{
  "abstract": "Background Pathologic tumor response and changes in the tumor microenvironment (TME) predict outcomes to immune checkpoint inhibitors, but are understudied in rare tumors. We investigated whether artificial intelligence (AI)-powered analyses of pretreatment and on-treatment biopsies may inform treatment outcomes to pembrolizumab.Methods We evaluated 256 baseline and 248 on-treatment biopsies from 84 patients with rare tumors (10 cohorts) in a phase II pembrolizumab trial. Intratumoral tumor-infiltrating lymphocyte (iTIL) density and tumor content (TC) were assessed on H&E-stained slides using a deep learning–based analyzer (Lunit SCOPE IO). Baseline iTIL and changes in iTIL and TC were correlated with progression-free survival (PFS) and overall survival (OS). Multiplex immunofluorescence was performed in 27 paired samples to assess TME changes.Results In the high-iTIL tumor group, a baseline iTIL of ≥60 cells/mm 2 was associated with favorable PFS (HR 0.49, 95% CI 0.25 to 0.99, p=0.046) and higher CD8+ and CD8+PD-1+ and lower FoxP3+CD8+PD-1+ T-cell density. However, this association with PFS was not seen in the overall cohort (HR 0.62, 95% CI 0.37 to 1.06, p=0.082). In paired biopsies, on-treatment increase in iTIL showed a trend toward improved PFS (HR 0.64, 95% CI 0.40 to 1.06, p=0.084) and was significantly associated with improved OS (HR 0.55, 95% CI 0.35 to 1.01, p=0.037). This increase was also associated with reduced spatial distance between CD8+ immune and tumor cells. Decreased TC during treatment was significantly associated with prolonged PFS and OS (PFS: HR 0.51, p=0.019; OS: HR 0.54, p=0.042). The combination of increased iTIL and decreased TC was significantly associated with better PFS (HR 0.36, p=0.009) and OS (HR 0.36, p=0.029).Conclusion AI-powered assessment of the TME before and during treatment may help inform treatment outcomes to pembrolizumab in patients with rare tumors.Trial registration number NCT02721732.",
  "authors": [
    {
      "affiliations": [
        "Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Mohamed H Derbala"
    },
    {
      "affiliations": [
        "Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Bettzy Stephen"
    },
    {
      "affiliations": [
        "Lunit Inc, Gangnam-gu, Seoul, Korea (the Republic of)"
      ],
      "name": "Woochan Hwang"
    },
    {
      "affiliations": [
        "Lunit Inc, Gangnam-gu, Seoul, Korea (the Republic of)"
      ],
      "name": "Chan-Young Ock"
    },
    {
      "affiliations": [
        "Lunit Inc, Gangnam-gu, Seoul, Korea (the Republic of)"
      ],
      "name": "Soohyun Hwang"
    },
    {
      "affiliations": [
        "Division of Immunology, Allergy and Retrovirology, Baylor College of Medicine, Houston, Texas, USA"
      ],
      "name": "Joud Hajjar"
    },
    {
      "affiliations": [
        "Lunit Inc, Gangnam-gu, Seoul, Korea (the Republic of)"
      ],
      "name": "Seungeun Lee"
    },
    {
      "affiliations": [
        "Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Jianling Zhou"
    },
    {
      "affiliations": [
        "Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Serdar A Gurses"
    },
    {
      "affiliations": [
        "Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Mohamed A Gouda"
    },
    {
      "affiliations": [
        "Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Kathryn E McGonagle"
    },
    {
      "affiliations": [
        "Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Anas Alshawa"
    },
    {
      "affiliations": [
        "Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Lilibeth Castillo"
    },
    {
      "affiliations": [
        "Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Abdulrazzak Zarifa"
    },
    {
      "affiliations": [
        "Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Siqing Fu"
    },
    {
      "affiliations": [
        "Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Sarina A Piha-Paul"
    },
    {
      "affiliations": [
        "Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Apostolia M Tsimberidou"
    },
    {
      "affiliations": [
        "Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Funda Meric-Bernstam"
    },
    {
      "affiliations": [
        "Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Luisa Maren Solis Soto"
    },
    {
      "affiliations": [
        "Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Maria Gabriela Raso"
    },
    {
      "affiliations": [
        "Lunit Inc, Gangnam-gu, Seoul, Korea (the Republic of)"
      ],
      "name": "Siraj Ali"
    },
    {
      "affiliations": [
        "Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA"
      ],
      "name": "Aung Naing"
    }
  ],
  "title": "Artificial intelligence-guided analysis of the tumor microenvironment predicts response to pembrolizumab in rare tumors",
  "uid": "0615a40c-2581-5d56-b2a0-021d209963ca"
}