{
  "abstract": "Background Although immune checkpoint inhibitors (ICIs) have long half-lives, preclinical and retrospective clinical studies across multiple tumor types suggest that the time-of-day of ICI infusion may influence therapeutic efficacy by aligning initial drug exposure with circadian peaks in T-cell responsiveness. The immunological basis of this phenomenon and its clinical relevance in hepatocellular carcinoma (HCC) remains unknown.Methods We followed patients with advanced HCC receiving ICI therapy at Johns Hopkins from 2021 to 2025, classifying them into a morning (first treatment before 12:00 hours) or afternoon (first treatment after 12:00 hours) group. We assessed clinical outcomes and compared immunological responses from baseline to early-on-treatment by profiling peripheral blood mononuclear cells using cytometry by time-of-flight and plasma cytokines using a 39-plex Luminex assay.Results Our cohort included 84 patients, 39 of whom received their first infusion in the morning. There were no statistically significant differences in baseline demographic or clinical characteristics between patients initiating therapy in the morning versus afternoon. The morning group had superior progression-free survival (multivariable HR 0.50, 95% CI 0.30 to 0.84, p<0.01) and higher odds of treatment response (multivariable OR 3.26, 95% CI 1.08 to 10.90, p<0.05), with no significant increase in immune-related adverse events. The timing of subsequent infusions after the first dose had no impact on outcomes. Immunological responses diverged after the initial dose, with morning-treated patients showing reduced interleukin (IL)-6 levels (p<0.01) and greater expansion of cytotoxic central memory CD8+ T cells (p=0.01) as well as cytotoxic effector and effector memory CD8+ T cells (p=0.06).Conclusions Morning first-dose infusion of ICIs in HCC was associated with improved clinical outcomes and distinct immune responses, including reduced IL-6 signaling and expansion of cytotoxic central memory CD8+ T cells. These findings suggest that the timing of the initial infusion can imprint an immunological program that shapes subsequent antitumor immunity, providing a mechanistic rationale for strategically scheduling ICI administration.",
  "authors": [
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA",
        "Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"
      ],
      "name": "Howard L Li"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA"
      ],
      "name": "Soren Charmsaz"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA"
      ],
      "name": "Benjamin J Reisman"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA"
      ],
      "name": "Franshisca Hayek"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA"
      ],
      "name": "Madelena Brancati"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA"
      ],
      "name": "James M Leatherman"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA"
      ],
      "name": "Carlotta Pazzi"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA",
        "Johns Hopkins University School of Medicine, Baltimore, Maryland, USA"
      ],
      "name": "Royce P Lee"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA"
      ],
      "name": "Xiyu Zhao"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA"
      ],
      "name": "Eric Christenson"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA"
      ],
      "name": "Waqar Arif"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA"
      ],
      "name": "Jeric Hernandez"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA"
      ],
      "name": "Caroline Ellis"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA"
      ],
      "name": "Nicole E Gross"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA"
      ],
      "name": "Chris Thoburn"
    },
    {
      "affiliations": [
        "F Hoffmann-La Roche Ltd, Basel, Switzerland"
      ],
      "name": "G Scott Chandler"
    },
    {
      "affiliations": [
        "F Hoffmann-La Roche Ltd, Basel, Switzerland",
        "Genentech Inc, South San Francisco, California, USA"
      ],
      "name": "Rajat Mohindra"
    },
    {
      "affiliations": [
        "Genentech Inc, South San Francisco, California, USA"
      ],
      "name": "Sanjay Bansal"
    },
    {
      "affiliations": [
        "Genentech Inc, South San Francisco, California, USA"
      ],
      "name": "Laura Tang"
    },
    {
      "affiliations": [
        "Genentech Inc, South San Francisco, California, USA"
      ],
      "name": "Aditi Guha"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA",
        "Ludwig Institute for Cancer Research, Baltimore, Maryland, USA"
      ],
      "name": "Chi V Dang"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA"
      ],
      "name": "Neeha Zaidi"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA"
      ],
      "name": "Elizabeth M Jaffee"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA"
      ],
      "name": "Daniel Laheru"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA"
      ],
      "name": "Daniel J Zabransky"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA"
      ],
      "name": "Marina Barretti"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA"
      ],
      "name": "Won Jin Ho"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA"
      ],
      "name": "Mark Yarchoan"
    },
    {
      "affiliations": [
        "Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA"
      ],
      "name": "Mari Nakazawa"
    }
  ],
  "title": "Time-of-day of first checkpoint inhibitor dose influences clinical outcomes and immune responses in hepatocellular carcinoma",
  "uid": "90b3e14b-02dc-5fd1-a096-f94b09833fbc"
}