{
  "abstract": "Background Chronic inflammatory disorders contribute to over 30% of global mortality and underlie major diseases such as cancer, fibrosis, and autoimmunity. Fibrosis is a hallmark of chronic inflammation following tissue injury that drives progressive organ dysfunction and cancer progression. Existing anti-fibrotic therapies are limited by modest efficacy and systemic toxicity. We hypothesize that the selective elimination of fibrogenic and inflammatory effector cells can disrupt self-perpetuating cycles of injury and inflammation, providing a targeted therapeutic avenue for chronic disease.Methods Using proximity-based surface proteomics, we identified the urokinase plasminogen activator receptor (uPAR) as broadly upregulated in senescent and chronically injured tissues across cancer and fibrotic contexts. This was corroborated by a meta-analysis of eight senescence-focused and sixteen cancer transcriptomic datasets, as well as immunohistochemical validation on patient tissue microarrays. uPAR, a GPI-anchored membrane protein central to wound healing and tissue remodeling, is consistently elevated during chronic inflammation in cancer and fibrosis. In a somatic tissue-engineered syngeneic mouse model of ovarian cancer, we demonstrated the anti-tumor efficacy of murine uPAR-targeted CAR T cells. We then generated clinical-grade human uPAR-targeting single-chain variable fragments (scFvs) through phage display and hybridoma screening, and validated their ability to eradicate both orthotopic and metastatic xenograft tumors.Results uPAR-targeted CAR T cells selectively eliminated senescent cells and attenuated fibrosis in preclinical models of liver and lung injury. In cancer, uPAR expression marks aggressive tumor cells undergoing epithelial-to-mesenchymal transition (EMT) and senescent stromal cells embedded in immunosuppressive niches. In multiple solid tumor models, including immune-excluded settings, human uPAR CAR T cells exhibited potent and durable anti-tumor activity. In an ovarian cancer model, adjuvant administration of uPAR CAR T cells post-surgical debulking effectively prevented metastatic recurrence. Therapeutic efficacy was tracked via noninvasive biomarkers, including circulating soluble uPAR and uPAR-targeted PET imaging. Despite detectable expression in subsets of myeloid cells, treatment with uPAR CAR T cells did not induce sustained myelodepletion in mice with a humanized immune system.Conclusions These findings establish uPAR-targeted CAR T cells as a promising therapeutic strategy across cancer, fibrosis, and degenerative diseases by eliminating shared pathological cell states that sustain chronic inflammation and tissue dysfunction ( figure 1).Abstract 299 Figure 1Abstract images (poster)",
  "authors": [
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Zeda Zhang"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Yu-jui Ho"
    },
    {
      "affiliations": [
        "Mount Sinai, New York, NY, USA"
      ],
      "name": "Xin Fang"
    },
    {
      "affiliations": [
        "UKT, Tubingen, Germany"
      ],
      "name": "Clemens Hinterleitner"
    },
    {
      "affiliations": [
        "Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA"
      ],
      "name": "Sascha Haubner"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Friderike Kogel"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Edwin Pratt"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Paul Romesser"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Britta Weigelt"
    },
    {
      "affiliations": [
        "University Children’s Hospital Tübingen, Tübingen, Tübingen, Germany"
      ],
      "name": "Judith Feucht"
    },
    {
      "affiliations": [
        "Icahn School of Medicine at Mount Sinai, New York, NY, USA"
      ],
      "name": "Dmitriy Zamarin"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Sohrab P Shah"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Jason Lewis"
    },
    {
      "affiliations": [
        "Moffitt Cancer Center, New York, NY, USA"
      ],
      "name": "Jorge Mansilla-Soto"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Aveline Filliol"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Michel Sadelain"
    },
    {
      "affiliations": [
        "Memorial Sloan Kettering Cancer Center, New York, NY, USA"
      ],
      "name": "Scott Lowe"
    }
  ],
  "title": "299 Targeting dysregulated wound healing programs in cancer and fibrosis with immune engineering",
  "uid": "3963111b-8655-5560-b601-30eeff09ea9d"
}