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@ARTICLE{Kaeuferle:300186,
      author       = {T. Kaeuferle and M. Zwermann and N. Stoll and P.
                      Ferrada-Ernst and L. Jablonowski and R. Zeidler and S.
                      Willier and D. Stenger and A. Yassin and R. Stripecke and T.
                      Feuchtinger$^*$},
      title        = {{A}ll-in-one {CRISPR}/{C}as-engineered
                      glucocorticoid-receptor knock-out {EBV}-gp350-{CAR} knock-in
                      {T} cells are potent and resistant to dexamethasone.},
      journal      = {Experimental hematology $\&$ oncology},
      volume       = {14},
      number       = {1},
      issn         = {2162-3619},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DKFZ-2025-00663},
      pages        = {40},
      year         = {2025},
      abstract     = {Epstein-Barr virus (EBV) reactivation in immunocompromised
                      patients and post-transplantation is associated with
                      morbidity, mortality and with the onset of a variety of
                      malignant diseases. Adoptive T-cell therapies have emerged
                      as promising therapeutic options, but post-transplant
                      immunosuppression jeopardizes the protective anti-EBV immune
                      surveillance by adoptively transferred T cells.Using an
                      all-in-one CRISPR/Cas-mediated approach, we inserted an
                      anti-EBV (gp350) CAR into the T-cell receptor (TRAC) locus
                      and simultaneously knocked-out the glucocorticoid receptor
                      (GR) on a good manufacturing practice (GMP)-compatible
                      platform.CAR knock-in (CARKI) was confirmed in primary human
                      T cells on genetic and on protein level with a mean
                      efficiency of $41\%.$ With $83\%,$ additional GR knock-out
                      was highly efficient in CARKI cells. On a functional level
                      CARKIGRKO T cells showed target-specific potency in terms of
                      cytokine secretion patterns, proliferative capacity and
                      cytotoxic activity against gp350-expressing target cells.
                      Further, CARKIGRKO T cells were insensitive to dexamethasone
                      treatment and maintained T-cell functionality. In contrast,
                      CARKIGRKO T cells were sensitive to the GR-independent
                      immunosuppressant cyclosporine A (CsA), thereby providing a
                      rescue treatment for patients in case of safety issues.The
                      study lays the proof-of-concept for virus-free all-in-one
                      GMP-manufacturing of glucocorticoid-resistant CAR T-cell
                      products. Further, the glucocorticoid-resistant gp350-CAR T
                      cells can provide a future therapeutic option for high-risk
                      post-transplant patients with EBV-reactivations or patients
                      with EBV-associated pathologies requiring steroid
                      treatment.},
      keywords     = {Adoptive T cell transfer (Other) / CAR T cells (Other) /
                      CRISPR/Cas (Other) / Dexamethasone (Other) / EBV (Other) /
                      Genetic engineering (Other) / Glucocorticoid receptor
                      (Other) / Steroid treatment (Other)},
      cin          = {FR01},
      ddc          = {610},
      cid          = {I:(DE-He78)FR01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40108708},
      pmc          = {pmc:PMC11921674},
      doi          = {10.1186/s40164-025-00631-w},
      url          = {https://inrepo02.dkfz.de/record/300186},
}