{
  "abstract": "Background Immune checkpoint inhibitors have revolutionized cancer therapy, yet a substantial proportion of patients exhibit primary or acquired resistance. Immunocytokines offer a strategy to enhance antitumor immunity by delivering cytokine signals selectively to the tumor microenvironment. Here, we describe the immunoconjugate anti-programmed cell death protein 1 (PD-1)-interleukin (IL)-18 (aPD1-IL18 mut), designed to couple PD-1-blockade with localized IL-18-mediated immune activation.Methods aPD1-IL18 mut was generated by chemically conjugating the anti-human PD-1 antibody Lipustobart to an IL-18 variant engineered to evade IL-18 binding protein. Its mechanism of action was characterized using human PD-1 transgenic mouse models. To assess the translational relevance of these in vivo findings, complementary in vitro assays were conducted on human tumor samples, alongside analyses of publicly available single-cell RNA sequencing datasets.Results In vitro, PD-1 engagement enhanced functional IL-18 activity, preserving interferon (IFN)-γ secretion even under IL-18BP pressure. In MC38 tumors, aPD1-IL18 mut induced robust CD8+ T cell-driven tumor control, accompanied by intratumoral accumulation of activated CD8+ T cells and a pronounced type 1-associated cytokine response. In anti-PD-1-resistant YUMM1.7 tumors, therapeutic efficacy instead relied predominantly on Th1-like CD4+ effector T cells, and aPD1-IL18mut stimulation was associated with enhanced activation, proliferation, IFN-γ, and granzyme B expression in PD-1+IL-18Rɑ+ CD4+ T cells. In human cancer digest cultures, aPD1-IL18mut elicited a dominant IL-18/IFN-γ-driven cytokine signature and enhanced tumor cell killing. Importantly, analyses of the immune infiltrate across multiple human solid tumor types identified analogous PD-1+IL-18Rɑ+ CD4+ Th1-like and CD8+ effector-like T-cell subsets with effector-associated and tumor-reactive transcriptional and protein signatures.Conclusions aPD1-IL18 mut activates T-cell populations with tumor-reactive features and promotes IFN-γ-driven inflammation across distinct tumor immune contexts. Its ability to activate CD8+ and CD4+ Th1-like effector cells, together with the presence of analogous subsets in multiple human cancers, provides mechanistic and translational support for PD-1-targeted IL-18 therapy.",
  "authors": [
    {
      "affiliations": [
        "Department of Biomedicine, University Hospital Basel, Basel, Switzerland"
      ],
      "name": "Nicole Oelgarth"
    },
    {
      "affiliations": [
        "Bright Peak Therapeutics, Allschwil, Switzerland"
      ],
      "name": "Kea Martin"
    },
    {
      "affiliations": [
        "Bright Peak Therapeutics, Allschwil, Switzerland"
      ],
      "name": "Fabian Junker"
    },
    {
      "affiliations": [
        "Department of Biomedicine, University Hospital Basel, Basel, Switzerland"
      ],
      "name": "Clara Serger"
    },
    {
      "affiliations": [
        "Bright Peak Therapeutics, Allschwil, Switzerland"
      ],
      "name": "Caoimhe Herr"
    },
    {
      "affiliations": [
        "Department of Biomedicine, University Hospital Basel, Basel, Switzerland"
      ],
      "name": "Mélanie Buchi"
    },
    {
      "affiliations": [
        "Bright Peak Therapeutics, Allschwil, Switzerland"
      ],
      "name": "Lilian Gremlich"
    },
    {
      "affiliations": [
        "Department of Biomedicine, University Hospital Basel, Basel, Switzerland"
      ],
      "name": "Irene Fusi"
    },
    {
      "affiliations": [
        "Department of Biomedicine, University Hospital Basel, Basel, Switzerland"
      ],
      "name": "Jonas Fürst"
    },
    {
      "affiliations": [
        "Department of Biomedicine, University Hospital Basel, Basel, Switzerland"
      ],
      "name": "Petra Herzig"
    },
    {
      "affiliations": [
        "Bright Peak Therapeutics, Allschwil, Switzerland"
      ],
      "name": "Philipp Moosmann"
    },
    {
      "affiliations": [
        "Department of Gynecology and Obstetrics, University Hospital Basel, Basel, Switzerland"
      ],
      "name": "Viola Heinzelmann-Schwarz"
    },
    {
      "affiliations": [
        "Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland"
      ],
      "name": "Kirsten D Mertz"
    },
    {
      "affiliations": [
        "Department of Visceral Surgery, Cantonal Hospital Basel-Landschaft, Liestal, Switzerland"
      ],
      "name": "Robert Rosenberg"
    },
    {
      "affiliations": [
        "Department of Biomedicine, University Hospital Basel, Basel, Switzerland"
      ],
      "name": "Karin Schaeuble"
    },
    {
      "affiliations": [
        "Bright Peak Therapeutics, Allschwil, Switzerland"
      ],
      "name": "Jean-Philippe Carralot"
    },
    {
      "affiliations": [
        "Department of Biomedicine, University Hospital Basel, Basel, Switzerland"
      ],
      "name": "Thuy T Luu"
    },
    {
      "affiliations": [
        "Bright Peak Therapeutics, Allschwil, Switzerland"
      ],
      "name": "Bertolt Kreft"
    },
    {
      "affiliations": [
        "Bright Peak Therapeutics, Allschwil, Switzerland"
      ],
      "name": "Vijaya Pattabiraman"
    },
    {
      "affiliations": [
        "Department of Biomedicine, University Hospital Basel, Basel, Switzerland",
        "Department of Medical Oncology, University Hospital Basel, Basel, Switzerland"
      ],
      "name": "Alfred Zippelius"
    }
  ],
  "title": "Anti-PD1-IL18 immunoconjugate promotes effector T cell-mediated antitumor immunity",
  "uid": "39f494c9-785a-53b2-8b7a-1c595bbf0338"
}