Time-of-day of first checkpoint inhibitor dose influences clinical outcomes and immune responses in hepatocellular carcinoma.
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.
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.
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).
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.
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.
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).
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
Li Li, Charmsaz Charmsaz, Reisman Reisman, Hayek Hayek, Brancati Brancati, Leatherman Leatherman, Pazzi Pazzi, Lee Lee, Zhao Zhao, Christenson Christenson, Arif Arif, Hernandez Hernandez, Ellis Ellis, Gross Gross, Thoburn Thoburn, Chandler Chandler, Mohindra Mohindra, Bansal Bansal, Tang Tang, Guha Guha, Dang Dang, Zaidi Zaidi, Jaffee Jaffee, Laheru Laheru, Zabransky Zabransky, Barretti Barretti, Ho Ho, Yarchoan Yarchoan, Nakazawa Nakazawa
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