5、消化系统肿瘤消化系统肿瘤 (18).pdf
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1、Accepted ArticleThis article has been accepted for publication and undergone full peer review but has not been through the copyediting,typesetting,pagination and proofreading process,which may lead to differences between this version and the Version of Record.Please cite this article as doi:10.1002/
2、hep.30482 This article is protected by copyright.All rights reserved.Article Type:Original Tremelimumab in combination with microwave ablation in patients with refractory biliary tract cancer Changqing Xie1,Austin G.Duffy2,Donna Mabry-Hrones2,Bradford Wood3,Elliot Levy3,Venkatesh Krishnasamy3,Javed
3、Khan4,Jun S.Wei4,David Agdashian2,Manoj Tyagi 4,Vineela Gangalapudi4,Suzanne Fioravanti2,Melissa Walker2,Victoria Anderson3,David Venzon5,William D.Figg6,Milan Sandhu2,David E.Kleiner6,Maria Pia Morelli1,Charalampos S Floudas1,Gagandeep Brar1,Seth M.Steinberg8,Firouzeh Korangy2,Tim F.Greten2,9 1 Hem
4、atology/Oncology Fellowship Program,National Heart,Lung,and Blood Institute/National Cancer Institute,National Institutes of Health 2 Gastrointestinal Malignancies Section,Center for Cancer Research,National Cancer Institute,National Institutes of Health 3 Radiology and Imaging Sciences,Center for C
5、ancer Research,National Institutes of Health 4 Genetics Branch,Center for Cancer Research,NCI,NIH,Bethesda,Maryland 5 Biostatistics and Data Management Section,NCI,NIH,Bethesda,Maryland 6 Clinical Pharmacology Program,Center for Cancer Research,National Cancer Institute,National Institutes of Health
6、 7 Laboratory of Pathology,Center for Cancer Research,National Cancer Institute,National Institutes of Health 8 Biostatistics and Data Management Section,Center for Cancer Research,National Institutes of Health 9 NCI CCR Liver Cancer Program Accepted Article This article is protected by copyright.Al
7、l rights reserved.Correspondence should be sent to:Tim F.Greten,MD.National Cancer Institute 9000 Rockville Pike,10/2B38B Bethesda,MD 20892 tim.gretennih.gov Abbreviations BTC:biliary tract cancer RFA:radiofrequency ablation ECOG:Eastern Cooperative Oncology Group HCC:hepatocellular carcinoma RECIST
8、:Response Evaluation Criteria in Solid Tumors DLT:dose-limiting toxicities AEs:Adverse events CI:confidence interval PFS:progression-free survival TTP:time to progression OS:overall survival CR:Complete response PR:Partial response PD:Progressive disease SD:Stable disease PBMC:Peripheral blood monon
9、uclear cells TCR:T cell receptor Accepted Article This article is protected by copyright.All rights reserved.Keywords:anti-CTLA4,immune checkpoint inhibitor,liver cancer Financial support This research was supported by the Intramural Research Program of the NIH,National Cancer Institute,Center for C
10、ancer Research and a Cooperative Research and Development Agreement between NCI and AstraZeneca.TFG is supported by the Intramural Research Program of the NIH,NCI(ZIA BC 011343).Abstract Background and Aim:Treatment options for patients with advanced biliary tract cancer are limited.Dysregulation of
11、 the immune system plays an important role in the pathogenesis of biliary tract cancer(BTC).This study aimed to investigate whether tremelimumab,an anti-CTLA4 inhibitor,could be combined safely with microwave ablation to enhance the effect of anti-CTLA4 treatment in patients with advanced BTC.Patien
12、ts were enrolled to receive monthly tremelimumab(10mg/kg,intravenously)for 6 doses,followed by infusions every 3 months until off-treatment criteria were met.Thirty-six days after the first tremelimumab dose,patients underwent subtotal microwave ablation.Interval imaging studies were performed every
13、 8 weeks.Adverse events were noted and managed.Tumor and peripheral blood samples were collected to perform immune monitoring and whole exome sequencing.Results:Twenty patients with refractory BTC were enrolled.Median age 56.5 years.No dose-limiting toxicities were encountered.The common treatment r
14、elated adverse events included lymphopenia,diarrhea and elevated transaminases.Among sixteen patients Accepted Article This article is protected by copyright.All rights reserved.evaluable for efficacy analysis,two(12.5%)patients achieved a confirmed partial response(lasting for 8.0 and 18.1 months,r
15、espectively),5 patients(31.3%)achieved stable disease.Median progression free survival,and overall survival were 3.4 months(95%CI 2.5-5.2 months),and 6.0 months(95%CI 3.8-8.8 months),respectively.Peripheral blood immune cell subset profiling showed increased circulating activated(HLA-DR positive)CD8
16、+T cells.TCRscreening showed tremelimumab expanded TCR repertoire but not reaching statistical significance(P=0.057).Conclusions:Tremelimumab in combination with tumor ablation is a potential new treatment strategy for patients with advanced BTC.Increased circulating activated CD8+T cells and TCR re
17、pertoire expansion induced by tremelimumab may contribute to treatment benefit.Introduction Biliary tract cancer(BTC)accounts for approximately 3%of all adult cancers,including cholangiocarcinoma(both intrahepatic and extrahepatic)and gallbladder cancer 1.Surgical resection is the only curative appr
18、oach for patients with local disease,however,the majority of patients present with advanced unresectable disease limiting the success of current treatment options 1-3.The combination of gemcitabine and cisplatin chemotherapy has become the standard first-line treatment regimen for advanced BTC with
19、a median survival of 11.7 months4.For patients who progress on first-line therapy,there is no standard second-line option 5.Frequently,the chemotherapy regimens used are extrapolated from data in pancreatic and other gastrointestinal cancers with limited or uncertain benefit.Recently,biomarker based
20、 targeted therapies have shown meaningful clinical activity against small subset of patient chemotherapy-refractory cholangiocarcinoma baring specific Accepted Article This article is protected by copyright.All rights reserved.gene mutations.A phase II study in patients with FGFR-altered advanced BT
21、C found impressive antitumour activity of BGJ398(a selective pan-FGFR kinase inhibitor),with a disease-control rate of 82%,and a manageable safety profile6.An interim analysis of data from BTC with IDH mutation showed a disease-control rate of 62%with IDH inhibitor 7.Emerging data suggest encouragin
22、g clinical activity with immune checkpoint inhibitors in liver cancers 8-10.However,the current response rates achievable with checkpoint inhibition alone in liver cancer is in the range of 17-20%11-13.Results from the biliary cohort of KEYNOTE-158 trial evaluating single agent pembrolizumab in 104
23、pateints with BTC showed overall response rate 5.8%14.Mounting evidence has shown that radiotherapy is able to enhance both local and systemic immunotherapy effects15-17.We have previously demonstrated positive antitumor activity of tremelimumab(an anti-CTLA-4 monoclonal antibody)in combination with
24、 radiofrequency ablation(RFA)in patients with advanced hepatocellular carcinoma(HCC)through the induced accumulation of intratumoral CD8+T cells 18.The study showed overall response rate was 26%.Based on the promsing results seen in HCC,we evaluated the safety and efficacy of tremelimumab in combina
25、tion with microwave ablation in patients with refractory biliary tract cancer.Patients and methods Patients Eligible patients were at least 18 years old and had pathologically confirmed BTC as defined by the Laboratory of Pathology at the National Cancer Institute(NCI)prior to enrollment.Additional
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