{
  "abstract": "Background IMGS-203 is a STING (Stimulator of Interferon Genes) agonist in development as an intratumorally administered therapy for glioblastoma multiforme (GBM). In multiple murine glioma models, including a humanized model with epigenetically silenced STING, IMGS-203 has demonstrated strong therapeutic activity, 1 supporting its translational potential. IMGS-203 acts directly on the immune suppressive myeloid stroma, which is prominent in GBM, and repolarizes these cells to a proinflammatory state. As an immune-modulating agent, IMGS-203 does not need to directly target tumor cells; instead, it induces a broad pro-inflammatory response driven by generalized type I interferon production within the tumor microenvironment. Intratumoral administration addresses both the challenge of sufficient local exposure and the risk of off-tumor side effects. Here, we describe the preclinical development of IMGS-203, including anti-tumor efficacy, pharmacokinetic, and safety studies.Methods For dose range finding studies, the mouse glioma cell line CT-2A was implanted orthotopically and treated with 0.5-10µg IMGS-203, starting 10-12 days post-implantation. Pharmacokinetics was assessed in mice following intravenous, intratumoral, or intracranial administration of 5-100µg IMGS-203. An LC-MS/MS assay with a lower limit of quantification of 1 ng/ml was developed to measure IMGS-203 concentrations in serum and tissue. Safety studies evaluating direct administration of IMGS-203 to healthy brain tissue were conducted in mice and dogs.Results Treatment of orthotopic CT-2A tumors with 2 doses of 1µg or 10µg IMGS-203 significantly improved survival compared to the PBS control group (p <0.01). At study completion (60 days), 50% of IMGS-203-treated mice were alive, whereas none of the control animals survived beyond 35 days. PK studies in mice confirmed a short serum half-life, of 18-32 minutes. Intravenous and intracranial administrations result in similar half-lifes, suggesting no specific retention of IMGS-203 in brain tissue. In dogs, no IMGS-203 was detectable in serum or cerebrospinal fluid at any timepoint following intracranial administration of up to 100µg. Safety studies showed that mice tolerated high dose intracranial IMGS-203, while dogs were more susceptible to local effects such as cerebral edema.Conclusions These data, together with previously published studies on potency, efficacy, and mechanism of action, 1–4 will support the submission of an investigational new drug application for IMGS-203 as a treatment for GBM. The advantage of using IMGS-203 to treat GBM is that it does not need to be delivered to every cell to be effective, but by impacting the tumor microenvironment, it triggers innate and adaptive immune activation, leading to a potent antitumor effect.References Najem H, Lea ST, Tripathi S, Hurley L, Chen CH, William I, Sooreshjani M, Bowie M, Hartley G, Dussold C, Pacheco S, Dmello C, Lee-Chang C, McCortney K, Steffens A, Walshon J, Ott M, Wei J, Marisetty A, Balyasnikova I, Stupp R, Lukas RV, Hu J, James CD, Horbinski CM, Lesniak MS, Ashley DM, Priebe W, Platanias LC, Curran MA, Heimberger AB. STING agonist 8803 reprograms the immune microenvironment and increases survival in preclinical models of glioblastoma. J Clin Invest. 2024 Jun 17;134(12):e175033.Ager CR, Zhang H, Wei Z, Jones P, Curran MA, Di Francesco ME. Discovery of IACS-8803 and IACS-8779, potent agonists of stimulator of interferon genes (STING) with robust systemic antitumor efficacy. Bioorg Med Chem Lett. 2019;29(20):126640.Ager CR, Boda A, Rajapakshe K, Lea ST, Di Francesco ME, Jayaprakash P, Slay RB, Morrow B, Prasad R, Dean MA, Duffy CR, Coarfa C, Jones P, Curran MA. High potency STING agonists engage unique myeloid pathways to reverse pancreatic cancer immune privilege. J Immunother Cancer. 2021 Aug;9(8):e003246.Salameh, A, Blezinger P, Conti L, Bolli E, Cossu C, Gagliardi C, Cavallo F, Barlow J, Curran M, Pericle F. 1023 Preclinical development of STING agonist 8803 (IMGS-203) for the treatment of solid tumors. Journal for ImmunoTherapy of Cancer. 2024;12:A1144-A1144. 10.1136/jitc-2024-SITC2024.1023.",
  "authors": [
    {
      "affiliations": [
        "ImmunoGenesis, Inc., Houston, TX, USA"
      ],
      "name": "Christine Gagliardi"
    },
    {
      "affiliations": [
        "ImmunoGenesis, Inc., Houston, TX, USA"
      ],
      "name": "Paul Blezinger"
    },
    {
      "affiliations": [
        "ImmunoGenesis, Inc., Houston, TX, USA"
      ],
      "name": "Ahmad Salameh"
    },
    {
      "affiliations": [
        "The University of Texas MD Anderson Cancer Center, Houston, TX, USA"
      ],
      "name": "Michael A Curran"
    },
    {
      "affiliations": [
        "ImmunoGenesis, Inc., Houston, TX, USA"
      ],
      "name": "James Barlow"
    },
    {
      "affiliations": [
        "ImmunoGenesis, Inc., Houston, TX, USA"
      ],
      "name": "Federica Pericle"
    }
  ],
  "title": "909 Intratumoral STING activation with IMGS-203 drives anti-tumor responses in glioblastoma: preclinical efficacy, safety, and pharmacokinetic profile",
  "uid": "3f2fe39a-7c98-517f-8ee1-a51d87ec4c20"
}