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@ARTICLE{Volkmar:301764,
      author       = {M. Volkmar$^*$ and D. Hoser and C. Lauenstein$^*$ and J.
                      Rebmann and A. Hotz-Wagenblatt$^*$ and J. H. Rieger$^*$ and
                      I. Poschke$^*$ and J. Becker$^*$ and A. B. Riemer$^*$ and M.
                      Sprick$^*$ and A. Trumpp$^*$ and O. Strobel and T.
                      Blankenstein and G. Willimsky$^*$ and R. Offringa$^*$},
      title        = {{E}nhanced mutanome analysis towards the induction of
                      neoepitope-reactive {T}-cell responses for personalized
                      immunotherapy of pancreatic cancer.},
      journal      = {Journal for ImmunoTherapy of Cancer},
      volume       = {13},
      number       = {6},
      issn         = {2051-1426},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DKFZ-2025-01144},
      pages        = {e011802},
      year         = {2025},
      note         = {#EA:D200#LA:D200# /},
      abstract     = {Personalized immunotherapy of pancreatic ductal
                      adenocarcinoma (PDAC) through T-cell mediated targeting of
                      tumor-specific, mutanome-encoded neoepitopes may offer new
                      opportunities to combat this disease, in particular by
                      countering recurrence after primary tumor resection.
                      However, the sensitive and accurate calling of somatic
                      mutations in PDAC tissue samples is compromised by the low
                      tumor cell content. Moreover, the repertoire of immunogenic
                      neoepitopes in PDAC is limited due to the low mutational
                      load of the majority of these tumors.We developed a workflow
                      involving the combined analysis of next-generation DNA and
                      RNA sequencing data from matched pairs of primary tumor
                      samples and patient-derived xenograft models towards the
                      enhanced detection of driver mutations as well as single
                      nucleotide variants encoding potentially immunogenic T-cell
                      neoepitopes. Subsequently, we immunized HLA/human T-cell
                      receptor (TCR) locus-transgenic mice with synthetic peptides
                      representing candidate neoepitopes, and molecularly cloned
                      the genes encoding TCRs targeting these epitopes.Application
                      of our pipeline resulted in the identification of greater
                      numbers of non-synonymous mutations encoding candidate
                      neoepitopes with increased confidence. Furthermore, we
                      provide proof of concept for the successful isolation of
                      HLA-restricted TCRs from humanized mice immunized with
                      different neoepitopes, several of which would not have been
                      selected based on mutanome analysis of PDAC tissue samples
                      alone. These TCRs mediate specific T-cell reactivity against
                      the tumor cells in which the corresponding mutations were
                      identified.Enhanced mutanome analysis and candidate
                      neoepitope selection increase the likelihood of identifying
                      therapeutically relevant neoepitopes, and thereby support
                      the optimization of personalized immunotherapy for PDAC and
                      other poorly immunogenic cancers.},
      keywords     = {Humans / Animals / Pancreatic Neoplasms: genetics /
                      Pancreatic Neoplasms: immunology / Pancreatic Neoplasms:
                      therapy / Mice / Precision Medicine: methods /
                      Immunotherapy: methods / Mutation / T-Lymphocytes:
                      immunology / Carcinoma, Pancreatic Ductal: immunology /
                      Carcinoma, Pancreatic Ductal: genetics / Carcinoma,
                      Pancreatic Ductal: therapy / Mice, Transgenic / Epitopes,
                      T-Lymphocyte: immunology / Epitopes, T-Lymphocyte: genetics
                      / Adoptive cell therapy - ACT (Other) / Gastrointestinal
                      Cancer (Other) / Immunotherapy (Other) / T cell Receptor -
                      TCR (Other) / Vaccine (Other) / Epitopes, T-Lymphocyte (NLM
                      Chemicals)},
      cin          = {D200 / D410 / A010 / W610},
      ddc          = {610},
      cid          = {I:(DE-He78)D200-20160331 / I:(DE-He78)D410-20160331 /
                      I:(DE-He78)A010-20160331 / I:(DE-He78)W610-20160331},
      pnm          = {314 - Immunologie und Krebs (POF4-314)},
      pid          = {G:(DE-HGF)POF4-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40461160},
      doi          = {10.1136/jitc-2025-011802},
      url          = {https://inrepo02.dkfz.de/record/301764},
}