{
  "abstract": "Background Optimizing T cell activation strength is emerging as a critical factor in improving adoptive cellular therapy (ACT). We previously reported that neoantigen-specific T cell receptor (TCR) clonotypes from a patient with metastatic melanoma exhibited enhanced resilience to repeated stimulation when initially activated at moderate levels.Methods Building on these observations, we applied transient, low-dose MEK inhibition (MEKi) to fine-tune T cell signal strength during early activation. We evaluated this combinatorial strategy in vitro using co-cultures of CD8+ T cells engineered with patient-derived neoantigen-specific TCRs, alongside chimeric antigen receptor-T cells, bispecific T cell engagers, and non-engineered tumor-infiltrating lymphocytes (TILs). In vivo efficacy was evaluated in a xenograft model with intravenous TCR-T cell transfer and systemic low-dose MEKi.Results MEKi co-treatment induced a more tempered activation profile that enhanced T cell proliferation, fitness, and persistence under strong stimulation. These effects were consistent across various in vitro and in vivo models for engineered T cells as well as primary melanoma-derived TILs. MEKi dampened the pro-inflammatory T cell activation profile, most notably diminishing tumor necrosis factor (TNF) secretion, mechanistically driven by coordinated and selective disruption of the key transcriptional regulators nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) and nuclear factor of activated T cells (NFAT) while partly preserving activator protein 1 (AP-1) activity.Conclusion These findings highlight moderate activation as a critical determinant of engineered T cell long-term performance. Low-dose MEKi offers a therapeutic tool for fine-tuning T cell activation and enhancing ACT efficacy.",
  "authors": [
    {
      "affiliations": [
        "School of Medicine and Health, III Medical Department, TUM University Hospital, Technical University of Munich, Munich, Germany",
        "Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, Munich, Germany"
      ],
      "name": "Franziska Füchsl"
    },
    {
      "affiliations": [
        "School of Medicine and Health, III Medical Department, TUM University Hospital, Technical University of Munich, Munich, Germany",
        "Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, Munich, Germany"
      ],
      "name": "Antonia Schwanzer"
    },
    {
      "affiliations": [
        "School of Medicine and Health, III Medical Department, TUM University Hospital, Technical University of Munich, Munich, Germany",
        "Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, Munich, Germany"
      ],
      "name": "Melanie Faber"
    },
    {
      "affiliations": [
        "School of Medicine and Health, III Medical Department, TUM University Hospital, Technical University of Munich, Munich, Germany",
        "Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, Munich, Germany"
      ],
      "name": "Leonie Rieger"
    },
    {
      "affiliations": [
        "School of Medicine and Health, III Medical Department, TUM University Hospital, Technical University of Munich, Munich, Germany",
        "Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, Munich, Germany"
      ],
      "name": "Gabriela Zuleger"
    },
    {
      "affiliations": [
        "School of Medicine and Health, III Medical Department, TUM University Hospital, Technical University of Munich, Munich, Germany",
        "Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, Munich, Germany"
      ],
      "name": "Priska Auf der Maur"
    },
    {
      "affiliations": [
        "School of Medicine and Health, III Medical Department, TUM University Hospital, Technical University of Munich, Munich, Germany",
        "Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, Munich, Germany"
      ],
      "name": "Emmanuel Cruz"
    },
    {
      "affiliations": [
        "Institute of Medical Microbiology Immunology and Hygiene, Technical University of Munich, Munich, Germany"
      ],
      "name": "Sarah Braun"
    },
    {
      "affiliations": [
        "Institute of Molecular Oncology and Functional Genomics, TUM School of Medicine and Health, Technical University of Munich, Munich, Germany"
      ],
      "name": "Rupert Öllinger"
    },
    {
      "affiliations": [
        "Institute of Medical Microbiology Immunology and Hygiene, Technical University of Munich, Munich, Germany",
        "German Center for Infection Research, Munich Site, Munich, Germany"
      ],
      "name": "Dirk H Busch"
    },
    {
      "affiliations": [
        "School of Medicine and Health, III Medical Department, TUM University Hospital, Technical University of Munich, Munich, Germany",
        "Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, Munich, Germany",
        "Bavarian Cancer Research Center, Erlangen, Germany",
        "German Cancer Consortium (DKTK), partner-site Munich, German Cancer Research Center (DKFZ), Heidelberg, Germany"
      ],
      "name": "Florian Bassermann"
    },
    {
      "affiliations": [
        "School of Medicine and Health, III Medical Department, TUM University Hospital, Technical University of Munich, Munich, Germany",
        "Center for Translational Cancer Research (TranslaTUM), Technical University of Munich, Munich, Germany",
        "German Cancer Consortium (DKTK), partner-site Munich, German Cancer Research Center (DKFZ), Heidelberg, Germany"
      ],
      "name": "Angela M Krackhardt"
    }
  ],
  "title": "Tempered signal strength via low-dose MEK inhibition optimizes therapeutic performance of engineered T cells",
  "uid": "98aa2b7e-4e7b-5e99-a191-1b0f49cec42f"
}