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Article(id=1248601467758731397, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1248601466106172220, articleNumber=1001-2494(2024)06-0469-07, orderNo=null, doi=null, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1698249600000, receivedDateStr=2023-10-26, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1775619387806, onlineDateStr=2026-04-08, pubDate=1711036800000, pubDateStr=2024-03-22, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1775619387806, onlineIssueDateStr=2026-04-08, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1775619387806, creator=13701087609, updateTime=1775619387806, updator=13701087609, issue=Issue{id=1248601466106172220, tenantId=1146029695717560320, journalId=1190317699101192196, year='2024', volume='59', issue='6', pageStart='469', pageEnd='558', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1775619387412, creator=13701087609, updateTime=1775619937245, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1248603772348420655, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1248601466106172220, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1248603772348420656, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1248601466106172220, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=469, endPage=475, ext={EN=ArticleExt(id=1248601468031361161, articleId=1248601467758731397, tenantId=1146029695717560320, journalId=1190317699101192196, language=EN, title=Advances in Immune Checkpoint Related Drugs and Diseases, columnId=1248601467007947584, journalTitle=Chinese Pharmaceutical Journal, columnName=Original article, runingTitle=null, highlight=null, articleAbstract=

Immune checkpoints (ICs) are the core of immunotherapy. Due to the advantages of strong targeting, long-term efficacy and good patient tolerance, immune checkpoint therapy has become a hot spot for the treatment of some major diseases such as malignant tumors. In this paper, the expression and immune mechanism of immunosuppression receptors and immunostimulatory receptors in recent years are summarized, and list the clinical research data of approved drugs targeting immune checkpoint is listed. It provides reference for future research of immune checkpoint and related drugs.

, correspAuthors=Jun LI, 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=Guoyin YAN, Jun LI), CN=ArticleExt(id=1248601470409531560, articleId=1248601467758731397, tenantId=1146029695717560320, journalId=1190317699101192196, language=CN, title=免疫检查点的相关药物与疾病研究进展, columnId=1196884516783571586, journalTitle=中国药学杂志, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

免疫检查点(immune checkpoints,ICs)是免疫治疗的核心。由于ICs治疗具有靶向性强、长效性、患者耐受性好等优点,成为恶性肿瘤等一些重大疾病的治疗热点。笔者总结了近年来免疫共抑制受体、免疫共刺激受体的表达及免疫机制,列出了已批准上市以ICs为靶点类药物和以ICs为靶点药物临床研究数据。概括了ICs在癌症、病毒感染、自身免疫性疾病治疗中的探索。为以后ICs及相关药物的研究提供参考。

, correspAuthors=李军, authorNote=null, correspAuthorsNote=
*李军,男,博士,副教授 研究方向:药物传递与生物治疗
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严国银,女,硕士研究生 研究方向:药物传递与生物治疗

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严国银,女,硕士研究生 研究方向:药物传递与生物治疗

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严国银,女,硕士研究生 研究方向:药物传递与生物治疗

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Nat Rev Immunol, 2017, 17(8):469-482., articleTitle=The unique immunological and microbial aspects of pregnancy, refAbstract=null), Reference(id=1248653104644772823, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1248601467758731397, doi=null, pmid=null, pmcid=null, year=2022, volume=308, issue=1, pageStart=40, pageEnd=54, url=null, language=null, rfNumber=[52], rfOrder=51, authorNames=ZHAO S J, MUYAYALO K P, LUO J, journalName=Immunol Rev, refType=null, unstructuredReference=ZHAO S J, MUYAYALO K P, LUO J, et al. Next generation of immune checkpoint molecules in maternal-fetal immunity[J]. Immunol Rev, 2022, 308(1):40-54., articleTitle=Next generation of immune checkpoint molecules in maternal-fetal immunity, refAbstract=null), Reference(id=1248653104716075993, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1248601467758731397, doi=null, pmid=null, pmcid=null, year=2019, volume=10, issue=null, pageStart=846, pageEnd=null, url=null, language=null, rfNumber=[53], rfOrder=52, authorNames=MIKO E, MEGGYES M, DOBA K, journalName=Front Immunol, refType=null, unstructuredReference=MIKO E, MEGGYES M, DOBA K, et al. Immune checkpoint molecules in reproductive immunology[J]. Front Immunol, 2019, 10:846. DOI: 10.3389/fimmu.2019.00846., articleTitle=Immune checkpoint molecules in reproductive immunology, refAbstract=null), Reference(id=1248653104787379163, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1248601467758731397, doi=null, pmid=null, pmcid=null, year=2020, volume=50, issue=2, pageStart=160, pageEnd=169, url=null, language=null, rfNumber=[54], rfOrder=53, authorNames=ZHANG Y H, SUN H X, journalName=Eur J Immunol, refType=null, unstructuredReference=ZHANG Y H, SUN H X. Immune checkpoint molecules in pregnancy: focus on regulatory T cells[J]. 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免疫共抑制受体 配体 表达点 机制与功能
程序性死亡受体1(programmed cell death protein 1,PD-1) 程序性死亡配体1(programmed cell death 1 ligand 1,PD-L1) T细胞、B细胞、自然杀伤(NK)细胞、树突状细胞(dendritic cell,DC)、PD-L2 抑制PI3K/AKT通路的激活和转导,抑制T细胞激活[3]
CTLA-4 分化簇80(CD80)、CD86 T细胞 下调辅助T细胞活动;加强调节T细胞(treg)免疫抑制活性[2]
B7-H3 DC 抑制干扰素γ(IFN-γ),白细胞介素2(interleukin-2,IL-2)下调T细胞反应[4]
v-set域包含T细胞激活抑制剂1 (v-set domain-containing T-cell activation inhibitor 1,VTCN1) 在一些实体瘤中高表达 抑制T细胞激活,细胞因子的产生[5]
B/T淋巴细胞弱化因子(B and T lymphocyte attenuator, BTLA) 疱疹病毒侵入介质(herpes virus invasion medium,HVEM) 活化的T细胞、T辅助1细胞 限制γδ T细胞数量和细胞因子分泌,抑制T细胞增殖[6]
CD160 HVEM 功能性NK细胞、T细胞毒性淋巴
细胞		 抑制CD4+T细胞增殖,介导T细胞受体(T cell receptor,TCR)信号转导[7]
淋巴细胞活化基因3(lymphocyte activation gene-3,LAG3) MHC Ⅱ类分子 活化的NK细胞、T淋巴细胞 抑制TCR再刺激后Ca2+通量;激活抗原提呈细胞、淋巴细胞[8]
T细胞免疫球蛋白黏蛋白-3(T cell immunoglobulin mucin 3,TIM-3) 半乳糖凝集素9(galectin-9,LGALS9) 单核细胞、DC、NK细胞 负调控IFN-γ的分泌;介导T细胞信号传导[9]
吲哚胺2,3-双加氧酶1(indoleamine 2,3-dioxygenase 1,IDO1) 淋巴器官成熟树突状细胞 降低响应调节性T细胞附近的色氨酸浓度,抑制T细胞免疫[10]
色氨酸2,3-双加氧酶(tryptophan 2,3 dioxygenase,TDO) 胎盘滋养层树突状细胞 降解色氨酸,抑制T细胞增殖,参与抗菌及炎症反应[11]
v域免疫球蛋白抑制T细胞激活(immunoglobulin suppressor of T cell activation, VISTA) - CD4+和CD8+T细胞、NK细胞 抑制CD4+和CD8+T细胞激活[12]
癌胚抗原相关细胞黏附分子1(carcinoembryonic antigen associated cell adhesion molecule 1,CEACAM1) - 粒细胞、淋巴细胞 参与细胞间黏附和信号介导,抑制B细胞受体介导的增殖[13]
信号调节蛋白α(Signal Regulatory Protein Alpha,SIRPα) CD47 髓系细胞、神经元细胞 介导SIRPα细胞质免疫感受器酪氨酸基序的磷酸化,抑制吞噬[14]
CD244 信号淋巴细胞激活分子家族成员2(signaling lymphocyte activating molecule family members 2,SLAMF2) NK细胞、TCR-γ/δ+ T细胞 增强NK细胞介导的细胞毒性和侵袭能力,诱导IFN-γ分泌[15]
T细胞免疫球蛋白和ITIM结构域蛋白(T cell immunoreceptor with Ig and ITIM Domains,TIGIT) 脊髓灰质炎病毒受体(poliovirus receptor PVR/CD155) 活化的T细胞、调节性T细胞、NK细胞 消除CD226信号传导,导致Treg细胞的基因表达和抑制功能增强[16]
CD96 PVR CD4+T细胞、CD8+T细胞、单核细胞、NK细胞 介导NK细胞对CD155的内化和黏附作用,介导肿瘤的识别和杀伤作用[17]
含免疫球蛋白和富含脯氨酸的受体1(immunoglobulin-containing and proline-rich receptor-1, IGPR-1) B7-H5 幼稚T细胞、DC、单核细胞、B细胞 具有双重免疫功能。在TCR信号传导存在下,抑制或增强T细胞增殖和细胞因子的产生[18]
腺苷A2A受体 腺苷 基底神经节的中型棘状神经元、淋巴样细胞 介导肿瘤微环境中的原发性免疫抑制,降低肿瘤坏死因子水平,导致CD8+T细胞浸润受损[19]
CD200R CD200 活化的T细胞、B细胞 降低髓系细胞活性,降低免疫应答[20]
G蛋白偶联受体65(G protein-coupled receptor 65,GPR65) - NK细胞 影响肿瘤微环境和肿瘤相关巨噬细胞的功能[21]
抑制性白细胞免疫球蛋白样受体(the leukocyte Ig-like receptor subfamily B, LILRB) 免疫球蛋白样转录因子2(ILT2)
免疫球蛋白样转录因子4(ILT4)		 NK细胞、T细胞、B细胞 抑制细胞毒性T细胞,诱导T细胞无能,调节骨髓细胞,促进调节T细胞[22]
v-set免疫球蛋白域蛋白4(v-set immunoglobulin domain protein 4,VSIG4) 巨噬细胞 参与肿瘤相关巨噬细胞复极化和T细胞活化的细胞因子,参与免疫细胞趋化因子的募集[23]
脊髓灰质炎病毒受体相关免疫球蛋白结构域(PVRIG) PVR相关蛋白2(PVRL2) NK细胞、T细胞 抑制活化T细胞的核因子,抑制T细胞和NK细胞对肿瘤细胞的反应强度[24]
唾液酸结合免疫球蛋白样凝集素(Siglecs) 唾液酸聚糖 单核细胞、中性粒细胞 通过蛋白酪氨酸磷酸酶、含src同源2结构域蛋白酪氨酸磷酸酶(SHP 2)的活化参与调节细胞内信号传导,抑制免疫细胞活化[25]
), ArticleFig(id=1248653098458174247, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1248601467758731397, language=CN, label=表1, caption=

免疫共抑制受体表达及免疫机制

, figureFileSmall=null, figureFileBig=null, tableContent=
免疫共抑制受体 配体 表达点 机制与功能
程序性死亡受体1(programmed cell death protein 1,PD-1) 程序性死亡配体1(programmed cell death 1 ligand 1,PD-L1) T细胞、B细胞、自然杀伤(NK)细胞、树突状细胞(dendritic cell,DC)、PD-L2 抑制PI3K/AKT通路的激活和转导,抑制T细胞激活[3]
CTLA-4 分化簇80(CD80)、CD86 T细胞 下调辅助T细胞活动;加强调节T细胞(treg)免疫抑制活性[2]
B7-H3 DC 抑制干扰素γ(IFN-γ),白细胞介素2(interleukin-2,IL-2)下调T细胞反应[4]
v-set域包含T细胞激活抑制剂1 (v-set domain-containing T-cell activation inhibitor 1,VTCN1) 在一些实体瘤中高表达 抑制T细胞激活,细胞因子的产生[5]
B/T淋巴细胞弱化因子(B and T lymphocyte attenuator, BTLA) 疱疹病毒侵入介质(herpes virus invasion medium,HVEM) 活化的T细胞、T辅助1细胞 限制γδ T细胞数量和细胞因子分泌,抑制T细胞增殖[6]
CD160 HVEM 功能性NK细胞、T细胞毒性淋巴
细胞		 抑制CD4+T细胞增殖,介导T细胞受体(T cell receptor,TCR)信号转导[7]
淋巴细胞活化基因3(lymphocyte activation gene-3,LAG3) MHC Ⅱ类分子 活化的NK细胞、T淋巴细胞 抑制TCR再刺激后Ca2+通量;激活抗原提呈细胞、淋巴细胞[8]
T细胞免疫球蛋白黏蛋白-3(T cell immunoglobulin mucin 3,TIM-3) 半乳糖凝集素9(galectin-9,LGALS9) 单核细胞、DC、NK细胞 负调控IFN-γ的分泌;介导T细胞信号传导[9]
吲哚胺2,3-双加氧酶1(indoleamine 2,3-dioxygenase 1,IDO1) 淋巴器官成熟树突状细胞 降低响应调节性T细胞附近的色氨酸浓度,抑制T细胞免疫[10]
色氨酸2,3-双加氧酶(tryptophan 2,3 dioxygenase,TDO) 胎盘滋养层树突状细胞 降解色氨酸,抑制T细胞增殖,参与抗菌及炎症反应[11]
v域免疫球蛋白抑制T细胞激活(immunoglobulin suppressor of T cell activation, VISTA) - CD4+和CD8+T细胞、NK细胞 抑制CD4+和CD8+T细胞激活[12]
癌胚抗原相关细胞黏附分子1(carcinoembryonic antigen associated cell adhesion molecule 1,CEACAM1) - 粒细胞、淋巴细胞 参与细胞间黏附和信号介导,抑制B细胞受体介导的增殖[13]
信号调节蛋白α(Signal Regulatory Protein Alpha,SIRPα) CD47 髓系细胞、神经元细胞 介导SIRPα细胞质免疫感受器酪氨酸基序的磷酸化,抑制吞噬[14]
CD244 信号淋巴细胞激活分子家族成员2(signaling lymphocyte activating molecule family members 2,SLAMF2) NK细胞、TCR-γ/δ+ T细胞 增强NK细胞介导的细胞毒性和侵袭能力,诱导IFN-γ分泌[15]
T细胞免疫球蛋白和ITIM结构域蛋白(T cell immunoreceptor with Ig and ITIM Domains,TIGIT) 脊髓灰质炎病毒受体(poliovirus receptor PVR/CD155) 活化的T细胞、调节性T细胞、NK细胞 消除CD226信号传导,导致Treg细胞的基因表达和抑制功能增强[16]
CD96 PVR CD4+T细胞、CD8+T细胞、单核细胞、NK细胞 介导NK细胞对CD155的内化和黏附作用,介导肿瘤的识别和杀伤作用[17]
含免疫球蛋白和富含脯氨酸的受体1(immunoglobulin-containing and proline-rich receptor-1, IGPR-1) B7-H5 幼稚T细胞、DC、单核细胞、B细胞 具有双重免疫功能。在TCR信号传导存在下,抑制或增强T细胞增殖和细胞因子的产生[18]
腺苷A2A受体 腺苷 基底神经节的中型棘状神经元、淋巴样细胞 介导肿瘤微环境中的原发性免疫抑制,降低肿瘤坏死因子水平,导致CD8+T细胞浸润受损[19]
CD200R CD200 活化的T细胞、B细胞 降低髓系细胞活性,降低免疫应答[20]
G蛋白偶联受体65(G protein-coupled receptor 65,GPR65) - NK细胞 影响肿瘤微环境和肿瘤相关巨噬细胞的功能[21]
抑制性白细胞免疫球蛋白样受体(the leukocyte Ig-like receptor subfamily B, LILRB) 免疫球蛋白样转录因子2(ILT2)
免疫球蛋白样转录因子4(ILT4)		 NK细胞、T细胞、B细胞 抑制细胞毒性T细胞,诱导T细胞无能,调节骨髓细胞,促进调节T细胞[22]
v-set免疫球蛋白域蛋白4(v-set immunoglobulin domain protein 4,VSIG4) 巨噬细胞 参与肿瘤相关巨噬细胞复极化和T细胞活化的细胞因子,参与免疫细胞趋化因子的募集[23]
脊髓灰质炎病毒受体相关免疫球蛋白结构域(PVRIG) PVR相关蛋白2(PVRL2) NK细胞、T细胞 抑制活化T细胞的核因子,抑制T细胞和NK细胞对肿瘤细胞的反应强度[24]
唾液酸结合免疫球蛋白样凝集素(Siglecs) 唾液酸聚糖 单核细胞、中性粒细胞 通过蛋白酪氨酸磷酸酶、含src同源2结构域蛋白酪氨酸磷酸酶(SHP 2)的活化参与调节细胞内信号传导,抑制免疫细胞活化[25]
), ArticleFig(id=1248653098537866026, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1248601467758731397, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
免疫共抑制受体 配体 表达点 机制与功能
CD266 PVR NK细胞、活化的CD4+T细胞 介导细胞黏附,神经分化并触发NK细胞效应器[26]
肿瘤坏死因子受体超家族成员4(tumor necrosis factor receptor superfamily, member 4, TNFRSF4/OX40) 肿瘤坏死因子配体超家族成员4(TNFSF4) 调节性T细胞、NK细胞、DC 上调T细胞的抗凋亡蛋白,以增强T细胞存活率,细胞因子产生,诱导CD4记忆T细胞扩增[27]
TNFRSF5 TNFSF5 单核细胞、DC、巨噬细胞 激活DC,增强抗原对T细胞的呈递,激活T细胞[28]
CD28 CD80、CD86 CD4 T细胞、CD8 T细胞 在T细胞表面交联增强Ca2+、IFN-γ的产生,促进T细胞增殖[29]
TNFRSF18 TNFSF18 效应T淋巴细胞、NK细胞、DC、巨噬细胞 增加TCR诱导的T细胞增殖和细胞因子的产生[30]
TNFRSF7 TNFSF7 T细胞、B细胞、NK细胞 通过核因子κB(nuclear factor kappa-B,NF-κB)途径激活CD8 T细胞;诱导抗凋亡分子和细胞因子受体的上调[31]
TNFRSF9/4-1BB TNFSF9 T细胞、NK细胞、调节性T细胞 激活NF-κB,增加TCR的信号传导,放大CD8 T细胞的细胞毒性[32]
诱导协同刺激分子(inducible T-cell costimulatory,ICOS) ICOSL DC、巨噬细胞、B细胞、T细胞 促进效应Th细胞的分化并增强细胞因子的分泌[33]
TNFRSF14/HVEM TNFSF14 活化的T细胞,NK细胞、未成熟的树突状细胞 介导NF-κB信号传导,产生IFN-γ,导致T细胞活化、增殖[34]
树突状细胞特异的胞间黏附分子-3捕获非整合素(DC-SIGN) 嗜乳脂蛋白2亚型A1(BTN2A1) DC、胎盘巨噬细胞 介导DC黏附、迁移、炎症、激活原代T细胞,触发免疫应答[35]
死亡受体3(death receptors,DR3) 肿瘤坏死因子配体超家族15(TNFSF15) CD4 T细胞、NK细胞 激活NF-κB,与IL-12和IL-18协同作用来增加IFN-γ的产生,调节细胞凋亡[36]
), ArticleFig(id=1248653098638529324, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1248601467758731397, language=CN, label=表2, caption=

免疫共刺激受体表达及免疫机制

, figureFileSmall=null, figureFileBig=null, tableContent=
免疫共抑制受体 配体 表达点 机制与功能
CD266 PVR NK细胞、活化的CD4+T细胞 介导细胞黏附,神经分化并触发NK细胞效应器[26]
肿瘤坏死因子受体超家族成员4(tumor necrosis factor receptor superfamily, member 4, TNFRSF4/OX40) 肿瘤坏死因子配体超家族成员4(TNFSF4) 调节性T细胞、NK细胞、DC 上调T细胞的抗凋亡蛋白,以增强T细胞存活率,细胞因子产生,诱导CD4记忆T细胞扩增[27]
TNFRSF5 TNFSF5 单核细胞、DC、巨噬细胞 激活DC,增强抗原对T细胞的呈递,激活T细胞[28]
CD28 CD80、CD86 CD4 T细胞、CD8 T细胞 在T细胞表面交联增强Ca2+、IFN-γ的产生,促进T细胞增殖[29]
TNFRSF18 TNFSF18 效应T淋巴细胞、NK细胞、DC、巨噬细胞 增加TCR诱导的T细胞增殖和细胞因子的产生[30]
TNFRSF7 TNFSF7 T细胞、B细胞、NK细胞 通过核因子κB(nuclear factor kappa-B,NF-κB)途径激活CD8 T细胞;诱导抗凋亡分子和细胞因子受体的上调[31]
TNFRSF9/4-1BB TNFSF9 T细胞、NK细胞、调节性T细胞 激活NF-κB,增加TCR的信号传导,放大CD8 T细胞的细胞毒性[32]
诱导协同刺激分子(inducible T-cell costimulatory,ICOS) ICOSL DC、巨噬细胞、B细胞、T细胞 促进效应Th细胞的分化并增强细胞因子的分泌[33]
TNFRSF14/HVEM TNFSF14 活化的T细胞,NK细胞、未成熟的树突状细胞 介导NF-κB信号传导,产生IFN-γ,导致T细胞活化、增殖[34]
树突状细胞特异的胞间黏附分子-3捕获非整合素(DC-SIGN) 嗜乳脂蛋白2亚型A1(BTN2A1) DC、胎盘巨噬细胞 介导DC黏附、迁移、炎症、激活原代T细胞,触发免疫应答[35]
死亡受体3(death receptors,DR3) 肿瘤坏死因子配体超家族15(TNFSF15) CD4 T细胞、NK细胞 激活NF-κB,与IL-12和IL-18协同作用来增加IFN-γ的产生,调节细胞凋亡[36]
), ArticleFig(id=1248653098751775536, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1248601467758731397, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
靶点 药物名称(商品名) 获批时间/年 药物状态 适应证
PD-L1 Atezolizuma(Tecentriq) 2016 mAb 血液系统恶性肿瘤、实体瘤
Avelumab(Bavencio) 2017 mAb 转移性默克尔细胞癌
Durvalumab(Imfinzi) 2017 mAb 局部晚期或转移性尿路上皮癌、小细胞肺癌
Sugemalimab(Cejemly) 2021 mAb 非鳞状非小细胞肺癌
Envafolimab 2021 mAb 不可切除或转移性微卫星高度不稳定或错配修复缺陷型成人晚期实体瘤
PD-1 Nivolumab(Opdivo) 2014 mAb 不可切除或转移性黑色素瘤及辅助治疗
Pembrolizumab(Keytruda) 2014 mAb 转移性黑色素瘤
Cemiplimab(Libtayo) 2018 mAb 转移性皮肤鳞状细胞癌、宫颈癌
Dostarlimab(Jemperli) 2021 mAb 治疗错配修复缺陷子宫内膜癌
Cemiplimab-RWLC(LIBTAYO) 2022 mAb 与铂类化疗联合用于晚期非小细胞肺癌(成人患者)
Toripalimab 2018 mAb 既往全身治疗失败的不可切除或转移性黑色素瘤
Sintilimab 2018 mAb 经过二线系统化疗的复发或难治经典型霍奇金淋巴瘤
Camrelizumab(AiRuiKa) 2019 mAb 治疗复发或难治性经典霍奇金淋巴瘤
Tislelizumab 2019 mAb 经系统治疗后不可切除、复发性局部晚期或转移性食管鳞状细胞癌
Prolgolimab(Forteca) 2020 mAb 无法手术切除的或转移性黑色素瘤
Penpulimab 2021 mAb 经典型霍奇金淋巴瘤
Zimberelimab 2021 mAb 治疗复发或难治性经典霍奇金淋巴瘤
Serplulimab 2022 mAb 治疗晚期不可切除或转移性微卫星不稳定性高实体瘤(成人患者)
Retifanlimab-dlwr(Zynyz) 2023 mAb 治疗患有转移性或复发性局部晚期默克尔细胞癌的成人患者
Toripalimab-tpzi(LOqtorzi) 2023 mAb 复发或转移性鼻咽癌含铂治疗后的二线及以上治疗、联用顺铂/吉西他滨一线治疗晚期复发或转移性鼻咽癌
PD-1、LAG-3 Nivolumab/Relatlimab 2022 mAb 转移性黑色素瘤
CTLA-4 Ipilimumab(Yervoy) 2011 mAb 转移性或不可切除的黑色素瘤
Tremelimumab(Imjudo) 2022 mAb 肝细胞癌、非小细胞肺癌
CD80、CD86 Abatacept(Orencia) 2021 可溶性融合蛋白 成人中至重度活动性类风湿关节炎和活动性银屑病关节炎
Belatacept(Nulojix) 2011 可溶性融合蛋白 预防器官排斥反应
CD86 Antithymocyte immunoglobulin (rabbit) 1998 抗胸腺细胞免疫球蛋白 预防肾移植排斥反应
HVEM Etanercept(Enbrel, Eticovo) 2020 融合蛋白 成人中度至重度活动性类风湿关节炎
LAG-3 Relatlimab 2022 mAb 治疗12岁或以上患有不可切除或转移性黑色素瘤的成人和儿童患者
腺苷A2A受体 Regadenoson(Lexiscan) 2008 小分子化合物 用于心肌灌注成像
Defibrotide(Defitelio) 2016 多肽 抗动脉粥样硬化
Theophylline(Elixophyllin) 2003 小分子化合物 慢性哮喘
Mefloquine(Mefloquine) 1989 小分子化合物 预防和治疗由恶性疟原虫和间日疟原虫引起的疟疾
Adenosine(Adenocard) 1989 小分子化合物 室上性心动过速
Lamotrigine(Lamictal) 1994 小分子化合物 癫痫、双相Ⅰ型障碍情绪稳定剂
Istradefylline(Nourianz) 2013 小分子化合物 帕金森
Adenosine Artenimol 2011 小分子化合物 单纯的恶性疟原虫感染
), ArticleFig(id=1248653098839855920, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1248601467758731397, language=CN, label=表3, caption=

已批准上市以ICs为靶点类药物

, figureFileSmall=null, figureFileBig=null, tableContent=
靶点 药物名称(商品名) 获批时间/年 药物状态 适应证
PD-L1 Atezolizuma(Tecentriq) 2016 mAb 血液系统恶性肿瘤、实体瘤
Avelumab(Bavencio) 2017 mAb 转移性默克尔细胞癌
Durvalumab(Imfinzi) 2017 mAb 局部晚期或转移性尿路上皮癌、小细胞肺癌
Sugemalimab(Cejemly) 2021 mAb 非鳞状非小细胞肺癌
Envafolimab 2021 mAb 不可切除或转移性微卫星高度不稳定或错配修复缺陷型成人晚期实体瘤
PD-1 Nivolumab(Opdivo) 2014 mAb 不可切除或转移性黑色素瘤及辅助治疗
Pembrolizumab(Keytruda) 2014 mAb 转移性黑色素瘤
Cemiplimab(Libtayo) 2018 mAb 转移性皮肤鳞状细胞癌、宫颈癌
Dostarlimab(Jemperli) 2021 mAb 治疗错配修复缺陷子宫内膜癌
Cemiplimab-RWLC(LIBTAYO) 2022 mAb 与铂类化疗联合用于晚期非小细胞肺癌(成人患者)
Toripalimab 2018 mAb 既往全身治疗失败的不可切除或转移性黑色素瘤
Sintilimab 2018 mAb 经过二线系统化疗的复发或难治经典型霍奇金淋巴瘤
Camrelizumab(AiRuiKa) 2019 mAb 治疗复发或难治性经典霍奇金淋巴瘤
Tislelizumab 2019 mAb 经系统治疗后不可切除、复发性局部晚期或转移性食管鳞状细胞癌
Prolgolimab(Forteca) 2020 mAb 无法手术切除的或转移性黑色素瘤
Penpulimab 2021 mAb 经典型霍奇金淋巴瘤
Zimberelimab 2021 mAb 治疗复发或难治性经典霍奇金淋巴瘤
Serplulimab 2022 mAb 治疗晚期不可切除或转移性微卫星不稳定性高实体瘤(成人患者)
Retifanlimab-dlwr(Zynyz) 2023 mAb 治疗患有转移性或复发性局部晚期默克尔细胞癌的成人患者
Toripalimab-tpzi(LOqtorzi) 2023 mAb 复发或转移性鼻咽癌含铂治疗后的二线及以上治疗、联用顺铂/吉西他滨一线治疗晚期复发或转移性鼻咽癌
PD-1、LAG-3 Nivolumab/Relatlimab 2022 mAb 转移性黑色素瘤
CTLA-4 Ipilimumab(Yervoy) 2011 mAb 转移性或不可切除的黑色素瘤
Tremelimumab(Imjudo) 2022 mAb 肝细胞癌、非小细胞肺癌
CD80、CD86 Abatacept(Orencia) 2021 可溶性融合蛋白 成人中至重度活动性类风湿关节炎和活动性银屑病关节炎
Belatacept(Nulojix) 2011 可溶性融合蛋白 预防器官排斥反应
CD86 Antithymocyte immunoglobulin (rabbit) 1998 抗胸腺细胞免疫球蛋白 预防肾移植排斥反应
HVEM Etanercept(Enbrel, Eticovo) 2020 融合蛋白 成人中度至重度活动性类风湿关节炎
LAG-3 Relatlimab 2022 mAb 治疗12岁或以上患有不可切除或转移性黑色素瘤的成人和儿童患者
腺苷A2A受体 Regadenoson(Lexiscan) 2008 小分子化合物 用于心肌灌注成像
Defibrotide(Defitelio) 2016 多肽 抗动脉粥样硬化
Theophylline(Elixophyllin) 2003 小分子化合物 慢性哮喘
Mefloquine(Mefloquine) 1989 小分子化合物 预防和治疗由恶性疟原虫和间日疟原虫引起的疟疾
Adenosine(Adenocard) 1989 小分子化合物 室上性心动过速
Lamotrigine(Lamictal) 1994 小分子化合物 癫痫、双相Ⅰ型障碍情绪稳定剂
Istradefylline(Nourianz) 2013 小分子化合物 帕金森
Adenosine Artenimol 2011 小分子化合物 单纯的恶性疟原虫感染
), ArticleFig(id=1248653098978267957, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1248601467758731397, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
靶点 药物名称 研究进展 药物状态 适应证
PD-L1 Envafolimab Ⅲ期 mAb 非小细胞肺癌
Cosibelimab Ⅲ期 mAb 转移性非鳞状非小细胞肺癌
CA-170 Ⅰ期 小分子化合物 晚期实体瘤
Anti-OX40 antibody BMS 986178 Ⅱ期 大环肽 小淋巴细胞淋巴瘤
PD-1 CT-011 Ⅱ期 mAb 弥漫大细胞弥漫/淋巴瘤
Spartalizumab Ⅲ期 mAb 复发或转移性鼻咽癌
Camrelizumab Ⅳ期 mAb 呼吸道肿瘤、胸部肿瘤
Sintilimab Ⅳ期 mAb 胃腺癌、已经手术切除的肢端黑色素瘤
Tislelizumab Ⅳ期 mAb B细胞恶性肿瘤
Toripalimab Ⅲ期 mAb 复发或转移性鼻咽癌
Retifanlimab Ⅲ期 mAb 转移性非小细胞肺癌、胰腺腺癌
AMP-224 Ⅰ期 mAb 结直肠癌
MEDI0680 Ⅱ期 mAb 肾癌、选择性恶性肿瘤
Budigalimab Ⅱ期 mAb 胰腺癌、艾滋病、肝癌
Geptanolimab Ⅱ期 mAb 肺泡软部分肉瘤、宫颈癌
CTLA-4 Tremelimumab Ⅲ期 mAb 间皮瘤、肝细胞癌、恶性黑色素瘤
CD86 Bryostatin 1 Ⅱ期 小分子化合物 艾滋病感染、阿尔茨海默病
CD80 Galiximab Ⅲ期 嵌合单克隆抗体 恶性淋巴瘤
CD276 Omburtamab Ⅲ期 mAb 放射免疫治疗神经母细胞瘤
Galectin-9 (R)-1-Para-nitro-phenyl-2-azido-ethanol 调查研究 小分子化合物 暂无数据
IDO Medical Cannabis Ⅳ期 小分子化合物 在慢性疼痛、癫痫、化疗引起的恶心和呕吐的治疗
Nabiximols Ⅳ期 小分子化合物 多发性硬化症
CEACAM1 TechnetiumTc-99m arcitumomab 调查研究 mAb 用于结直肠肿瘤的成像
PVR Myristic acid 调查研究 小分子化合物 暂无数据
Sphingosine Ⅰ期 小分子化合物 胰腺恶性肿瘤
CD40L Ruplizumab Ⅱ期 mAb 狼疮性肾炎、移植排斥
CD40 Lucatumumab Ⅱ期 拮抗剂抗体 多发性骨髓瘤
Dacetuzumab Ⅱ期 mAb 多发性骨髓瘤、白血病
CD276 Omburtamab Ⅲ期 mAb 结缔组织增生小圆细胞瘤、恶性腹膜肿瘤
CD70 Cusatuzumab Ⅱ期 mAb 血液系统恶性肿瘤、急性髓系白血病
4-1BBL Urelumab Ⅱ期 mAb 黑素瘤、胰腺恶性肿瘤
Adenosine A2A receptor Binodenoson Ⅲ期 小分子化合物 冠状动脉疾病
Atl146e Ⅲ期 小分子化合物 冠状动脉疾病
Apadenoson Ⅲ期 小分子化合物 心血管疾病
Theobromine Ⅲ期 小分子化合物 急性气管支气管炎
Enprofylline Ⅱ期 小分子化合物 哮喘、慢性阻塞性肺病
Doxofylline Ⅳ期 小分子化合物 哮喘
8-Chlorotheophylline 调查研究 小分子化合物 预防和治疗晕动病的恶心、呕吐或眩晕
KW-6356 Ⅱ期 小分子化合物 帕金森
TNFRSF5 Lucatumumab Ⅰ期 mAb 淋巴瘤
TNFRSF9 Dacetuzumab Ⅱ期 mAb 弥漫大B细胞淋巴瘤
Urelumab Ⅱ期 mAb 膀胱癌、黑色素瘤
), ArticleFig(id=1248653099099902777, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1248601467758731397, language=CN, label=表4, caption=

以ICs为靶点药物临床研究数据

, figureFileSmall=null, figureFileBig=null, tableContent=
靶点 药物名称 研究进展 药物状态 适应证
PD-L1 Envafolimab Ⅲ期 mAb 非小细胞肺癌
Cosibelimab Ⅲ期 mAb 转移性非鳞状非小细胞肺癌
CA-170 Ⅰ期 小分子化合物 晚期实体瘤
Anti-OX40 antibody BMS 986178 Ⅱ期 大环肽 小淋巴细胞淋巴瘤
PD-1 CT-011 Ⅱ期 mAb 弥漫大细胞弥漫/淋巴瘤
Spartalizumab Ⅲ期 mAb 复发或转移性鼻咽癌
Camrelizumab Ⅳ期 mAb 呼吸道肿瘤、胸部肿瘤
Sintilimab Ⅳ期 mAb 胃腺癌、已经手术切除的肢端黑色素瘤
Tislelizumab Ⅳ期 mAb B细胞恶性肿瘤
Toripalimab Ⅲ期 mAb 复发或转移性鼻咽癌
Retifanlimab Ⅲ期 mAb 转移性非小细胞肺癌、胰腺腺癌
AMP-224 Ⅰ期 mAb 结直肠癌
MEDI0680 Ⅱ期 mAb 肾癌、选择性恶性肿瘤
Budigalimab Ⅱ期 mAb 胰腺癌、艾滋病、肝癌
Geptanolimab Ⅱ期 mAb 肺泡软部分肉瘤、宫颈癌
CTLA-4 Tremelimumab Ⅲ期 mAb 间皮瘤、肝细胞癌、恶性黑色素瘤
CD86 Bryostatin 1 Ⅱ期 小分子化合物 艾滋病感染、阿尔茨海默病
CD80 Galiximab Ⅲ期 嵌合单克隆抗体 恶性淋巴瘤
CD276 Omburtamab Ⅲ期 mAb 放射免疫治疗神经母细胞瘤
Galectin-9 (R)-1-Para-nitro-phenyl-2-azido-ethanol 调查研究 小分子化合物 暂无数据
IDO Medical Cannabis Ⅳ期 小分子化合物 在慢性疼痛、癫痫、化疗引起的恶心和呕吐的治疗
Nabiximols Ⅳ期 小分子化合物 多发性硬化症
CEACAM1 TechnetiumTc-99m arcitumomab 调查研究 mAb 用于结直肠肿瘤的成像
PVR Myristic acid 调查研究 小分子化合物 暂无数据
Sphingosine Ⅰ期 小分子化合物 胰腺恶性肿瘤
CD40L Ruplizumab Ⅱ期 mAb 狼疮性肾炎、移植排斥
CD40 Lucatumumab Ⅱ期 拮抗剂抗体 多发性骨髓瘤
Dacetuzumab Ⅱ期 mAb 多发性骨髓瘤、白血病
CD276 Omburtamab Ⅲ期 mAb 结缔组织增生小圆细胞瘤、恶性腹膜肿瘤
CD70 Cusatuzumab Ⅱ期 mAb 血液系统恶性肿瘤、急性髓系白血病
4-1BBL Urelumab Ⅱ期 mAb 黑素瘤、胰腺恶性肿瘤
Adenosine A2A receptor Binodenoson Ⅲ期 小分子化合物 冠状动脉疾病
Atl146e Ⅲ期 小分子化合物 冠状动脉疾病
Apadenoson Ⅲ期 小分子化合物 心血管疾病
Theobromine Ⅲ期 小分子化合物 急性气管支气管炎
Enprofylline Ⅱ期 小分子化合物 哮喘、慢性阻塞性肺病
Doxofylline Ⅳ期 小分子化合物 哮喘
8-Chlorotheophylline 调查研究 小分子化合物 预防和治疗晕动病的恶心、呕吐或眩晕
KW-6356 Ⅱ期 小分子化合物 帕金森
TNFRSF5 Lucatumumab Ⅰ期 mAb 淋巴瘤
TNFRSF9 Dacetuzumab Ⅱ期 mAb 弥漫大B细胞淋巴瘤
Urelumab Ⅱ期 mAb 膀胱癌、黑色素瘤
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免疫检查点的相关药物与疾病研究进展
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严国银 , 李军 *
中国药学杂志 | 研究论文 2024,59(6): 469-475
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中国药学杂志 | 研究论文 2024, 59(6): 469-475
免疫检查点的相关药物与疾病研究进展
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严国银, 李军*
作者信息
  • 海南大学药学院, 热带生物资源教育部重点实验室, 海口 570228

    • 严国银,女,硕士研究生 研究方向:药物传递与生物治疗

通讯作者:

*李军,男,博士,副教授 研究方向:药物传递与生物治疗
Advances in Immune Checkpoint Related Drugs and Diseases
Guoyin YAN, Jun LI*
Affiliations
  • Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmacy, Hainan University, Haikou 570228, China
出版时间: 2024-03-22
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摘要
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免疫检查点(immune checkpoints,ICs)是免疫治疗的核心。由于ICs治疗具有靶向性强、长效性、患者耐受性好等优点,成为恶性肿瘤等一些重大疾病的治疗热点。笔者总结了近年来免疫共抑制受体、免疫共刺激受体的表达及免疫机制,列出了已批准上市以ICs为靶点类药物和以ICs为靶点药物临床研究数据。概括了ICs在癌症、病毒感染、自身免疫性疾病治疗中的探索。为以后ICs及相关药物的研究提供参考。

免疫检查点  /  靶点药物  /  免疫相关不良事件

Immune checkpoints (ICs) are the core of immunotherapy. Due to the advantages of strong targeting, long-term efficacy and good patient tolerance, immune checkpoint therapy has become a hot spot for the treatment of some major diseases such as malignant tumors. In this paper, the expression and immune mechanism of immunosuppression receptors and immunostimulatory receptors in recent years are summarized, and list the clinical research data of approved drugs targeting immune checkpoint is listed. It provides reference for future research of immune checkpoint and related drugs.

immune checkpoint  /  target drug  /  immune-related adverse event
严国银, 李军. 免疫检查点的相关药物与疾病研究进展. 中国药学杂志, 2024 , 59 (6) : 469 -475 .
Guoyin YAN, Jun LI. Advances in Immune Checkpoint Related Drugs and Diseases[J]. Chinese Pharmaceutical Journal, 2024 , 59 (6) : 469 -475 .
正文
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随着免疫治疗的兴起,免疫检查点(immune checkpoints,ICs)也受到广泛关注。ICs对于维持免疫稳态至关重要,越来越多的ICs被人们探索用于肿瘤等疾病的治疗中。在一些肿瘤的治疗中,可以使用ICs系统来逃避抗肿瘤免疫反应。尽管如此,基于ICs的疗法在临床实践仍存在许多问题,如自身免疫相关不良反应、耐药及反应延迟等。因此,对于ICs的免疫机制、ICs的新靶点需要更多、更深入地研究。
1 ICs及配体免疫机制与功能
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ICs是一种免疫信号,可以调节免疫反应,避免外来物质对正常组织的破坏,在维持自身抗原耐受性的过程中发挥作用。T细胞的活化需要2个关键信号,见图1。第一个信号通过主要组织相容性复合物分子抗原(major histocompatibility complex, MHC)呈递给T细胞;第二个信号通过T细胞表面的受体与抗原呈递细胞(antigen-presenting cells, APC)表面的配体结合来传递[1]。受体和配体的复合物被称为ICs。一旦形成受体和配体复合物,就会传递抑制或刺激T细胞激活的信号。第一个ICs细胞毒T淋巴细胞相关抗原4(cytotoxic T lymphocyte-associated antigen-4, CTLA-4)被证实可抑制T细胞反应并可增强抗肿瘤免疫作用和肿瘤排斥,开创了ICs治疗的先河[2]。随后许多其他免疫共抑制和免疫共刺激检查点及其靶点通路被发现(表1~2)。这些ICs受体及其配体的表达在不同的组织、细胞类型和细胞亚群中,表达水平也有明显的差异。除T细胞外,ICs分子还参与调节自然杀伤(natural killer,NK)细胞、先天淋巴细胞和髓系细胞的免疫反应。
2 ICs药物研究概况
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2.1 ICs药物使用概况
由于ICs治疗具有选择性好、长效、患者耐受性好的优点,免疫性治疗被广泛探索。Liang等[37]使用美国临床肿瘤学会价值框架(ASCO-VF)和欧洲治疗实体癌的药物的临床获益量表(ESMO-MCBS)评估ICs抑制剂的临床益处,发现ICs抑制剂的临床益处似乎比其他批准的癌症药物更大。
针对ICs疗法的工作机制大致可分为3类:一是增强ICs原本的免疫作用,这一类以重组蛋白质、单克隆抗体、核酸和工程细胞的形式存在;二是耗尽表达ICs免疫细胞受体,即一些ICs受体可以用作自身免疫疾病中致病性免疫细胞的生物标志物;三是联合使用ICs药物[38]。根据Drug bank数据库统计显示(表3~4),关于ICs药物研究主要是癌症、免疫排斥、类风湿性关节炎及病毒感染等免疫性疾病,目前获批临床的ICs主要集中在非小细胞肺癌、肝癌、霍奇金淋巴瘤中。主要研究的靶点还是PD-1与PD-L1。在国内2022版的《CSCO免疫检查点抑制剂临床应用指南》中涉及了11个ICs抑制剂关于18个瘤种的治疗方案。尽管这些药物显著改善了许多癌症患者的预后,但也有研究表明,大部分患者对ICs阻断剂的反应仅限于特定类型小部分患者,对于PD-1与PD-L1的相关药物反应率很少超过40%[39]。同时由于大多数为单克隆抗体,药动学/药效学可能是高度可变的,其作用机制依赖于与动态免疫系统的接触。抗体治疗还需要高剂量和有创给药。具有免疫原性,不稳定、不易储存和运输等缺点[40]。所以除了免疫单药之外,为提高免疫治疗的疗效,免疫联合治疗策略也在不断丰富。包括免疫联合抗血管生成、双免疫联合治疗等。
2.2 ICs药物不良反应与防治
虽然抑制检查点受体可增强细胞毒性T细胞的抗肿瘤免疫活性,但这些药物也可能会增加自身免疫反应。包括ICs相关的肺炎、ICs相关内分泌疾病、ICs相关心脏毒性及ICs相关的其他疾病[41]。免疫相关不良事件(immune-related adverse reactions, irAEs)一般是器官特异性的,而不是同时涉及患者的多个器官,毒性发作经常延迟。联合用药也会增加irAEs的发生率、严重程度。irAEs的频率还取决于所使用的药物、暴露时间和给药剂量、患者的内在危险因素。由于该反应的迟发性可能会对患者造成永久性损害,irAEs在辅助治疗中具有挑战性。对于irAEs的治疗应参考特定毒性的专门指南,尤其是重度和一些难治性irAEs。除少数例外情况外,应继续密切监测1级毒性,而2级毒性需要停药,对于高级别毒性,应永久停药[42]。随着ICs的使用越来越普遍,一些少见的irAEs的数量也会增加,因此怀疑和鉴别诊断对于治疗和量身定制的管理策略至关重要[43]。
3 ICs在疾病中的研究
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ICs是维持自我耐受和进行抗原特异性免疫反应的关键调控机制。对免疫反应进行调节,可以有效清除侵入的病原体,同时保持对自身抗原的耐受性。现在ICs已经被广泛探索治疗自身免疫性疾病和各种形式的癌症中。
3.1 ICs在癌症中的研究
目前,关于ICs的药物研究在癌症的治疗还是最多的。与传统的单纯化疗或放疗严重的不良反应相比,ICs治疗具有选择性好、长效、患者耐受性好的优点[43]。近年来,癌症疫苗、过继细胞转移方案、ICs治疗在几种癌症的临床治疗中都显示出不同程度的成功。ICs及它们的配体在肿瘤微环境中上调,可以负向调节T细胞参与针对特定抗原的生理免疫反应的激活途径,使ICs治疗具有相应的靶向性[44]。如对于恶性癌症的治疗,其中效果明显的是目前上市的PD-1、CTLA-4两类ICs阻断剂,它们可有效针对一些实体瘤如黑色素瘤的治疗。通过蛋白激酶B和细胞外调节蛋白激酶等信号通路诱导效应T细胞凋亡,恢复抗肿瘤免疫,逆转免疫逃逸,促进肿瘤细胞死亡[45]。除了已上市的关于CTLA-4、PD-1与PD-L1的抗体,还有许多的其他靶点的抗体在研究中。同时许多临床前模型和临床试验也正在评估ICs作为单一或联合疗法治疗各种恶性肿瘤的疗效。越来越多的联合治疗在提高治疗疗效的同时,也可能加重irAEs[46]。
3.2 ICs在病毒感染性疾病中的研究
除了癌症的免疫监视外,免疫系统的主要功能是防御感染因子,如病毒、细菌和真菌等。在慢性病毒感染中,病毒通过免疫系统逃避消除,并通过调节或调节宿主免疫反应建立持续感染[47]。病毒特异性CD8+ T细胞在感染初期部分抑制艾滋病毒(human immunodeficiency virus,HIV)的复制,随着病毒抗原水平的持续升高,HIV特异性T细胞逐渐耗尽,失去有效杀死被感染细胞的能力。HIV感染期间强烈的促炎免疫激活以及感染期间T细胞亚群失衡都导致了T细胞的衰竭[48]。有效的HIV疗法需在抗逆转录病毒疗法(anti-retroviral therapy, ART)期间诱导功能性CD8+T细胞并清除潜伏的病毒。有研究表明,通过PD-1和CTLA-4等共抑制性分子可作为低水平HIV/猴免疫缺陷病毒(simian immunodeficiency virus, SIV)病毒复制的生物标志物,促进潜伏感染和破坏HIV特异性T细胞的细胞毒性功能[49]。PD-1/PD-L1通路阻断可恢复HIV特异性CD4+和CD8+ T细胞功能,提示该通路在持续的病毒感染中起作用。与PD-1相似,有研究发现CTLA-4在驱使HIV特异性T细胞衰竭方面发挥重要作用[50]。但单独使用ICs阻断剂并不能显著提高T细胞反应。ICs可以作为潜在的协同治疗艾滋病病毒的联合药物,可以将HIV疫苗与ICs结合起来可以提高CD8+T细胞在其他感染的功能,对于治疗HIV是一种有效的策略,但只是局限于体外实验,对于应用至临床实践中还需更加深入地探索研究。在病毒感染中实现成功的免疫治疗,需解决病毒特异性免疫反应被大量的抗原病毒载量强烈抑制或沉默的问题[47]。
3.3 ICs在妊娠并发症中的研究
妊娠具有主动免疫耐受的模式。在妊娠的胚胎着床、胎盘、胎儿发育及分娩等多个阶段需要不同的免疫环境[51]。母体-胎儿耐受性建立不足会导致早期妊娠失败,例如反复妊娠流产,妊娠中晚期的并发症,如早产和子痫前期,严重危害母婴健康[52]。通过促进母胎耐受性和胎儿发育,在整个妊娠期间存在Treg细胞。Treg群体是异质的,它表达不同的ICs分子,有利于免疫抑制功能[53]。这些分子的缺失或失调可能会干扰母体与胎儿之间的免疫平衡,进而导致妊娠丢失或其他妊娠并发症的发生。CTLA-4,PD-1,TIM-3,LAG-3,TIGIT和HLA-G的ICs在母体免疫应答中的参与和作用已通过动物实验证明对于先兆子痫、Treg缺乏和病理性妊娠是潜在的治疗靶点,这些ICs通路在母胎耐受建立和维持中发挥积极作用,促进正常妊娠。同时抗CTLA-4 (ipilimumab) 、抗PD-1药物 (Nivolumab、Pembrolizumab和Cemiplimab) 和抗PD-L1药物 (Atezolizumab、Avelumab、和Durvalumab) 不仅已被批准用于多种固体和血液系统的恶性肿瘤,同时它们还参与母体与胎儿免疫中,调节母体与胎儿蜕膜免疫和血管重塑。多种负共刺激分子及其配体的表达在母体-胎儿界面也具有阶段变化,并且它们的异常表达与多种妊娠相关疾病有关[22,54]。在妊娠并发症的免疫治疗策略中,ICs的上调可能起作用。但生殖免疫学领域对ICs负调节因子的研究还十分缺乏,亟待开展。
4 结语
收起
现在大部分关于ICs的药物研究都集中于癌症、自身免疫性疾病、病毒感染等疾病。单一药物的疗效并不显著,为提高ICs的治疗疗效,许多临床前模型和临床试验也正在评估ICs作为联合疗法治疗各种恶性肿瘤的疗效。这些策略包括针对多种ICs的联合治疗,包括PD-1、CTLA-4、TIM-3和LAG-3,这些ICs通常在免疫细胞上共同表达;联合用药如多种ICs抑制剂/激活剂;联合细胞毒性药物、抗癌疫苗、细胞因子、常规化疗药物、放疗等。基于ICs对于癌症、病毒感染等疾病的治疗仍有很长的路,但如何选择最合适的检查点抑制剂或激活特定的肿瘤类型、优化组合治疗、寻找新的有效的ICs,开发新靶点ICs药物,提高治疗率,扩大临床适应证、irAEs的防治仍然是目前面临的问题。为提高下一代靶向ICs药物的疗效,有必要拓宽我们对ICs所触发的信号传导和分子途径的理解,探索更多的ICs联合治疗方式同时还应对ICs的反应/耐药性的复杂性进行更深入的了解,对可能产生的irAEs及时地进行预防、评估、治疗、监测。
基金
收起
  • 国家自然科学基金项目资助(31560261)
  • 海南省重点研发项目资助(ZDYF2020155)
  • 中国药学会-以岭生物医药创新基金项目资助(CPAYLJ201902)
  • 海南省自然科学基金项目资助(818MS039)
文献
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2024年第59卷第6期
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  • 接收时间：2023-10-26
  • 首发时间：2026-04-08
  • 出版时间：2024-03-22
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  • 收稿日期：2023-10-26
基金
国家自然科学基金项目资助(31560261)
海南省重点研发项目资助(ZDYF2020155)
中国药学会-以岭生物医药创新基金项目资助(CPAYLJ201902)
海南省自然科学基金项目资助(818MS039)
作者信息
    海南大学药学院, 热带生物资源教育部重点实验室, 海口 570228

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*李军,男,博士,副教授 研究方向:药物传递与生物治疗
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