免疫检查点抑制剂的联合治疗在胰腺癌中的研究进展

doi:10.11904/j.issn.1002-3070.2022.01.009

摘要/Abstract

摘要： 胰腺癌的恶性程度极高,发现时通常已至晚期,中位生存时间极短,严重威胁人类生命健康。并且与其他癌种相比,近些年取得的治疗进展也十分有限。免疫检查点抑制剂(Immune checkpoint inhibitors,ICIs)作为近几年的新兴药物已在多个肿瘤中获得了令人振奋的治疗效果,但是在胰腺癌中却遭遇了滑铁卢。胰腺癌对ICIs治疗不敏感的原因可能包括以下几个方面:一是胰腺癌抗原性弱,不足以激活免疫系统;二是免疫微环境中致密的结缔组织阻碍药物浸润;三是大量免疫抑制细胞构成的免疫抑制微环境,抑制T淋巴细胞活化等。但最新的研究表明以ICIs为基础的联合治疗方案能够通过增加肿瘤抗原的暴露,打破间质屏障及改善免疫抑制微环境等方法增加胰腺癌对ICIs治疗的敏感性,从而发挥积极的抗肿瘤作用。本文将以ICIs为基础的联合治疗方案在胰腺癌治疗领域所取得的进展进行综述。

关键词: 胰腺癌, 免疫检查点抑制剂, 联合治疗

Abstract: Pancreatic cancer is extremely malignant.It is usually in the advanced stage when discovered,and the median survival time is extremely short,which seriously threatens human life and health.Compared with other cancers,the treatment progress made in recent years is also very limited.Immune checkpoint inhibitors(ICIs),as emerging drugs in recent years,have achieved exciting therapeutic effects in multiple tumors,but they have encountered Waterloo in pancreatic cancer.The reasons why pancreatic cancer is not sensitive to ICIs treatment may include the following aspects:first,pancreatic cancer is weak antigenic and insufficient to activate the immune system;second,the dense connective tissue in the immune microenvironment hinders drug infiltration;third,the immunosuppressive microenvironment formed by a large number of immunosuppressive cells inhibits the activation of T lymphocytes.However,the latest research shows that ICIs-based combination therapy can increase the sensitivity of pancreatic cancer to ICIs treatment by increasing the exposure of tumor antigens,breaking the interstitial barrier,and improving the immunosuppressive microenvironment,thereby exerting a positive anti-tumor effect.This article reviews the progress made in the field of pancreatic cancer treatment based on ICIs-based combination therapy.

Key words: Pancreatic cancer, Immune checkpoint inhibitors, Combination therapy

中图分类号:

R735.9

刘金爽, 张文静, 黎清炜, 李志伟. 免疫检查点抑制剂的联合治疗在胰腺癌中的研究进展[J]. 实用肿瘤学杂志, 2022, 36(1): 49-53.

LIU Jinshuang, ZHAGN Wenjing, LI Qingwei, LI Zhiwei. Research progress of therapies combined immune checkpoint inhibitors in pancreatic cancer[J]. Journal of Practical Oncology, 2022, 36(1): 49-53.

参考文献

1 Sung H,Ferlay J,Siegel RL,et al.Global cancer statistics 2020:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J].CA Cancer J Clin,2021,71(3):209-249.
2 Klebanoff CA,Gattinoni L,Restifo NP.CD8⁺T-cell memory in tumor immunology and immunotherapy[J].Immunol Rev,2006,211(1):214-224.
3 Aldarouish M,Wang C.Trends and advances in tumor immunology and lung cancer immunotherapy[J].J Exp Clin Cancer Res,2016,35(1):157.
4 Dany M,Nganga R,Chidiac A,et al.Advances in immunotherapy for melanoma management[J].Hum Vaccin Immunother,2016,12(10):2501-2511.
5 Luchini C,Bibeau F,Ligtenberg MJL,et al.ESMO recommendations on microsatellite instability testing for immunotherapy in cancer,and its relationship with PD-1/PD-L1 expression and tumour mutational burden:a systematic review-based approach[J].Ann Oncol,2019,30(8):1232-1243.
6 Clark CE,Hingorani SR,Mick R,et al.Dynamics of the immune reaction to pancreatic cancer from inception to invasion[J].Cancer Res,2007,67(19):9518-9527.
7 Steimle V,Siegrist CA,Mottet A,et al.Regulation of MHC class II expression by interferon-gamma mediated by the transactivator gene CIITA[J].Science,1994,265:106-109.
8 Knudsen ES,Vail P,Balaji U,et al.Stratification of pancreatic ductal adenocarcinoma:combinatorial genetic,stromal,and immunologic markers[J].Clin Cancer Res,2017,23:4429-4440.
9 Sideras K,Braat H,Kwekkeboom J,et al.Role of the immune system in pancreatic cancer progression and immune modulating treatment strategies[J].Cancer Treat Rev,2014,40(4):513-522.
10 Reits EA,Hodge JW,Herberts CA,et al.Radiation modulates the peptide repertoire,enhances MHC class I expression,and induces successful antitumor immunotherapy[J].J Exp Med,2006,203(4):1259-1271.
11 Xie C,Duffy AG,Brar G,et al.Correction:Immune checkpoint blockade in Combination with stereotactic body radiotherapy in patients with metastatic pancreatic ductal adenocarcinoma[J].Clin Cancer Res,2021,27(1):358-358.
12 Aglietta M,Barone C,Sawyer MB,et al.A phase I dose escalation trial of tremelimumab(CP-675,206)in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer[J].Ann Oncol,2014,25(9):1750-1755.
13 Wainberg ZA,Hochster HS,George B,et al.Phase I study of nivolumab(nivo)+ nab-paclitaxel(nab-P)± gemcitabine(Gem)in solid tumors:Interim results from the pancreatic cancer(PC)cohorts[J].Clin Oncol,2017,35:412.
14 Weiss GJ,Blaydorn L,Beck J,et al.Phase Ib/II study of gemcitabine,nab-paclitaxel,and pembrolizumab in metastatic pancreatic adenocarcinoma[J].Invest New Drugs,2018,36:96-102.
15 Soares KC,Rucki AA,Wu AA,et al.PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors[J].J Immunother,2015,38(1):1-11.
16 Le DT,Lutz E,Uram JN,et al.Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer[J].J Immunother,2013,36(7):382-389.
17 Ady JW,Heffner J,Klein E,et al.Oncolytic viral therapy for pancreatic cancer:current research and future directions[J].Oncolytic Virother,2014,3:35-46.
18 Noonan AM,Farren MR,Geyer SM,et al.Randomized phase 2 trial of the oncolytic virus Pelareorep(Reolysin)in upfront treatment of metastatic pancreatic adenocarcinoma[J].Mol Ther,2016,24:1150-1158.
19 Kazerounian S,Lawler J.Integration of pro-and anti-angiogenic signals by endothelial cells[J].J Cell Commun Signal,2018,12(1):171-179.
20 Teh J,Narasimhan V,Schultz S,et al.Re:pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma[J].Eur Urol,2019,76:126-127.
21 Llovet J,Shepard KV,Finn RS,et al.A phase Ib trial of lenvatinib(LEN)plus pembrolizumab(PEMBRO)in unresectable hepatocellular carcinoma(uHCC):Updated results[J].Ann Oncol,2019,30(Suppl 5):286-287.
22 Wang J,Zhang Z,Zhang F,et al.Efficacy and safety of anti-PD-1 antibody SHR-1210 combined with apatinib in first-line treatment for advanced lung squamous carcinoma:a phase II study[J].Ann Oncol,2019,30(Supplement 9):171.
23 Chen M,Yang S,Fan L,et al.Combined antiangiogenic therapy and immunotherapy is effective for pancreatic cancer with mismatch repair proficiency but high tumor mutation burden:a case report[J].Pancreas,2019,48(9):1232-1236.
24 Sharma NS,Gupta VK,Garrido VT,et al.Targeting tumor-intrinsic hexosamine biosynthesis sensitizes pancreatic cancer to anti-PD1 therapy[J].J Clin Invest,2020,130(1):451-465.
25 Rhim AD,Oberstein PE,Thomas DH,et al.Stromal elements act to restrain,rather than support,pancreatic ductal adenocarcinoma[J].Cancer Cell,2014,25(6):735-747.
26 Jiang H,Hegde S,Knolhoff BL,et al.Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy[J].Nat Med,2016,22:851-860.
27 Panni RZ,Herndon JM,Zuo C,et al.Agonism of CD11b reprograms innate immunity to sensitize pancreatic cancer to immunotherapies[J].Sci Transl Med,2019,11(499):9240.
28 Mace TA,Shakya R,Pitarresi JR,et al.IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer[J].Gut,2018,67(2):320-332.
29 Rotte A,Combination of CTLA-4 and PD-1 blockers for treatment of cancer[J].J Exp Clin Cancer Res,2019,38(1):255.
30 Mitchell TC,Hamid O,Smith DC,et al.Preliminary results from a Phase I/II study of epacadostat(incb024360)in combination with pembrolizumab in patients with selected advanced cancers[J].J Clin Oncol,2018,36(32):3223-3230.
31 Duraiswamy J,Kaluza KM,Freeman GJ,et al.Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors[J].Cancer Res,2013,73(12):3591-3603.
32 O'Reilly EM,Oh DY,Dhani N,et al.Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma:a phase 2 randomized clinical Trial[J].JAMA Oncol,2019,5(10):1431-1438.

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