{
  "abstract": "Background Low response rates to immune checkpoint inhibitors (ICI) are attributed to a lack of anti-tumor T cells. Induction of anti-tumor T cell expansion by tumor necrosis may enhance the efficacy of ICIs.Methods This is a translational study of two prospective, multi-center Phase 2 studies ( NCT03259867, NCT04701476) of liver-present HCC, NSCLC and gastric cancer, who had progressed on immunotherapy. Patients received ICI Q3W IV starting day 1, Trans-arterial Tirapazamine embolization (TATE) on Days 8, 29 and on demand to achieve optimal tumor necrosis confirmed by MRI scans. Peripheral blood mononuclear cells (PBMCs) were collected at Days 8 (post ICI pre-TATE), 22, 43 and 63 (post TATE) for RNA extraction and analysis of CDR3 of T cell receptors (TCR) by next generation sequencing (NGS) (figure 1). PBMCs were also purified by a Ficoll gradient and stained with antibody cocktails for multi-channel flow cytometry to examine clonal expansion and cell profiles. Cytotoxicity against tumor was evaluated with inclusion of propidium iodide in tumor. The extent of clonal expansion of CDR3 was correlated with the clinical outcome, particularly the abscopal effect in extra-hepatic lesions.Results TATE+ICI achieved a promising 50% response in the study population who progressed on immunotherapy. Mechanism of the response was investigated through analysis of cell populations in PBMCs and T cell clonality. Compared to the pre-TATE baseline sample, new T cells clones comprised of 60-70% of all CDR3 clones were generated after TATE. Among them, 20-50 CDR3 clones achieved high copy numbers ranged from 500 to over 8000. In addition, a few populations of pre-existing CDR3 clones were expanded by over 100 folds from the pre-TATE baseline. These clones also exhibited a steady increase with each TATE procedure, supporting a causal relationship with TATE. Multi-channel flow cytometry showed a significant expansion of CD8+ central memory and effector memory T cells, which are consistent with a population of tumor-cytotoxic population. Details of the data and cytotoxicity of the PBMCs toward tumor cells will be presented. Clinical responders correlated with more CDR3 expansion.Conclusions TATE plus ICI can expand anti-tumor T cells in various cancers with liver metastasis, and the activity correlated with clinical efficacy in salvaging advanced immunotherapy-refractory patients. Further investigation is warranted to confirm the efficacy of expanded T cells.Acknowledgements Funding was provided by Teclison, Inc.Trial Registration NCT03259867, NCT04701476Ethics Approval UCI #16-94; China Medical Univ. LT004/CMUH113-REC1-025; Chang-Gung Memorial Linkou Hospital, LT004/#202400098A0; TSGH LT004/B202501001Abstract 594 Figure 1Expansion and newly generated CDR3 clones after tumor necrosis-inducing therapy",
  "authors": [
    {
      "affiliations": [
        "Chang Gung University, Taoyuan, Taiwan"
      ],
      "name": "Chia-Yu Yang"
    },
    {
      "affiliations": [
        "Chang Gung University, Taoyuan, Taiwan"
      ],
      "name": "Ian Yi-Feng Chang"
    },
    {
      "affiliations": [
        "University of California, Irvine, Orange, CA, USA"
      ],
      "name": "Mahmoud K Singer"
    },
    {
      "affiliations": [
        "University of California, Irvine, Orange, CA, USA"
      ],
      "name": "Farshid Dayyani"
    },
    {
      "affiliations": [
        "University of California, Irvine, Orange, CA, USA"
      ],
      "name": "David K Imagawa"
    },
    {
      "affiliations": [
        "University of California, Irvine, Orange, CA, USA"
      ],
      "name": "Dayantha Fernando"
    },
    {
      "affiliations": [
        "Chang Gung University, Taoyuan, Taiwan"
      ],
      "name": "Kun-ming Chan"
    },
    {
      "affiliations": [
        "Chang Gung University, Taoyuan, Taiwan"
      ],
      "name": "Kuei-An Chen"
    },
    {
      "affiliations": [
        "Chang Gung University, Taoyuan, Taiwan"
      ],
      "name": "Ying-Chieh Lai"
    },
    {
      "affiliations": [
        "Chinese Medical University, Hsin Chu, Taiwan"
      ],
      "name": "Chih-yuan Chung"
    },
    {
      "affiliations": [
        "Triservice General Hospital, Taipei, Taiwan"
      ],
      "name": "Chang-hsien Liu"
    },
    {
      "affiliations": [
        "Teclison, Inc, Princeton, NJ, USA"
      ],
      "name": "Wei-Chou Chang"
    },
    {
      "affiliations": [
        "Triservice General Hospital, Taipei, Taiwan"
      ],
      "name": "Teng-wei Chen"
    },
    {
      "affiliations": [
        "Chang Gung University, Taoyuan, Taiwan"
      ],
      "name": "Cheng-Lun Ku"
    },
    {
      "affiliations": [
        "Teclison, Inc, Princeton, NJ, USA"
      ],
      "name": "Ray Lee"
    },
    {
      "affiliations": [
        "University of California, Irvine, Orange, CA, USA"
      ],
      "name": "Nadine Abi-Jaoudeh"
    }
  ],
  "title": "594 Tumor necrosis-induced expansion of anti-tumor T cells enhanced the efficacy of immune checkpoint inhibitors (ICIs) and salvaged patients with immunotherapy-refractory cancers",
  "uid": "70d78aa1-4edc-5bc1-b211-65df239d6a92"
}