{
  "abstract": "Background Checkpoint inhibitors (CPIs) and CAR-T therapies have revolutionised cancer treatment, yet most patients with solid tumors fail to respond due to immune exclusion and immunosuppressive tumor microenvironments (TME). These adaptive therapies depend on effector cell infiltration and activation within the tumor. LIfT BioSciences has developed Immunomodulatory Alpha Neutrophils (IMANs), the worlds first off-the-shelf, allogeneic neutrophil-based cell therapy derived from CD34+ haematopoietic stem cells (HSCs) or induced pluripotent stem cells (iPSCs). IMANs are functionally engineered to reverse the immunosuppressive myeloid landscape, restore innate immune competence, and enable downstream activation of adaptive immune responses in solid tumors.Methods IMANs were generated via a proprietary, GMP-compliant differentiation process that yields a novel neutrophil lineage with enhanced persistence and anti-tumor activity. IMAN biodistribution, persistence and mechanism of action were assessed in tumour-bearing humanized mice and in ex vivo platforms, including tumor histoculture, tumor-on-a-chip and patient-derived organoid (PDX-O) models. Combination efficacy was evaluated with CPIs (eg. nivolumab) and CAR-T cells in resistant tumour models.Results Following IV administration, IMANs exhibited physiological biodistribution and consistent tumor infiltration up to 21 days in vivo, aligning with 4 week in vitro persistence. IMAN infiltration preceded robust recruitment of T and NK cells. In histoculture and tumor-on-a-chip models, IMANs enhanced effector cell recruitment, resulting in increased tumor cell death. Co-culture with IMANs upregulated activation markers (OX40, 4-1BB, CD25, CD69), increased IFN-γ secretion, and enhanced cytotoxicity of allogeneic tumour-infiltrating lymphocytes (TILs) and PBMCs. In a histoculture model of head and neck squamous cell carcinoma (HNSCC), IMANs combined with nivolumab induced greater tumor cytotoxicity than CPI alone. Notably, IMANs synergised with CAR-T cells to enhance tumor clearance in models of treatment-resistant cervical and pancreatic cancers. In PDX-O models, IMANs exhibited robust, antigen-independent cytotoxicity across multiple solid tumor types, demonstrating potential to target antigen escape variants that drive metastatic progression, a factor implicated in 90% of cancer deaths.Conclusions IMANs represent a novel immunotherapy platform designed to restore innate immune competence and remodel the TME in support of anti-tumor immunity. By replacing immunosuppressive neutrophils with engineered immunostimulatory counterparts, IMANs activate both innate and adaptive responses, converting cold tumours into immune-responsive sites. IMANs synergy with CPIs and CAR-Ts, alongside potent efficacy as a monotherapy in antigen-escape contexts, supports their development as both a foundational and combinatorial strategy in solid tumor immunotherapy. With long-lived function, scalable off-the-shelf manufacturing, and lower cost-of-goods profile than many cell therapies, IMANs offer broad clinical potential across oncology and immune-mediated diseases.Ethics Approval All studies involving human material were conducted in accordance with the Declaration of Helsinki and received approval from the appropriate institutional review boards. Informed consent was obtained from all human donors prior to sample collection. All animal studies were reviewed and approved by the relevant institutional animal care and use committees and conducted in compliance with applicable regulations and ethical guidelines.",
  "authors": [
    {
      "affiliations": [
        "LIT BiSciences, London, UK"
      ],
      "name": "Aoife M McGinley"
    },
    {
      "affiliations": [
        "LIT BiSciences, London, UK"
      ],
      "name": "Samuel Florence"
    },
    {
      "affiliations": [
        "LIT BiSciences, London, UK"
      ],
      "name": "Connor McGarrity-Cottrell"
    },
    {
      "affiliations": [
        "LIT BiSciences, London, UK"
      ],
      "name": "Natalia Becares"
    },
    {
      "affiliations": [
        "LIT BiSciences, London, UK"
      ],
      "name": "Mihil Patel"
    },
    {
      "affiliations": [
        "LIT BiSciences, London, UK"
      ],
      "name": "James Roper"
    },
    {
      "affiliations": [
        "LIT BiSciences, London, UK"
      ],
      "name": "Durva Patel"
    },
    {
      "affiliations": [
        "LIT BiSciences, London, UK"
      ],
      "name": "Oxana Polyakova"
    },
    {
      "affiliations": [
        "LIT BiSciences, London, UK"
      ],
      "name": "Alex Blyth"
    },
    {
      "affiliations": [
        "LIT BiSciences, London, UK"
      ],
      "name": "Mark A Exley"
    }
  ],
  "title": "645 IMANs: a transformative allogeneic neutrophil cell therapy for rejuvenating innate immunity and overcoming treatment resistance in solid tumours",
  "uid": "cbdebfbf-14b6-5e16-ba1d-193d35e7760a"
}