title: Personalized peptide vaccine-induced immune response associated with long-term survival of a metastatic cholangiocarcinoma patient.
abstract: We report a novel experimental immunotherapeutic approach in a patient with metastatic intrahepatic cholangiocarcinoma. In the 5year course of the disease, the initial tumor mass, two local recurrences and a lung metastasis were surgically removed. Lacking alternative treatment options, aiming at the induction of anti-tumor T cells responses, we initiated a personalized multi-peptide vaccination, based on in-depth analysis of tumor antigens (immunopeptidome) and sequencing.
  
  
  
  Tumors were characterized by immunohistochemistry, next-generation sequencing and mass spectrometry of HLA ligands.
  
  
  
  Although several tumor-specific neo-epitopes were predicted in silico, none could be validated by mass spectrometry. Instead, a personalized multi-peptide vaccine containing non-mutated tumor-associated epitopes was designed and applied. Immunomonitoring showed vaccine-induced T cell responses to three out of seven peptides administered. The pulmonary metastasis resected after start of vaccination showed strong immune cell infiltration and perforin positivity, in contrast to the previous lesions. The patient remains clinically healthy, without any radiologically detectable tumors since March 2013 and the vaccination is continued.
  
  
  
  This remarkable clinical course encourages formal clinical studies on adjuvant personalized peptide vaccination in cholangiocarcinoma.
  
  
  
  Metastatic cholangiocarcinomas, cancers that originate from the liver bile ducts, have very limited treatment options and a fatal prognosis. We describe a novel therapeutic approach in such a patient using a personalized multi-peptide vaccine. This vaccine, developed based on the characterization of the patient's tumor, evoked detectable anti-tumor immune responses, associating with long-term tumor-free survival.
authors.affiliation: University Hospital Tübingen, Department of General, Visceral and Transplant Surgery, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany; University of Tübingen, Interfaculty Institute for Cell Biology, Department of Immunology, Auf der Morgenstelle 15, 72076 Tübingen, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) partner site Tübingen, Germany. Electronic address: markus.loeffler@med.uni-tuebingen.de.
authors.forename: Markus W
authors.initials: MW
authors.lastname: Löffler
authors.affiliation: University of Tübingen, Interfaculty Institute for Cell Biology, Department of Immunology, Auf der Morgenstelle 15, 72076 Tübingen, Germany.
authors.forename: P Anoop
authors.initials: PA
authors.lastname: Chandran
authors.affiliation: University of Tübingen, Interfaculty Institute for Cell Biology, Department of Immunology, Auf der Morgenstelle 15, 72076 Tübingen, Germany; Current address: Immatics Biotechnologies GmbH, Paul Ehrlich Str. 15, 72076 Tübingen, Germany.
authors.forename: Karoline
authors.initials: K
authors.lastname: Laske
authors.affiliation: University Hospital Tübingen, Institute of Medical Genetics and Applied Genomics, Calwerstr. 7, 72076 Tübingen, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Schroeder
authors.affiliation: University Hospital Tübingen, Institute of Pathology, Liebermeisterstr. 8, 72076 Tübingen, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) partner site Tübingen, Germany.
authors.forename: Irina
authors.initials: I
authors.lastname: Bonzheim
authors.affiliation: University of Tübingen, Interfaculty Institute for Cell Biology, Department of Immunology, Auf der Morgenstelle 15, 72076 Tübingen, Germany; University of Tübingen, Center for Bioinformatics, Sand 14, 72076 Tübingen, Germany; University of Tübingen, Dept. of Computer Science, Sand 14, 72076 Tübingen, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Walzer
authors.affiliation: University Hospital Tübingen, Institute of Medical Genetics and Applied Genomics, Calwerstr. 7, 72076 Tübingen, Germany.
authors.forename: Franz J
authors.initials: FJ
authors.lastname: Hilke
authors.affiliation: University of Tübingen, Interfaculty Institute for Cell Biology, Department of Immunology, Auf der Morgenstelle 15, 72076 Tübingen, Germany.
authors.forename: Nico
authors.initials: N
authors.lastname: Trautwein
authors.affiliation: University of Tübingen, Interfaculty Institute for Cell Biology, Department of Immunology, Auf der Morgenstelle 15, 72076 Tübingen, Germany; Current address: Immatics Biotechnologies GmbH, Paul Ehrlich Str. 15, 72076 Tübingen, Germany.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Kowalewski
authors.affiliation: University of Tübingen, Interfaculty Institute for Cell Biology, Department of Immunology, Auf der Morgenstelle 15, 72076 Tübingen, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Schuster
authors.affiliation: University of Tübingen, Interfaculty Institute for Cell Biology, Department of Immunology, Auf der Morgenstelle 15, 72076 Tübingen, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Günder
authors.affiliation: NMI Natural and Medical Sciences Institute at the University of Tübingen, Markwiesenstrasse 55, 72770 Reutlingen, Germany.
authors.forename: Viviana A
authors.initials: VA
authors.lastname: Carcamo Yañez
authors.affiliation: University of Tübingen, Center for Bioinformatics, Sand 14, 72076 Tübingen, Germany; University of Tübingen, Dept. of Computer Science, Sand 14, 72076 Tübingen, Germany.
authors.forename: Christopher
authors.initials: C
authors.lastname: Mohr
authors.affiliation: University Hospital Tübingen, Institute of Medical Genetics and Applied Genomics, Calwerstr. 7, 72076 Tübingen, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Sturm
authors.affiliation: University Hospital Tübingen, Institute of Medical Genetics and Applied Genomics, Calwerstr. 7, 72076 Tübingen, Germany.
authors.forename: Huu-Phuc
authors.initials: HP
authors.lastname: Nguyen
authors.affiliation: University Hospital Tübingen, Institute of Medical Genetics and Applied Genomics, Calwerstr. 7, 72076 Tübingen, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.affiliation: University Hospital Tübingen, Institute of Medical Genetics and Applied Genomics, Calwerstr. 7, 72076 Tübingen, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) partner site Tübingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Bauer
authors.affiliation: University of Tübingen, Center for Bioinformatics, Sand 14, 72076 Tübingen, Germany; University of Tübingen, Quantitative Biology Center (QBiC), Auf der Morgenstelle 10, 72076 Tübingen, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Nahnsen
authors.affiliation: University Hospital Tübingen, Department of General, Visceral and Transplant Surgery, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany.
authors.forename: Silvio
authors.initials: S
authors.lastname: Nadalin
authors.affiliation: University Hospital Tübingen, Department of General, Visceral and Transplant Surgery, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany.
authors.forename: Derek
authors.initials: D
authors.lastname: Zieker
authors.affiliation: University Hospital Tübingen, Department of General, Visceral and Transplant Surgery, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany; Current address: Klinikum Konstanz, Luisenstr. 7, 78464 Konstanz, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Glatzle
authors.affiliation: University Hospital Tübingen, Department of General, Visceral and Transplant Surgery, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany.
authors.forename: Karolin
authors.initials: K
authors.lastname: Thiel
authors.affiliation: NMI Natural and Medical Sciences Institute at the University of Tübingen, Markwiesenstrasse 55, 72770 Reutlingen, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schneiderhan-Marra
authors.affiliation: University Hospital Tübingen, Department of Diagnostic and Interventional Radiology, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Clasen
authors.affiliation: University Hospital Tübingen, Institute of Pathology, Liebermeisterstr. 8, 72076 Tübingen, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Bösmüller
authors.affiliation: University Hospital Tübingen, Institute of Pathology, Liebermeisterstr. 8, 72076 Tübingen, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) partner site Tübingen, Germany.
authors.forename: Falko
authors.initials: F
authors.lastname: Fend
authors.affiliation: University of Tübingen, Center for Bioinformatics, Sand 14, 72076 Tübingen, Germany; University of Tübingen, Dept. of Computer Science, Sand 14, 72076 Tübingen, Germany; University of Tübingen, Quantitative Biology Center (QBiC), Auf der Morgenstelle 10, 72076 Tübingen, Germany; Max Planck Institute for Developmental Biology, Spemannstr. 35, 72076 Tübingen, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) partner site Tübingen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Kohlbacher
authors.affiliation: University of Tübingen, Interfaculty Institute for Cell Biology, Department of Immunology, Auf der Morgenstelle 15, 72076 Tübingen, Germany.
authors.forename: Cécile
authors.initials: C
authors.lastname: Gouttefangeas
authors.affiliation: University of Tübingen, Interfaculty Institute for Cell Biology, Department of Immunology, Auf der Morgenstelle 15, 72076 Tübingen, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) partner site Tübingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Stevanović
authors.affiliation: University Hospital Tübingen, Department of General, Visceral and Transplant Surgery, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) partner site Tübingen, Germany.
authors.forename: Alfred
authors.initials: A
authors.lastname: Königsrainer
authors.affiliation: University of Tübingen, Interfaculty Institute for Cell Biology, Department of Immunology, Auf der Morgenstelle 15, 72076 Tübingen, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) partner site Tübingen, Germany.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Rammensee
mesh_terms: D001650:Bile Duct Neoplasms; D019496:Cancer Vaccines; D018281:Cholangiocarcinoma; D006801:Humans; D009364:Neoplasm Recurrence, Local; D022223:Vaccines, Subunit
chemical_list: D019496:Cancer Vaccines; D022223:Vaccines, Subunit
keywords: Anti-tumor T cell response; Cholangiocarcinoma; HLA; Immunopeptidome; Immunotherapy; Peptides; Primary liver cancer