{
  "abstract": "Background Current immunotherapy regimens most often fail due to an insufficient T cell response and/or immune-related adverse events (irAEs) which lead to treatment discontinuation. Additionally, many cancers likely require combination immunotherapies which may further increase irAE. This is exemplified in our preclinical models of dual targeting of regulatory T cells with a phosphoinositide 3-kinase δ (PI3Kδ) inhibitor and antibodies to LAG-3. Indeed, while this approach in preclinical models of triple-negative breast cancer shows excellent tumor control, treatment is poorly tolerated and results in significant toxicity. Given the emerging relevance of these targets in human breast cancer, we explored strategies to sustain tumor immunity while mitigating toxicity using these therapeutic modalities.Methods Different approaches to combination immunotherapies employing a PI3Kδ inhibitor (PI-3065) with LAG-3 targeting treatments were tested in a mouse model of triple-negative breast cancer to optimize tumor control while limiting irAE.Results Systemic targeting of the LAG-3 ligand FGL1 did not provide additional anticancer benefit but markedly worsened irAE. Localized delivery of anti-LAG-3 antibodies to the tumor microenvironment promoted tumor control while reducing the overall number of animals experiencing severe irAE compared with those receiving systemic LAG-3 blockade. However, intermittent dosing of the PI3Kδ inhibitor in combination with anti-LAG-3 treatment prevented the initial development of irAE and enabled excellent tumor control without systemic adverse effects.Conclusions Our data demonstrated that refining immunotherapy delivery approaches can improve tolerability that ultimately transforms treatment success.",
  "authors": [
    {
      "affiliations": [
        "Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK"
      ],
      "name": "Sarah Nicol Lauder"
    },
    {
      "affiliations": [
        "Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK"
      ],
      "name": "Ana Pires"
    },
    {
      "affiliations": [
        "Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK"
      ],
      "name": "Michelle Somerville"
    },
    {
      "affiliations": [
        "Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK"
      ],
      "name": "Lorenzo Capitani"
    },
    {
      "affiliations": [
        "Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK"
      ],
      "name": "Kathryn Smart"
    },
    {
      "affiliations": [
        "Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK"
      ],
      "name": "James Geary"
    },
    {
      "affiliations": [
        "Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK"
      ],
      "name": "Emily M Mills"
    },
    {
      "affiliations": [
        "UCL Cancer Institute, University College London, London, UK"
      ],
      "name": "Bart Vanhaesebroeck"
    },
    {
      "affiliations": [
        "Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK"
      ],
      "name": "Andrew Godkin"
    },
    {
      "affiliations": [
        "Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK"
      ],
      "name": "Awen Gallimore"
    }
  ],
  "title": "Optimizing anti-PI3Kδ and anti-LAG-3 immunotherapy dosing regimens in a mouse model of triple-negative breast cancer improves outcome by removing treatment-related adverse events",
  "uid": "8a1c5d36-0817-5e84-820a-d706de73d773"
}