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000131571 0247_ $$2doi$$a10.1101/mcs.a001974
000131571 0247_ $$2pmid$$apmid:28619747
000131571 0247_ $$2pmc$$apmc:PMC5593153
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000131571 037__ $$aDKFZ-2017-06203
000131571 041__ $$aeng
000131571 082__ $$a610
000131571 1001_ $$aCzink, Elena$$b0
000131571 245__ $$aSuccessful immune checkpoint blockade in a patient with advanced stage microsatellite-unstable biliary tract cancer.
000131571 260__ $$aCold Spring Harbor, NY$$bCSH Press$$c2017
000131571 3367_ $$2DRIVER$$aarticle
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000131571 520__ $$aCancers acquire multiple somatic mutations that can lead to the generation of immunogenic mutation-induced neoantigens. These neoantigens can be recognized by the host's immune system. However, continuous stimulation of immune cells against tumor antigens can lead to immune cell exhaustion, which allows uncontrolled outgrowth of tumor cells. Recently, immune checkpoint inhibitors have emerged as a novel approach to overcome immune cell exhaustion and reactivate antitumor immune responses. In particular, antibodies blocking the exhaustion-mediating programmed death receptor (PD-1)/programmed death receptor ligand (PD-L1) pathway have shown clinical efficacy. The effects were particularly pronounced in tumors with DNA mismatch repair (MMR) deficiency and a high mutational load, which typically occur in the colon and endometrium. Here, we report on a 24-yr-old woman diagnosed with extrahepatic cholangiocarcinoma who showed strong and durable response to the immune checkpoint inhibitor pembrolizumab, although treatment was initiated at an advanced stage of disease. The patient's tumor displayed DNA MMR deficiency and microsatellite instability (MSI) but lacked other features commonly discussed as predictors of response toward checkpoint blockade, such as PD-L1 expression or dense infiltration with cytotoxic T cells. Notably, high levels of HLA class I and II antigen expression were detected in the tumor, suggesting a potential causal relation between functionality of the tumor's antigen presentation machinery and the success of immune checkpoint blockade. We suggest determining MSI status in combination with HLA class I and II antigen expression in tumors potentially eligible for immune checkpoint blockade even in the absence of conventional markers predictive for anti-PD-1/PD-L1 therapy and in entities not commonly linked to the MSI phenotype. Further studies are required to determine the value of these markers for predicting the success of immune checkpoint blockade.
000131571 536__ $$0G:(DE-HGF)POF3-317$$a317 - Translational cancer research (POF3-317)$$cPOF3-317$$fPOF III$$x0
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000131571 650_7 $$2NLM Chemicals$$aAntibodies, Monoclonal
000131571 650_7 $$2NLM Chemicals$$aAntibodies, Monoclonal, Humanized
000131571 650_7 $$2NLM Chemicals$$aAntineoplastic Agents
000131571 650_7 $$2NLM Chemicals$$aB7-H1 Antigen
000131571 650_7 $$2NLM Chemicals$$aBiomarkers, Tumor
000131571 650_7 $$2NLM Chemicals$$aCD274 protein, human
000131571 650_7 $$2NLM Chemicals$$aProgrammed Cell Death 1 Receptor
000131571 650_7 $$0DPT0O3T46P$$2NLM Chemicals$$apembrolizumab
000131571 7001_ $$0P:(DE-HGF)0$$aKloor, Matthias$$b1
000131571 7001_ $$aGoeppert, Benjamin$$b2
000131571 7001_ $$0P:(DE-He78)f0144d171d26dbedb67c9db1df35629d$$aFröhling, Stefan$$b3$$udkfz
000131571 7001_ $$0P:(DE-He78)a8e85c1bd89741ab0c2a28032ba81359$$aUhrig, Sebastian$$b4$$udkfz
000131571 7001_ $$aWeber, Tim F$$b5
000131571 7001_ $$aMeinel, Jörn$$b6
000131571 7001_ $$aSutter, Christian$$b7
000131571 7001_ $$aWeiss, Karl Heinz$$b8
000131571 7001_ $$aSchirmacher, Peter$$b9
000131571 7001_ $$0P:(DE-He78)11747cd1dc061b9333c0e3a3ff31bf2f$$avon Knebel Doeberitz, Magnus$$b10$$udkfz
000131571 7001_ $$aJäger, Dirk$$b11
000131571 7001_ $$aSpringfeld, Christoph$$b12
000131571 773__ $$0PERI:(DE-600)2835759-0$$a10.1101/mcs.a001974$$gVol. 3, no. 5, p. a001974 -$$n5$$pa001974 -$$tCold Spring Harbor molecular case studies$$v3$$x2373-2873$$y2017
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000131571 9141_ $$y2017
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000131571 915__ $$0StatID:(DE-HGF)0310$$2StatID$$aDBCoverage$$bNCBI Molecular Biology Database
000131571 9201_ $$0I:(DE-He78)G100-20160331$$kG100$$lTranslationale Onkologie$$x0
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