癌[15]、肝癌[16]、胃癌[17]、肾癌[18]、前列腺癌[19]等。然而,治疗结果却不尽如人意。一项基于对CAR-T治疗实体肿瘤疗效的Meta分析,其产生的综合有效率也仅有9%[20]。
CAR-T细胞疗法在实体瘤中疗效受多种因素的影响。第一,实体肿瘤中肿瘤特异性抗原(tumor-specific antigens,TSAs)的缺乏。在目前大多数实体肿瘤中,大多治疗靶点是肿瘤相关抗原(tumor-associated antigens, TAAs),例如,GD2[21],HER2[22],EGFRvIII[23],CEA[24],PSMA[25],mesothelin[26],B7-H3[27]。然而,肿瘤相关抗原的特异性不高,容易引发CAR-T细胞在实体肿瘤治疗中的脱靶效应[28]。Lamers等[29]开展的一项临床试验发现,12例晚期肾细胞癌的患者中有4例因严重的肝损伤而终止实验。这归因于CAIX-CAR-T也靶向表达CAIX的胆管上皮细胞,引起细胞损伤。第二,恶性肿瘤抗原具有高度异质性。对于同一患者,即使在同一部位的肿瘤,甚至在同一肿瘤上的肿瘤细胞也可能表达不相同的肿瘤抗原。此外,肿瘤治疗前后肿瘤抗原的数量或类型也可能不同[30]。传统的CAR-T细胞只针对一种肿瘤表面抗原,从而导致不表达或过表达其他抗原的肿瘤细胞逃逸,最终导致肿瘤复发。因此,肿瘤抗原的异质性增加了实体肿瘤治疗的难度和肿瘤复发的可能性。O'Rourke等[23]在一项靶向EGFRvIII-CAR-T首次人体研究中,外周单次输入CAR-T细胞治疗后,71%胶质母细胞瘤患者EGFRvIII抗原表达水平较治疗前降低,且发生适应性耐药。第三,与血液恶性肿瘤情况不同的是,CAR-T细胞与实体肿瘤细胞之间存在2个主要的屏障(包括实体肿瘤组织中的血管屏障和间质屏障)。在临床上,CAR-T细胞经常通过静脉注射注射到体内。然而,由于输入的CAR-T细胞与实体肿瘤细胞之间存在屏障,只有少量的CAR-T细胞进入实体肿瘤内部,大部分留在外周循环中。Moon等[31]发现抗mesothelin-CAR-T细胞过表达CCR2b后,小鼠中CAR-T细胞向恶性胸膜间皮瘤转移数量增加了12.5倍以上,抗肿瘤作用明显得到改善。第四,肿瘤微环境破坏并抑制了实体肿瘤治疗中CAR-T细胞的活性,导致CAR-T细胞无法有效识别和杀死肿瘤细胞[32]。与天然T细胞相似,浸润在肿瘤组织中的CAR-T细胞被PD-1/PD-L1信号强烈抑制,直接抑制CAR-T细胞效应功能[33]。研究报道显示,抗PD1(α-PD-1)治疗确实可用于增强CAR-T细胞的抗肿瘤活性[34],提示CAR-T联合PD-1阻断可能是一种很有前景的肿瘤免疫治疗策略,可以增强抗肿瘤疗效,扩大治疗范围。
3 CAR-T细胞治疗与阻断PD-1联合应用的原理
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T细胞的表面由许多具有不同类型和功能的分子组成,包括提供激活信号的共刺激分子(CD28,4-1BB)和抑制信号的免疫检查点分子(CTLA-4/PD-1)。与内源性T细胞一样,CAR-T细胞的功能很容易受到实体肿瘤中免疫抑制微环境的影响,如肿瘤细胞上抑制性配体PD-L1/PD-L2的表达[33]。PD-1是T细胞激活后显著表达的一个免疫检查点受体。CAR-T细胞的分化和耗竭表型与其PD-1表达上调相关[35-36]。PD-1:PD-L1/L2通路在抑制T细胞反应和增加T细胞对凋亡的敏感性方面发挥重要作用。因此,肿瘤诱导的T细胞功能下调使用通过免疫检查点抑制剂来逆转,该抑制剂可以阻断PD-1介导的信号级联,并在肿瘤微环境中维持T细胞的激活和功能持久性。Cherkassky等[33]发现,在小鼠胸膜间皮瘤原位模型中,CD28/4-1BB mesothelin特异性靶向的CAR-T细胞上调PD-1和LAG-3后,抗肿瘤效应下降。通过抗PD-1抗体、细胞内在PD-1 shRNA,或PD-1显性阴性受体阻断PD-1的方法,恢复CD28-CAR-T细胞的效应功能。另外,在一项Ⅰ期临床试验中,Gargett等[37]发现在转移性黑色素瘤患者体内,特异性靶向GD2的CAR-T细胞在经抗原反复刺激后,同时上调PD-1和PD-L1,且引发因激活诱发的细胞死亡(activation-induced cell death,AICD),阻断PD-1后,可降低经抗原反复刺激后,CAR-T细胞 AICD 的发生。这些发现证实了CAR-T细胞的衰竭,更类似于慢性病毒感染模型[38],即CAR-T细胞衰竭是由于长期暴露于充满抑制性肿瘤微环境中,反复经抗原刺激的结果。因此,阻断PD-1后,可以有效改善实体瘤中免疫微环境对CAR-T细胞活力的抑制作用。这些发现为人类CAR-T细胞在实体肿瘤中的衰竭提供了机制上的见解,并提示PD-1阻断可能是提高CAR-T细胞治疗效力的有效策略。
4 CAR-T细胞治疗与阻断PD-1在实体瘤中联合应用研究现状
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虽然CAR-T细胞疗法在血液恶性肿瘤中取得了显著的疗效,然而,T细胞扩增受限和持续时间短,仍然是CAR-T细胞治疗后疗效不佳和复发的主要原因之一。Joseph等[39]对患者来源的CAR-T细胞进行全面评估以确定治疗成功和失败的机制。通过基因组、表型和功能评估发现,完全缓解的慢性淋巴细胞白血病(chronic lymphocytic leukemia,CLL)患者的CAR-T细胞有记忆相关基因富集,包括IL-6/STAT3;持续缓解患者体内CD27+CD45RO-CD8+T细胞增加,且这些淋巴细胞具有记忆样特征。而无应答患者,CAR-T细胞上调了与效应细胞分化、糖酵解、耗竭和凋亡相关的通路。PD-L1/PD-1通路能够直接抑制CAR-T细胞中共刺激结构域CD28信号,从而抑制CAR-T细胞的功能[40]。故而,阻断PD-1可能是提高CAR-T细胞在血液恶性肿瘤中治疗疗效的方法之一。一项在宾夕法尼亚儿童医院(Children's Hospital of Pennsylvania, CHOP)开展的小型、单中心研究中,在CD19 CAR-T疗法基础上加用PD-1阻断治疗14例既往接受过多次治疗的B-ALL患儿(13例使用派姆单抗,1例使用纳武利尤单抗),结果发现14例患者中有7例维持了部分缓解(partial response,PR)或完全缓解(complete response,CR)。6例接受PD-1抑制剂治疗的患者中有3例出现修复B细胞再生障碍,提示CAR-T功能仍在继续。1例患者中,在开始使用派姆单抗的几天内,CAR-T细胞显著增殖。该队列显示的初步证据表明,检查点抑制剂可以有效和安全地与CAR-T细胞联合治疗复发的B-ALL儿童,该策略可能增强CAR-T细胞的效果和持久性[41]。因此,阻断PD-1和CAR-T联用在血液恶性肿瘤中取得良好疗效,推动了这种联用方式在实体瘤的研究。目前这种联用方式在已报道的临床前研究主要集中在肺癌、脑胶质瘤及肝癌中(表1);正在进行临床试验的研究主要集中在结直肠癌,脑胶质瘤及卵巢癌(表2)。这种组合方法在实体瘤临床前或临床试验的研究主要是通过外源性(单克隆抗体)和内源性(基因工程)方法阻断PD-1,改善CAR-T细胞的活性(图2)。
4.1 CAR-T细胞治疗与阻断PD-1联合应用方法的临床前研究
4.1.1 外源性方法—与抗PD-1抗体联用
临床前实验结果表明,CAR-T细胞治疗结合抗PD-1单抗可以提高CAR-T细胞活性,促进肿瘤细胞死亡。John等[43]首次发现抗PD-1抗体可以提高CAR-T细胞对HER-2+肿瘤的治疗活性。实验证明,经抗原特异性刺激后,特异性靶向HER-2的 CD8+ CAR-T细胞上的PD-1表达水平显著升高。当加入抗PD-1单抗后,不仅能增强CAR-T细胞的体外增殖能力和功能,引起体内已形成的肿瘤消退,并且在小鼠体内不会引起自身免疫,同时,骨髓源性抑制细胞(MDSCs)在肿瘤微环境中的比例降低。Moon等[44]发现抗NY-ESO-1 T细胞受体工程的T细胞出现严重的功能减退,同时伴有PD-1、TIM-3和LAG-3的表达上调。注射抗PD-1抗体后,可控制肿瘤生长的速率,发挥抗肿瘤效应。
4.1.2 内源性方法—利用基因工程干扰CAR-T细胞中PD-1的表达
抗PD-1抗体的原位分泌:CAR-T细胞可产生PD-1/PD-L1阻断scFvs,阻断与配体结合的区域。Ping等[45]设计了一种能够分泌具有生物活性的α-PD-1 scFv的CAR-T细胞。在皮下和原位异种移植模型中,自分泌α-PD-1 scFv增加CAR-T细胞功能和抑瘤率。Li等[46]研究设计了一种CAR-T细胞分泌靶向PD-1的检查点抑制剂,并评估了它们在肺癌异种移植小鼠模型中的疗效。与未经处理的CAR-T相比,抗PD-1的CAR-T细胞具有更强的可扩展性和更有效的肿瘤消退作用。
PD-1显性阴性受体(dominant negative receptor,DNR) PD-1显性阴性受体(PD-1 DNR)缺乏细胞内信号转导域,作为一个诱骗受体与机体PD-1受体竞争,当遇到PD-L1配体时,可将抑制信号转换为激活信号,消除PD-L1信号对T细胞的抑制。Cherkassky 等[33]证实了CAR-T细胞在体内经抗原反复刺激后,其分泌细胞因子的功能受到抑制。为了直接对抗PD-1对CAR-T介导的抑制作用,他们使用逆转录病毒载体将CAR-T介导的共刺激与PD-1 DNR结合,以竞争PD-1配体。在间皮瘤和肺癌小鼠模型中,CD28 CD19特异性CAR-T细胞与PD-1 DNR共转导后,显著增强了CAR-T细胞活性,抗肿瘤能力增加,肿瘤负荷降低,小鼠生存时间延长。Qin等[47]设计了一种PD-1 DNR( dPD1z)和一种针对PD-L1的CAR载体(CAR-PD-L1z)的CAR-T细胞。dPD1z CAR-T和PD-L1z CAR-T细胞能有效地裂解PD-L1+肿瘤细胞,增强细胞因子的分泌,并显著抑制非小细胞肺癌、胃癌和肝癌患者来源的异种移植瘤(PDX)的生长。
PD-1基因编辑:PD-1基因敲除也是抑制PD-1表达一种有效策略,主要采用CRISPR/Cas9[48]或TALEN[49]等基因编辑技术编辑PDCD1基因组来沉默PD-1的表达。Guo等[50]发现GPC3-CAR-T细胞中PD-1的破坏增强了特异性CAR依赖的细胞毒性功能和细胞因子的分泌,而不影响GPC3-CAR-T细胞的CD4和CD8亚群构成和激活状态。并且增加了GPC3-CAR-T细胞中Akt的活化水平和抗凋亡蛋白Bcl-xL的表达水平。这表明在PD-L1+GPC3+HCC下,干扰PD-1表达可以保护GPC3-CAR T细胞免于衰竭。体内试验也证明,干扰PD-1表达增强了GPC3-CAR-T细胞的体内抗肿瘤疗效、存活率、细胞因子的产生和肿瘤组织中GPC3-CAR-T细胞的浸润。因此,PD-1缺失的CAR-T细胞比野生型CAR-T细胞表现出更强的CAR依赖性抗肿瘤作用。为了克服PD-1对CAR-T细胞的抑制作用,Hu等[51]同样用CRISPR/Cas9核糖核酸蛋白介导的编辑来破坏人原代T细胞的PD-1基因位点,显著减少表达PD-1hi细胞群体占比。这种减少对CAR-T细胞的增殖影响不大,但在体外极大增强了CAR-T细胞细胞因子的产生和对表达PD-L1癌细胞的细胞毒性。并与有无αPD-1抗体阻断的CAR-T细胞相比,PD-1缺失的CAR-T细胞在体内显示出更强的肿瘤杀伤作用和复发预防作用。Ren等[52]也发现CRISPR/Cas9在CAR-T细胞中破坏PD-1后,体外和动物模型中显示出抗肿瘤活性增强,且与非基因编辑的CAR-T细胞相比,其活性并没有发生显著性变化。这些研究说明通过CRISPR/Cas9编辑的PD1-CAR-T细胞治疗效果有显著提高,也说明基因组工程可增强下一代细胞治疗的潜力。
PD-1/CD28嵌合开关:PD-1/CD28嵌合开关受体(chimeric-switch receptor,CSR)通过融合PD-1的胞外结构域和CD28的跨膜结构域和胞内结构域来改善免疫抑制。因此,将PD-1通路的抑制信号转化为CD28的激活信号,发挥抗肿瘤效果。Liu等[53]引入了一种基因工程的“开关”受体结构,将PD-1的细胞外结构域与CD28的跨膜结构域融合引入CAR-T细胞,构建靶向间皮素MSLN和前列腺干细胞抗原PSCA-CAR-T。他们发现,这些PD-1/CD28 CAR-T的抗肿瘤效果优于CAR-T和派姆单抗联用,肿瘤体积显著减小,增强了CAR-T细胞的效应功能和体内持久性。Chen等[54]人将c-Met作为CAR-T的靶点,并在体内外检测了c-Met CAR-T的有效性和安全性。在cMet-PD-1/CD28 CAR-T中优化PD-1/CD28 CSR的结构,发现PD-1/CD28 CSR逆转PD-1免疫抑制,提高cMet CAR-T的疗效,增强了cMet CAR-T在胃癌中的抗肿瘤能力,降低IL-6的释放水平,降低细胞因子释放综合征(CRS)的发生率。
4.2 CAR-T细胞治疗与阻断PD-1联合应用方法的临床试验研究
临床前研究结果推动了CAR-T细胞治疗与阻断PD-1联合应用方法的临床试验研究。在一项CAR-T细胞联合派姆单抗治疗神经母细胞瘤(NB)患者的I期临床研究中,总共纳入11例复发或难治性NB患者。队列1是单独接受CAR-T细胞治疗,队列2是接受CAR-T加环磷酰胺和氟达拉滨(Cy/Flu)治疗,队列3是接受CAR-T、Cy/Flu和PD-1抑制剂(派姆单抗)治疗。Heczey等[55]发现这11例接受了CAR-T细胞治疗的患者,没有发生剂量限制毒性。在队列1中检测到CAR-T,但是Cy/Flu引起的淋巴细胞消耗增加了循环中白细胞介素-15(IL-15)(P=0.003),并使CAR-T体内扩增增加了3个log (P=0.03)。但派姆单抗的加入并没有进一步增强这种积累或持久性。虽然在派姆单抗治疗队列中观察到1例患者完全缓解,但还不能从这一小群患者中得出结论。Prasad等[26]开发了一种mesothelin靶向的CAR-T细胞疗法治疗恶性胸膜疾病(malignant pleural disease,MPM)。在27例患者中,25例MPM胸膜内注射0.3~60 mol·L-1 CAR-T细胞/kg是安全的,并且耐受性良好。并且在39%的患者外周血中检测到CAR-T细胞持续100 d。在这项研究中,MPM患者也接受了派姆单抗联用的治疗方案。结果发现在这些患者中,CAR-T细胞输入后,患者的中位总生存期为23.9个月(1年总生存期,83%)。8例患者病情稳定持续≥6个月;2例PET显像显示代谢完全缓解。综上,CAR-T细胞和PD-1抑制联合疗法应在实体瘤患者中进一步评估。同时,使用内源性方法干扰PD-1表达的安全性和有效性正在研究中,如CAR-T细胞表达PD-1抗体治疗EGFR家族阳性晚期实体瘤[肺、肝、胃癌(NCT02862028)],敲除CAR-T中PD-1基因临床试验也正在研究中(NCT03525782,NCT03706326,NCT03545815和NCT03747965)。虽然目前正在进行的CAR-T细胞治疗与阻断PD-1联合应用的临床试验总共有26项(表2),但CAR-T联合PD-1阻断是否为临床试验的合理策略及其治疗疗效还有待进一步阐明。
5 讨论与展望
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CAR-T在实体肿瘤中的疗效不如在血液恶性肿瘤中的显著,这与实体肿瘤中抑制性免疫微环境有关。免疫抑制通路的存在,特别是PD-1:PD-L1/L2通路的存在,限制了CAR-T细胞的功能和持久性。干扰PD-1是增强CAR-T细胞功能的有效途径。目前干扰PD-1的研究主要有外源性和内源性这两种方法,都可以显著提高CAR-T细胞的功能,但每种方法仍旧存在一些挑战。
在生理条件下,PD-1:PD-L1/L2通路可防止T细胞过度活化,并促进对自身抗原的耐受,以避免自身免疫的发展。内源性方法—阻断PD-1的单克隆抗体,如派姆单抗和尼鲁单抗[56-57],可以恢复耗竭的T细胞功能,并在各种癌症患者中产生强大的抗肿瘤免疫反应,但全身给予免疫检查点通路阻断抗体仍然有破坏免疫稳态的风险,产生独特的免疫相关不良反应,甚至威胁生命。而且,抗PD-1抗体在发挥作用之前,抗体的Fc端结构域被肿瘤相关巨噬细胞捕获;再者,抗体半衰期较短,需要定期和重复给药,增加了患者的经济负担,依从性也较差[55]。
因此,相比于外源性方法,通过基因工程的方法干扰CAR-T细胞中PD-1的表达,不仅可以消除抗PD-1抗体持续给药的需要,而且也是一种相对安全的用药方法。目前内源性方法主要是: CAR-T细胞中表达PD-1显性阴性受体、PD-1或PD-1/CD28嵌合开关受体,或分泌PD-1阻断单链可变片段,以及在CAR-T细胞上敲除PD-1基因等。
CAR-T细胞过表达PD-1显性负性受体(PD-1 DNR),该受体缺乏PD-1跨膜和细胞内信号域,可持续阻断PD-1信号。但是,PD-1 DNR和PD-L1/2结合亲和力会受到限制。而且,Heczey等[58]报道使用单剂量M28z、PD-1、DNR、CAR-T细胞治疗后[55],肿瘤复发。说明除PD-1外,多种共抑制受体(如CTLA-4,TIM-3、LAG3和TIGIT)也在耗竭的T细胞上表达,同时靶向多种抑制途径(如CTLA-4/PD-1阻断剂)可能进一步增强CAR-T细胞的效力。
另外,利用CRISPR/Cas9[59]、TALEN[60]等技术敲除CAR-T细胞上PD-1的表达,消除PD-1/PD-L1引起的免疫抑制,提高CAR-T的疗效。然而,适当表达PD-1可以保护CD8+ T细胞不受过度刺激、过度增殖和终末分化。PD-1的完全缺失可能导致CD8+ T细胞的衰竭。因此,完全敲除PD-1可能会对CAR-T的活性产生不利影响[61]。
因此,在CAR结构中转染可分泌PD-1抗体的基因序列,CAR-T与肿瘤细胞结合时可通过旁分泌或自分泌方式分泌PD-1抗体。CAR-T存活时间不仅更长,而且由于分泌的PD-1可定位在肿瘤附近,可以避免全身应用免疫检查点抑制剂所引起的相关毒性[62-63]。然而,在CAR质粒中加入PD-1抗体基因序列的设计不仅大大增加CAR质粒的长度,也提高CAR-T细胞感染的难度。而且单链抗体分泌的差异最终可能导致不同的临床结果。因此需要更详细的研究来确定CAR-T细胞中自传递α-PD-1单链抗体的最佳形式。
与以上几种方法相比,使用CD28/PD-1 CSR修饰传统CAR-T细胞[63],可将PD-L1抑制信号转化为CD28共刺激信号,保护CAR-T细胞免受PD-L1介导的抑制。然而,由于PD-1转换受体中缺乏CD3结构域,这些CAR-T细胞必须依赖传统CAR对TSA的识别,从而限制了它们对异质性肿瘤的疗效。故而,进一步识别T细胞的特征及优化CAR-T的功能对于修改CAR结构来增加CAR-T细胞疗效至关重要。
综上,CAR-T细胞疗法和阻断PD-1联合治疗确实具有协同作用,可能为癌症患者提供新的希望。然而,通过外源性方法和内源性方法阻断PD-1均存在各自的优劣势,同时这种组合方式可能导致T细胞的过度活化,最终导致毒性增强,如细胞因子释放综合征或神经损伤。因此,CAR-T和阻断PD-1联合治疗必须要综合多种因素,如低应答率,毒性,以及特异性肿瘤相关靶点等,同时需要通过反复的临床前和临床试验来优化,对治疗方案的可行性、安全性和有效性进行详细评估,以期达到最小化毒性和最大化恶性肿瘤患者的治疗效果,也为未来的临床实践提供更合理的免疫治疗药物联用原则。
基金
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  • 国家自然科学基金项目资助(82104318)
  • 江苏省重点研发计划(社会发展)专项资助(BE2021644)
文献
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2024年第59卷第11期
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doi: 10.11669/cpj.2024.11.002
  • 接收时间：2022-03-15
  • 首发时间：2025-11-25
  • 出版时间：2024-06-08
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  • 收稿日期：2022-03-15
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国家自然科学基金项目资助(82104318)
江苏省重点研发计划(社会发展)专项资助(BE2021644)
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    1 苏州大学附属第一医院临床药理实验室,江苏 苏州 215006
    2 苏州大学药物研究与转化交叉研究所, 江苏 苏州 215123

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*缪丽燕,女,博士,主任药师,教授,博士生导师 研究方向:分子影像与临床药理 Tel:(0512) 67972988
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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
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红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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