{
  "abstract": "Background XTX301 is a tumor-activated IL-12 designed to potently stimulate anti-tumor immunity and reprogram the tumor microenvironment (TME) of poorly immunogenic ‘cold’ tumors towards an inflamed or ‘hot’ state. The tumor-activated design enables localized activity of XTX301 in the TME, thereby widening the therapeutic index relative to recombinant human (rh)IL-12.Methods This phase 1 dose-escalation study of intravenous XTX301 monotherapy in patients with metastatic solid tumors evaluates safety/tolerability, PK/PD and anti-tumor activity using a standard 3+3 design to determine dosing schedule and a recommended phase 2 dose (RP2D). Translational analyses were performed in peripheral blood and in tumor biopsies of patients for whom paired biopsies and ctDNA were obtained before and during treatment.Results As of 3 June 2025, 55 patients were treated at multiple doses (5 to 120µg/kg) and schedules. Consistent with the tumor-activated design, treatment-related AEs (TRAEs) were primarily low grade—no G4 or G5 TRAEs reported. TRAEs ≥15% (any grade) were AST increased (29%); ALT increased, fatigue, nausea (24% each); cytokine release syndrome (CRS, 22%); chills and WBC decreased (20% each); headache, platelet count decreased, and pyrexia (16% each). G3 TRAEs ≥5% were ALT increased (7%), AST increased (6%) and WBC decreased (6%). Two patients (4%) discontinued due to TRAEs. One DLT (mucositis) was reported at the highest dose tested—RP2D determination is ongoing. Pharmacokinetics (n=45 patients) showed a relatively dose-proportional exposure without peripheral cleavage of XTX301. Pharmacodynamics demonstrated a sustained dose dependent increase in IFNγ production that was maintained without tachyphylaxis ( figure 1), robust increases in CD8+ T cells in tumors and differentiation of T cells towards effector/memory phenotype consistent with IL-12 biology (figure 2).Conclusions XTX301, a tumor-activated IL-12, was generally well-tolerated at doses more than 100-fold greater than the maximum tolerated dose of rhIL-12. XTX301 administration led to sustained IFNγ production without tachyphylaxis and transformed the TME towards an inflamed state with increased T cell infiltration and differentiation towards effector/memory phenotype, warranting continued evaluation as monotherapy or in immunotherapy combinations.Ethics Approval This study was approved by Advarra Institutional Review Board, approval number Pro00067431. All study participants gave informed consent before taking part in the study.Trial Registration NCT05684965Abstract 567 Figure 1XTX301 induces dose-dependent increase in IFN- γ without tachyphylaxis. Serum IFN-γ concentrations were measured by Meso Scale Discovery (MSD) assay in XTX301-treated patients. (A) Time course showing average IFN- γ levels with dosing cycles indicated (yellow: priming dose [ie, single 15ug/kg dose 3 weeks prior to first full dose]; red: full dose Q6W). (B) Area under the curve (AUC) for log2-transformed average IFN- γ concentration from Cycle 2 Day 1 to Cycle 4 Day 1Abstract 567 Figure 2XTX301 treatment enhances CD8+ T cell infiltration across multiple analytical platforms. Tumor biopsies and fine needle aspirate samples were collected pre-treatment and on-treatment (Cycle 2, days 2-5) from a head and neck cancer patient treated with XTX301. (A) Immunohistochemistry: CD8+ T cells (percentage of Tumor-Infiltrating Immune Cells, TIIC) increased on-treatment. (B) Flow cytometry from fine needle aspirates:%CD8+ T cells (% of CD3+) increased from ~20% to ~47%. (C) Multiplex immunofluorescence: CD3+CD8+ cell density (cells/mm²) showed consistent elevation on-treatment across all tissue compartments compared to pre-treatment. Results demonstrate robust CD8+ T cell infiltration following XTX301 treatment",
  "authors": [
    {
      "affiliations": [
        "Washington University School of Medicine, St. Louis, MO, USA"
      ],
      "name": "Douglas Adkins"
    },
    {
      "affiliations": [
        "Medical College of Wisconsin, Milwaukee, WI, USA"
      ],
      "name": "William Bradley"
    },
    {
      "affiliations": [
        "The Ohio State University Comprehensive Cancer Center, Plain City, OH, USA"
      ],
      "name": "Richard Wu"
    },
    {
      "affiliations": [
        "Hackensack University Medical Center – John Theurer Cancer Center, Hackensack, NJ, USA"
      ],
      "name": "Martin Gutierrez"
    },
    {
      "affiliations": [
        "UC Davis Comprehensive Cancer Center, Sacramento, CA, USA"
      ],
      "name": "Tianhong Li"
    },
    {
      "affiliations": [
        "UH Cleveland Medical Center, Cleveland, OH, USA"
      ],
      "name": "Amit Mahipal"
    },
    {
      "affiliations": [
        "Gabrail Cancer Center, Canton, OH, USA"
      ],
      "name": "Nashat Y Gabrail"
    },
    {
      "affiliations": [
        "HealthPartners Frauenshuh Cancer Center, St Louis Park, MN, USA"
      ],
      "name": "Jayanthi Vijayakumar"
    },
    {
      "affiliations": [
        "Tranquil Clinical Research, Houston, TX, USA"
      ],
      "name": "John Knecht"
    },
    {
      "affiliations": [
        "Xilio Therapeutics, Waltham, MA, USA"
      ],
      "name": "Ekta Patel"
    },
    {
      "affiliations": [
        "Xilio Therapeutics, Waltham, MA, USA"
      ],
      "name": "Myra W Popejoy"
    },
    {
      "affiliations": [
        "Xilio Therapeutics, Waltham, MA, USA"
      ],
      "name": "Scott McConnell"
    },
    {
      "affiliations": [
        "Xilio Therapeutics, Waltham, MA, USA"
      ],
      "name": "David Crowe"
    },
    {
      "affiliations": [
        "Xilio Therapeutics, Waltham, MA, USA"
      ],
      "name": "Sattanathan Paramasivan"
    },
    {
      "affiliations": [
        "Xilio Therapeutics, Waltham, MA, USA"
      ],
      "name": "Damiano Fantini"
    },
    {
      "affiliations": [
        "Xilio Therapeutics, Waltham, MA, USA"
      ],
      "name": "Emeline S Bacqué"
    },
    {
      "affiliations": [
        "Xilio Therapeutics, Waltham, MA, USA"
      ],
      "name": "Aika Siu"
    },
    {
      "affiliations": [
        "Xilio Therapeutics, Waltham, MA, USA"
      ],
      "name": "Bruce Dezube"
    },
    {
      "affiliations": [
        "Yale New Haven Hospital, Yale Cancer Center, New Haven, CT, USA"
      ],
      "name": "Thuy T Tran"
    },
    {
      "affiliations": [
        "UPMC Hillman Cancer Center, Pittsburgh, PA, USA"
      ],
      "name": "Diwakar Davar"
    }
  ],
  "title": "567 XTX301, a tumor-activated Interleukin-12 (IL-12), demonstrated IL-12 pharmacology in patients with advanced solid tumors: pharmacodynamic data from first-in-human phase 1 study (NCT05684965)",
  "uid": "6f297ae0-ac5b-55ae-9692-d3288524c26c"
}