{
  "abstract": "Introduction CT041, a Claudin18.2-specific CAR-T cell therapy in gastrointestinal tumors, has demonstrated encouraging efficacy and a manageable safety profile. However, the responsive and resistant mechanisms to CT041 therapy remain poorly understood.Methods An exploratory biomarker analysis of the phase 1 CT041-CG4006 clinical trial ( NCT03874897) was conducted. Dynamic samples from primary tumors (PT) were collected at baseline and disease progression, and dynamic samples from peripheral blood and malignant ascites were obtained at days 0, 3, and 7 from 35 gastric cancer (GC) patients. Single-cell/nuclei RNA sequencing, spatial transcriptomics, multiplex immunofluorescence detection, and in vivo and in vitro molecular and functional experiments were conducted.Results Higher infiltration of GZMK+CD8+ T cells, which exhibited a progenitor exhausted-like (Tpex) state, were identified in PT of responders. Baseline GZMK+ Tpex infiltration manifested superior potential as a predictor of CT041 response and positively correlated with better prognosis. Spatial multi-omics analyses uncovered coordinated cellular interactions centered around GZMK+ Tpex, including their interplay with IRF8+ B cells and CLEC10A+ dendritic cells via IFN-γ and antigen presentation pathways, which contributed to the formation of tertiary lymphoid structures and sensitization to CT041 treatment. In CT041-resistant cases, higher infiltrates of IQGAP3+CLDN18.2+ cancer cells were observed. Overexpression of IQGAP3 increased the proliferative, metastatic, and invasive capacity of CLDN18.2+ GC cell lines, and impaired the cytotoxicity of CAR-T cells in vitro. Moreover, poor efficacy of CAR-T cells was found in IQGAP3+CLDN18.2+ patient-derived xenograft GC models, which were featured by enhanced TGF-β1 levels and decreased CAR-T cell infiltration. Mechanistically, IQGAP3+CLDN18.2+ cancer cells hindered the infiltration of GZMK+ Tpex and synergized with IL6+ fibroblasts to foster an immunosuppressive milieu, where enhanced TGF-β signaling and epithelial-to-mesenchymal transition activity of cancer cells were discovered. Eventually, dynamic monitoring of blood and ascites samples identified CAR-T cell subsets with memory phenotype and the ability to infiltrate tumors correlated with a favorable response.Conclusion The biological significance and clinical implications of GZMK+ Tpex in determining response to CAR-T cell treatment of GC, and IQGAP3+CLDN18.2+ cancer cells as related to resistance were underscored, which were conducive to guiding patient selection for CT041 therapy and offered insights into resistance mechanisms.Abstract O15 Figure 1Overview of the study design and the schematic summary of systemic and local immunity mediating response and resistance to Claudin18.2-specific CAR-T cell therapy in gastric cancer",
  "authors": [
    {
      "affiliations": [
        "Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China"
      ],
      "name": "Haoxin Peng"
    },
    {
      "affiliations": [
        "Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China"
      ],
      "name": "Yang Chen"
    },
    {
      "affiliations": [
        "Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China"
      ],
      "name": "Xiaoyi Chong"
    },
    {
      "affiliations": [
        "Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China"
      ],
      "name": "Dan Liu"
    },
    {
      "affiliations": [
        "Department of Radiation Oncology, Peking University Cancer Hospital & Institute, Beijing, China"
      ],
      "name": "Yueting Liang"
    },
    {
      "affiliations": [
        "Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, China"
      ],
      "name": "Lin Shen"
    }
  ],
  "title": "O15 Unveiling biomarkers of response and resistance to claudin18.2-targeted CAR-T cell therapy (CT041) in gastric cancer: a phase 1 biomarker analyses",
  "uid": "5b965723-bce7-5742-b841-6904540f20b1"
}