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@ARTICLE{MurciaPienkowski:305606,
      author       = {V. Murcia Pienkowski and T. Boschert$^*$ and P. Skoczylas
                      and A. Sanecka-Duin and M. Jasiński and B. Król-Józaga
                      and G. Mazzocco and S. Stachura and L. Bunse$^*$ and J.
                      Kaczmarczyk and E. Green$^*$ and A. Blum},
      title        = {{C}omputational identification of cross-reactive {TCR}
                      epitopes with {ARD}itox.},
      journal      = {Journal of cancer research and clinical oncology},
      volume       = {151},
      number       = {12},
      issn         = {0301-1585},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {DKFZ-2025-02256},
      pages        = {311},
      year         = {2025},
      note         = {#LA:D170#},
      abstract     = {Cellular immunotherapies, such as those utilizing T
                      lymphocytes expressing native or engineered T cell receptors
                      (TCRs), have demonstrated therapeutic efficacy. However,
                      some engineered high-affinity TCRs have caused fatal
                      off-target immunotoxicity due to targeting epitopes later
                      found to be expressed by both tumor cells and healthy
                      tissues. Unfortunately, TCRs can be cross-reactive to
                      epitopes with highly distinct sequences, making prediction
                      difficult, and the exquisite sequence specificity of TCRs
                      means that safety studies in mice miss human-specific
                      epitopes.To address this issue, we developed ARDitox, a
                      novel in silico method based on computational immunology and
                      artificial intelligence (AI) for predicting and analyzing
                      potential TCR off-target toxicities. We tested the
                      performance of ARDitox on four TCRs reported to target
                      tumor-associated antigens, two of which are known to cause
                      clinical immunotoxicity (MAGEA3112-120 and MAGEA3168-176
                      epitopes), one of which has experimentally identified
                      off-target antigens (AFP158-166 epitope), and the last one
                      for which no cross-reactive epitopes are known
                      (NY-ESO-1157-165).ARDitox confirmed the previously
                      identified immunotoxic epitopes. We then expanded our
                      analyses to a novel TCR targeting the tumor-associated
                      antigen NLGN4X, frequently upregulated in gliomas. For this
                      target, ARDitox identified a cross-reactive peptide that
                      would not have been found using mouse models, highlighting
                      the value of our computational approach.Our findings
                      underscore the value of the ARDitox in silico method for the
                      early and reliable identification of off-target epitopes for
                      further preclinical evaluation. This platform strongly
                      supports the development of safer TCR-mediated
                      immunotherapies.},
      keywords     = {Humans / Epitopes, T-Lymphocyte: immunology / Cross
                      Reactions: immunology / Receptors, Antigen, T-Cell:
                      immunology / Computational Biology: methods / Antigens,
                      Neoplasm: immunology / Mice / Animals / Computer Simulation
                      / Artificial Intelligence / T-Lymphocytes: immunology / 3R
                      (Other) / Cell therapy (Other) / Cross-reactivity (Other) /
                      Off-target toxicity (Other) / Safety (Other) / TCR (Other) /
                      Epitopes, T-Lymphocyte (NLM Chemicals) / Receptors, Antigen,
                      T-Cell (NLM Chemicals) / Antigens, Neoplasm (NLM Chemicals)},
      cin          = {D170 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)D170-20160331 / 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:41175267},
      doi          = {10.1007/s00432-025-06330-7},
      url          = {https://inrepo02.dkfz.de/record/305606},
}