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@ARTICLE{Quandt:142110,
      author       = {J. Quandt$^*$ and C. Schlude$^*$ and M. Bartoschek$^*$ and
                      R. Will$^*$ and A. Cid-Arregui$^*$ and S. Schölch and C.
                      Reissfelder and J. Weitz and M. Schneider and S. Wiemann$^*$
                      and F. Momburg$^*$ and P. Beckhove$^*$},
      title        = {{L}ong-peptide vaccination with driver gene mutations in
                      p53 and {K}ras induces cancer mutation-specific effector as
                      well as regulatory {T} cell responses.},
      journal      = {OncoImmunology},
      volume       = {7},
      number       = {12},
      issn         = {2162-402X},
      address      = {Abingdon},
      publisher    = {Taylor $\&$ Franics},
      reportid     = {DKFZ-2018-02340},
      pages        = {e1500671 -},
      year         = {2018},
      abstract     = {Mutated proteins arising from somatic mutations in tumors
                      are promising targets for cancer immunotherapy. They
                      represent true tumor-specific antigens (TSAs) as they are
                      exclusively expressed in tumors, reduce the risk of
                      autoimmunity and are more likely to overcome tolerance
                      compared to wild-type (wt) sequences. Hence, we designed a
                      panel of long peptides (LPs, 28-35 aa) comprising driver
                      gene mutations in TP35 and KRAS frequently found in
                      gastrointestinal tumors to test their combined
                      immunotherapeutic potential. We found increased numbers of T
                      cells responsive against respective mutated and wt peptides
                      in colorectal cancer patients that carry the tested
                      mutations in their tumors than patients with other
                      mutations. Further, active immunization of
                      HLA(-A2/DR1)-humanized mice with mixes of the same mutated
                      LPs yielded simultaneous, polyvalent CD8+/CD4+ T cell
                      responses against the majority of peptides. Peptide-specific
                      T cells possessed a multifunctional cytokine profile with
                      CD4+ T cells showing a TH1-like phenotype. Two mutated
                      peptides (Kras[G12V], p53[R248W]) induced significantly
                      higher T cell responses than corresponding wt sequences and
                      comprised HLA-A2/DR1-restricted mutated epitopes. However,
                      vaccination with the same highly immunogenic LPs strongly
                      increased systemic regulatory T cells (Treg) numbers in a
                      syngeneic sarcoma model over-expressing these mutated
                      protein variants and resulted in accelerated tumor
                      outgrowth. In contrast, tumor outgrowth was delayed when
                      vaccination was directed against tumor-intrinsic Kras/Tp53
                      mutations of lower immunogenicity. Conclusively, we show
                      that LP vaccination targeting multiple mutated TSAs elicits
                      polyvalent, multifunctional, and mutation-specific effector
                      T cells capable of targeting tumors. However, the success of
                      this therapeutic approach can be hampered by
                      vaccination-induced, TSA-specific Tregs.},
      cin          = {D015 / B050 / W110 / D120 / D122},
      ddc          = {610},
      cid          = {I:(DE-He78)D015-20160331 / I:(DE-He78)B050-20160331 /
                      I:(DE-He78)W110-20160331 / I:(DE-He78)D120-20160331 /
                      I:(DE-He78)D122-20160331},
      pnm          = {314 - Tumor immunology (POF3-314)},
      pid          = {G:(DE-HGF)POF3-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30524892},
      pmc          = {pmc:PMC6279329},
      doi          = {10.1080/2162402X.2018.1500671},
      url          = {https://inrepo02.dkfz.de/record/142110},
}