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@ARTICLE{Czink:131571,
      author       = {E. Czink and M. Kloor$^*$ and B. Goeppert and S.
                      Fröhling$^*$ and S. Uhrig$^*$ and T. F. Weber and J. Meinel
                      and C. Sutter and K. H. Weiss and P. Schirmacher and M. von
                      Knebel Doeberitz$^*$ and D. Jäger and C. Springfeld},
      title        = {{S}uccessful immune checkpoint blockade in a patient with
                      advanced stage microsatellite-unstable biliary tract
                      cancer.},
      journal      = {Cold Spring Harbor molecular case studies},
      volume       = {3},
      number       = {5},
      issn         = {2373-2873},
      address      = {Cold Spring Harbor, NY},
      publisher    = {CSH Press},
      reportid     = {DKFZ-2017-06203},
      pages        = {a001974 -},
      year         = {2017},
      abstract     = {Cancers 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.},
      keywords     = {Antibodies, Monoclonal (NLM Chemicals) / Antibodies,
                      Monoclonal, Humanized (NLM Chemicals) / Antineoplastic
                      Agents (NLM Chemicals) / B7-H1 Antigen (NLM Chemicals) /
                      Biomarkers, Tumor (NLM Chemicals) / CD274 protein, human
                      (NLM Chemicals) / Programmed Cell Death 1 Receptor (NLM
                      Chemicals) / pembrolizumab (NLM Chemicals)},
      cin          = {G100 / G200 / G010 / G105},
      ddc          = {610},
      cid          = {I:(DE-He78)G100-20160331 / I:(DE-He78)G200-20160331 /
                      I:(DE-He78)G010-20160331 / I:(DE-He78)G105-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:28619747},
      pmc          = {pmc:PMC5593153},
      doi          = {10.1101/mcs.a001974},
      url          = {https://inrepo02.dkfz.de/record/131571},
}