{
  "abstract": "Background Immune checkpoint inhibitors have revolutionized cancer treatment, providing hope to many patients who were previously deemed uncurable. Unfortunately, only a minority of patients benefits from this type of immunotherapy. One of the key factors limiting immunotherapy efficacy in cancer is immunosuppression, systemically and of the tumor microenvironment (TME). The main culprits are the numerous myeloid cells with an immunosuppressive phenotype and their bone marrow progenitors. 1 Myeloid cells’ plasticity in the TME makes them an unattractive therapeutic target. We therefore direct our focus on their bone marrow progenitors (figure 1). Preceded by comprehensive academic work from Mount Sinai investigators on the nanobiologic platform, Trained Therapeutix developed RIDE-001, a nanomedicine-based innate immunotherapy designed to reprogram myeloid progenitor cells in the bone marrow to generate durable, anti-tumor responses.2 3 Methods RIDE-001 is composed of apolipoprotein A1, phospholipids, cholesterol, and is surface-decorated with a muramyl dipeptide-derivative. Owing to its composition, which is derived from endogenous high-density lipoprotein, its small size and rod-like morphology, RIDE-001 activates the intracellular pattern recognition receptor NOD2. To evaluate RIDE-001’s potency in vitro, we developed standardized assays using a NOD2 reporter cell line and primary human innate immune cells. We used the MC38 colorectal cancer and the highly immunosuppressive B16F10 melanoma mouse models to evaluate RIDE-001’s anti-tumor activity. Safety and translational pharmacology were assessed in repeat-dose studies in rats and cynomolgus monkeys.Results An intravenous, three dose RIDE-001 regimen exerted strong anti-tumor efficacy in vivo in both the MC38 (figure 2A) and B16F10 (figure 2B) tumor mouse models. RIDE-001 effectively induced trained immunity in vitro in primary human immune cells (figure 2C). Extensive dose range finding studies in rats and cynomolgus monkeys revealed that RIDE-001 was safe at the highest dose tested and induced the anticipated immunological responses at the lowest dose tested. As a testament to its safety profile, multiple intravenous RIDE-001 doses were well tolerated and induced innate immune responses in a dose-dependent manner in both species (figure 2D, E).Conclusions Therapeutically targeting myeloid progenitor cells with intravenously dosed RIDE-001 is a promising novel immunotherapy strategy to treat cancer. RIDE-001’s pharmacological activity translates across primary human immune cells, mice, rats and non-human primates. Spurred by its excellent safety profile, Trained Therapeutix has initiated GMP manufacturing of RIDE-001 in anticipation of the first clinical studies in patients with solid tumors. Its successful clinical development is a potential breakthrough for cancer patients who do not benefit from checkpoint inhibition due to myeloid-driven immunosuppression.References Hegde S, Giotti B, Soong BY, Halasz L, Berichel JL, Magen A, Kloeckner B, Mattiuz R, Park MD, Marks A, Belabed M, Hamon P, Chin T, Troncoso L, Lee JJ, Ahimovic D, Bale M, Chung G, D’souza D, Angeliadis K, Dawson T, Kim-Schulze S, Flores RM, Kaufman AJ, Ginhoux F, Josefowicz SZ, Ma S, Tsankov AM, Marron TU, Brown BD, Merad M. Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumors. bioRxiv [Preprint]. 2024.Mulder WJM, van Leent MMT, Lameijer M, Fisher EA, Fayad ZA, Pérez-Medina C. High-density lipoprotein nanobiologics for precision medicine. Acc Chem Res. 2018;51(1):127–137.Priem B, van Leent MMT, Teunissen AJP, Sofias AM, Mourits VP, Willemsen L, Klein ED, Oosterwijk RS, Meerwaldt AE, Munitz J, Prévot G, Vera Verschuur A, Nauta SA, van Leeuwen EM, Fisher EL, de Jong KAM, Zhao Y, Toner YC, Soultanidis G, Calcagno C, Bomans PHH, Friedrich H, Sommerdijk N, Reiner T, Duivenvoorden R, Zupančič E, Di Martino JS, Kluza E, Rashidian M, Ploegh HL, Dijkhuizen RM, Hak S, Pérez-Medina C, Bravo-Cordero JJ, de Winther MPJ, Joosten LAB, van Elsas A, Fayad ZA, Rialdi A, Torre D, Guccione E, Ochando J, Netea MG, Griffioen AW, Mulder WJM. Trained immunity-promoting nanobiologic therapy suppresses tumor growth and potentiates checkpoint inhibition. Cell. 2020 Oct 29;183(3):786–801.Abstract 1178 Figure 1RIDE-001 mechanism of action. (A) RIDE-001 targets bone marrow, triggering epigenetic changes in HSPCs, inducing production of ‘trained’ myeloid cells, (B) polarizing the tumor microenvironment from immunosuppressive to (C) anti-tumoralAbstract 1178 Figure 2RIDE-001 anti-tumor immunity, safety and pharmacology. RIDE-001 induces anti-tumor immunity in MC38 (A) and B16F10 (B) tumor models, trains human myeloid cells (C) and safely induced innate immune responses in rats (D) and cynomolgus monkeys (E)",
  "authors": [
    {
      "affiliations": [
        "Trained Therapeutix, Oss, Netherlands"
      ],
      "name": "Joost Kreijtz"
    },
    {
      "affiliations": [
        "Trained Therapeutix, Oss, Netherlands"
      ],
      "name": "Glenn Cremers"
    },
    {
      "affiliations": [
        "Trained Therapeutix, Oss, Netherlands"
      ],
      "name": "Thijs Beldman"
    },
    {
      "affiliations": [
        "Trained Therapeutix, Oss, Netherlands"
      ],
      "name": "Bram Priem"
    },
    {
      "affiliations": [
        "Trained Therapeutix, Oss, Netherlands"
      ],
      "name": "Marielle Thewissen"
    },
    {
      "affiliations": [
        "Trained Therapeutix, Oss, Netherlands"
      ],
      "name": "Foppe van der Meulen"
    },
    {
      "affiliations": [
        "JandS Preclinical Solutions, Amsterdam, Netherlands"
      ],
      "name": "Julien Villaudy"
    },
    {
      "affiliations": [
        "JandS Preclinical Solutions, Amsterdam, Netherlands"
      ],
      "name": "Sjeng Horbach"
    },
    {
      "affiliations": [
        "Trained Therapeutix, Oss, Netherlands"
      ],
      "name": "Cristianne Rijcken"
    },
    {
      "affiliations": [
        "Radboud University Medical Center, Nijmegen, Netherlands"
      ],
      "name": "Mihai Netea"
    },
    {
      "affiliations": [
        "Comprehensive Cancer Center Munich of the Technical University Munich and the Ludwig Maximilian University, Munich, Germany",
        "University Medical Center and Princess Maxima Center, Utrecht, Netherlands"
      ],
      "name": "Alexander Eggermont"
    },
    {
      "affiliations": [
        "Trained Therapeutix, Oss, Netherlands"
      ],
      "name": "Willem Mulder"
    }
  ],
  "title": "1178 RIDE-001: a well-tolerated innate immunotherapy to treat cancer by targeting and reprogramming bone marrow progenitor cells",
  "uid": "1cb94ad9-7ad6-5a3b-b9ac-b900127c6a24"
}