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@ARTICLE{Prasad:294332,
      author       = {R. Prasad and A. Rehman and L. Rehman and F. Darbaniyan and
                      V. Blumenberg$^*$ and M.-L. Schubert and U. Mor and E.
                      Zamir$^*$ and S. Schmidt$^*$ and T. Hayase and C. Chia-Chi
                      and L. K. McDaniel and I. Flores and P. Strati and R. Nair
                      and D. Chihara and L. E. Fayad and S. Ahmed and S. P. Iyer
                      and M. L. Wang and P. Jain and L. J. Nastoupil and J. R.
                      Westin and R. Arora and J. G. Turner and F. Khawaja and R.
                      Wu and J. B. Dennison and M. Menges and M. Hidalgo-Vargas
                      and K. M. Reid and M. L. Davila and P. Dreger and F. Korell
                      and A. Schmitt and M. R. Tanner and R. E. Champlin and C. R.
                      Flowers and E. J. Shpall and S. Hanash and S. S. Neelapu and
                      M. Schmitt and M. Subklewe$^*$ and J. Fahrmann and C.
                      Stein-Thoeringer and E. Elinav$^*$ and M. D. Jain and E.
                      Hayase and R. R. Jenq and N. Y. Saini},
      title        = {{A}ntibiotic-induced loss of gut microbiome metabolic
                      output correlates with clinical responses to {CAR} {T}-cell
                      therapy.},
      journal      = {Blood},
      volume       = {145},
      number       = {8},
      issn         = {0006-4971},
      address      = {Washington, DC},
      publisher    = {American Society of Hematology},
      reportid     = {DKFZ-2024-02165},
      pages        = {823-839},
      year         = {2025},
      note         = {2025 Feb 20;145(8):823-839},
      abstract     = {Antibiotic-induced microbiome dysbiosis is widespread in
                      oncology, adversely affecting outcomes and side effects of
                      various cancer treatments, including immune checkpoint
                      inhibitors and chimeric antigen receptor T (CAR-T) cell
                      therapies. In this study, we observed that prior exposure to
                      broad-spectrum ABX with extended anaerobic coverage like
                      piperacillin-tazobactam and meropenem was associated with
                      worsened anti-CD19 CAR-T therapy survival outcomes in large
                      B-cell lymphoma patients (n=422), compared to other ABX
                      classes. In a discovery subset of these patients (n=67), we
                      found that the use of these ABX was in turn associated with
                      substantial dysbiosis of gut microbiome function, resulting
                      in significant alterations of the gut and blood metabolome,
                      including microbial effectors such as short-chain fatty
                      acids (SCFAs) and other anionic metabolites, findings that
                      were largely reproduced in an external validation cohort
                      (n=58). Broader evaluation of circulating microbial
                      metabolites revealed reductions in indole and cresol
                      derivatives, as well as trimethylamine N-oxide, in patients
                      who received ABX treatment (discovery n=40, validation
                      n=28). These findings were recapitulated in an
                      immune-competent CAR-T mouse model, where meropenem-induced
                      dysbiosis led to a systemic dysmetabolome and decreased
                      murine anti-CD19 CAR-T efficacy. Furthermore, we demonstrate
                      that SCFAs can enhance the metabolic fitness of CAR-T cells,
                      leading to improved tumor killing capacity. Together, these
                      results suggest that broad-spectrum ABX deplete
                      metabolically active commensals whose metabolites are
                      essential for enhancing CAR-T efficacy, shedding light on
                      the intricate relationship between ABX exposure, microbiome
                      function and their impact on CAR-T cell efficacy. This
                      highlights the potential for modulating the microbiome to
                      augment CAR-T immunotherapy.},
      cin          = {D480 / MU01 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)D480-20160331 / I:(DE-He78)MU01-20160331 /
                      I:(DE-He78)HD01-20160331},
      pnm          = {314 - Immunologie und Krebs (POF4-314)},
      pid          = {G:(DE-HGF)POF4-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39441941},
      doi          = {10.1182/blood.2024025366},
      url          = {https://inrepo02.dkfz.de/record/294332},
}