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@ARTICLE{Bodden:282725,
      author       = {M. Bodden and A. Häcker and J. Röder and A. Kiefer and C.
                      Zhang and A. Bhatti and J. Pfeifer Serrahima and E.
                      Ullrich$^*$ and I. Kühnel and W. S. Wels$^*$},
      title        = {{C}o-{E}xpression of an {IL}-15 {S}uperagonist
                      {F}acilitates {S}elf-{E}nrichment of {GD}2-{T}argeted
                      {CAR}-{NK} {C}ells and {M}ediates {P}otent {C}ell {K}illing
                      in the {A}bsence of {IL}-2.},
      journal      = {Cancers},
      volume       = {15},
      number       = {17},
      issn         = {2072-6694},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {DKFZ-2023-01851},
      pages        = {4310},
      year         = {2023},
      abstract     = {In contrast to T lymphocytes, natural killer (NK) cells do
                      not require prior sensitization but are rapidly activated
                      upon encountering virally infected or neoplastic cells. In
                      addition, NK cells can be safely applied in an allogeneic
                      setting, making them important effector cells for the
                      development of off-the-shelf therapeutics for adoptive
                      cancer immunotherapy. To further enhance their therapeutic
                      potential, here, we engineered continuously expanding NK-92
                      cells as a clinically relevant model to express a humanized
                      second-generation chimeric antigen receptor (CAR) with a
                      composite CD28-CD3ζ signaling domain (hu14.18.28.z) that
                      targets the disialoganglioside GD2, which is expressed at
                      high levels by neuroblastoma cells and other tumors of
                      neuroectodermal origin. In a separate approach, we fused an
                      IL-15 superagonist (RD-IL15) to the GD2-CAR via a P2A
                      processing site. Lentivirally transduced NK-92/hu14.18.28.z
                      and $NK-92/hu14.18.28.z_RD-IL15$ cells both displayed high
                      and stable CAR surface expression and specific cytotoxicity
                      toward GD2-positive tumor cells. GD2-CAR NK cells carrying
                      the RD-IL15 construct in addition expressed the IL-15
                      superagonist, resulting in self-enrichment and targeted cell
                      killing in the absence of exogenous IL-2. Furthermore,
                      co-culture with RD-IL15-secreting GD2-CAR NK cells markedly
                      enhanced proliferation and cytotoxicity of bystander immune
                      cells in a paracrine manner. Our results demonstrate that
                      GD2-CAR NK cells co-expressing the IL-15 superagonist
                      mediate potent direct and indirect antitumor effects,
                      suggesting this strategy as a promising approach for the
                      further development of functionally enhanced cellular
                      therapeutics.},
      keywords     = {GD2 (Other) / NK-92 (Other) / chimeric antigen receptor
                      (Other) / interleukin-15 (Other) / natural killer cells
                      (Other)},
      cin          = {FM01},
      ddc          = {610},
      cid          = {I:(DE-He78)FM01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37686586},
      pmc          = {pmc:PMC10486391},
      doi          = {10.3390/cancers15174310},
      url          = {https://inrepo02.dkfz.de/record/282725},
}