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      author       = {B. M. C. Jebaraj and A. Müller and R. P. Dheenadayalan and
                      S. Endres and P. M. Roessner$^*$ and F. Seyfried and C.
                      Walliser and M. Wist and J. Qi and E. Tausch and D.
                      Mertens$^*$ and J. A. Fox and K.-M. Debatin and L. H. Meyer
                      and P. Taverna and M. Seiffert$^*$ and P. Gierschik and S.
      title        = {{E}valuation of vecabrutinib as a model for non-covalent
                      {BTK}/{ITK} inhibition for treatment of chronic lymphocytic
      journal      = {Blood},
      volume       = {139},
      number       = {6},
      issn         = {0006-4971},
      address      = {Washington, DC},
      publisher    = {American Society of Hematology},
      reportid     = {DKFZ-2021-02287},
      pages        = {859-875},
      year         = {2022},
      note         = {2022 Feb 10;139(6):859-875},
      abstract     = {Covalent Bruton tyrosine kinase (BTK) inhibitors such as
                      ibrutinib have proven to be highly beneficial in the
                      treatment of chronic lymphocytic leukemia (CLL).
                      Interestingly, the off-target inhibition of IL-2-inducible
                      T-cell kinase (ITK) by ibrutinib may also play a role in
                      modulating the tumor microenvironment, potentially enhancing
                      the treatment benefit. However, resistance to covalently
                      binding BTK inhibitors can develop by a mutation in cysteine
                      481 of BTK (C481S), which prevents the irreversible binding
                      of the drugs. In the present study we performed pre-clinical
                      characterization of vecabrutinib, a next generation
                      non-covalent BTK inhibitor, with ITK inhibitory properties
                      similar to those of ibrutinib. Unlike ibrutinib and other
                      covalent BTK inhibitors, vecabrutinib showed retention of
                      the inhibitory effect on C481S BTK mutants in vitro, similar
                      to that of wildtype BTK. In the murine Eµ-TCL1 adoptive
                      transfer model, vecabrutinib reduced tumor burden and
                      significantly improved survival. Vecabrutinib treatment led
                      to a decrease in CD8+ effector and memory T-cell
                      populations, while the naïve populations were increased. Of
                      importance, vecabrutinib treatment significantly reduced
                      frequency of regulatory CD4+ T-cells (Tregs) in vivo. Unlike
                      ibrutinib, vecabrutinib treatment showed minimal adverse
                      impact on activation and proliferation of isolated T-cells.
                      Lastly, combination treatment of vecabrutinib with
                      venetoclax was found to augment treatment efficacy,
                      significantly improve survival and lead to favourable
                      reprogramming of the microenvironment in the murine Eµ-TCL1
                      model. Thus, non-covalent BTK/ITK inhibitors such as
                      vecabrutinib may be efficacious in C481S BTK mutant CLL,
                      while preserving the T-cell immunomodulatory function of
      cin          = {B060 / B061},
      ddc          = {610},
      cid          = {I:(DE-He78)B060-20160331 / I:(DE-He78)B061-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34662393},
      doi          = {10.1182/blood.2021011516},
      url          = {https://inrepo02.dkfz.de/record/177081},