Speaker
Description
Accumulated evidence suggests that the antitumour efficacy of immune checkpoint inhibitors (ICI) may depend on infusion time-of-day. Although circadian regulation of many immune processes has been documented \cite{l}, the mechanisms of such dosing time dependency remain unclear. To investigate this, we developed models of ICI pharmacokinetic (PK) and pharmacodynamic (PD) accounting for key circadian rhythms.
First, simulations of an existing PK model \cite{b} - extended to incorporate parameter circadian variability - showed no dosing time differences in either central or peripheral exposure. Sobol sensitivity analyses indicated that this behaviour was mainly driven by ICI slow clearance. Similar results were obtained when modelling patient-reported clearance modifications over weekly cycles.
Inspired by \cite{j}, we developed models of ICI PD stepwise, starting with a tumour-free model of T-cell trafficking and extending it to include tumour-driven T-cell activation, antigen-presenting cell dynamics, and cancer-mediated inhibition of cytotoxic T cells reversed by ICI. Parameters were calibrated using clinical data or preclinical extrapolation \cite{w,f}. Models achieved a good fit to data. Sensitivity analyses are ongoing to identify parameters driving infusion time-of-day dependencies.
This work provides a mechanistic framework to investigate ICI chronoPK-PD. An ongoing prospective study will generate circadian immunological data to refine and validate these models.
Bibliography
@article{j,
title = {A {Computational} {Model} of {Neoadjuvant} {PD}-1 {Inhibition} in {Non}-{Small} {Cell} {Lung} {Cancer}},
volume = {21},
issn = {1550-7416},
url = {https://pmc.ncbi.nlm.nih.gov/articles/PMC6591205/},
doi = {10.1208/s12248-019-0350-x},
abstract = {Immunotherapy and immune checkpoint blocking antibodies such as anti-PD-1 are approved and significantly improve the survival of advanced non-small cell lung cancer (NSCLC) patients, but there has been little success in identifying biomarkers capable of separating the responders from non-responders before the onset of the therapy. In this study, we developed a quantitative system pharmacology (QSP) model to represent the anti-tumor immune response in human NSCLC that integrated our knowledge of tumor growth, antigen processing and presentation, T cell activation and distribution, antibody pharmacokinetics, and immune checkpoint dynamics. The model was calibrated with the available data and was used to identify potential biomarkers as well as patient-specific response based on the patient parameters. The model predicted that in addition to tumor mutational burden (TMB), a known biomarker for anti-PD-1 therapy in NSCLC, the number of effector T cells and regulatory T cells in the tumor and blood is a predictor of the responders. Furthermore, the model simulated a set of 12 patients with known TMB and MHC/antigen-binding affinity from a recent clinical trial (ClinicalTrials.gov number, NCT02259621) on neoadjuvant nivolumab therapy in resectable lung cancer and predicted an augmented durable response in patients with adjuvant nivolumab treatment in addition to the clinical trial protocol of neoadjuvant nivolumab treatment followed by resection. Overall, the model provides a valuable framework to model tumor immunity and response to immune checkpoint blockers to enhance biomarker discovery and performing virtual clinical trials to aid in design and interpretation of the current trials with fewer patients.},
number = {5},
urldate = {2025-10-03},
journal = {The AAPS Journal},
author = {Jafarnejad, Mohammad and Gong, Chang and Gabrielson, Edward and Bartelink, Imke H. and Vicini, Paolo and Wang, Bing and Narwal, Rajesh and Roskos, Lorin and Popel, Aleksander S.},
month = jun,
year = {2019},
pages = {79},
}
@article{l,
title = {Circadian {Regulation} of {Drug} {Responses}: {Toward} {Sex}-{Specific} and {Personalized} {Chronotherapy}},
volume = {64},
issn = {0362-1642, 1545-4304},
shorttitle = {Circadian {Regulation} of {Drug} {Responses}},
url = {https://www.annualreviews.org/content/journals/10.1146/annurev-pharmtox-051920-095416},
doi = {10.1146/annurev-pharmtox-051920-095416},
abstract = {Today\'s challenge for precision medicine involves the integration of the impact of molecular clocks on drug pharmacokinetics, toxicity, and efficacy toward personalized chronotherapy. Meaningful improvements of tolerability and/or efficacy of medications through proper administration timing have been confirmed over the past decade for immunotherapy and chemotherapy against cancer, as well as for commonly used pharmacological agents in cardiovascular, metabolic, inflammatory, and neurological conditions. Experimental and human studies have recently revealed sexually dimorphic circadian drug responses. Dedicated randomized clinical trials should now aim to issue personalized circadian timing recommendations for daily medical practice, integrating innovative technologies for remote longitudinal monitoring of circadian metrics, statistical prediction of molecular clock function from single-timepoint biopsies, and multiscale biorhythmic mathematical modelling. Importantly, chronofit patients with a robust circadian function, who would benefit most from personalized chronotherapy, need to be identified. Conversely, nonchronofit patients could benefit from the emerging pharmacological class of chronobiotics targeting the circadian clock.},
language = {fr},
number = {Volume 64, 2024},
urldate = {2025-10-02},
journal = {Annual Review of Pharmacology and Toxicology},
publisher = {Annual Reviews},
author = {Lévi, Francis A. and Okyar, Alper and Hadadi, Eva and Innominato, Pasquale F. and Ballesta, Annabelle},
month = jan,
year = {2024},
pages = {89--114},
}
@article{f,
title = {Circadian control of tumor immunosuppression affects efficacy of immune checkpoint blockade},
volume = {25},
copyright = {2024 The Author(s), under exclusive licence to Springer Nature America, Inc.},
issn = {1529-2916},
url = {https://www.nature.com/articles/s41590-024-01859-0},
doi = {10.1038/s41590-024-01859-0},
abstract = {The circadian clock is a critical regulator of immunity, and this circadian control of immune modulation has an essential function in host defense and tumor immunosurveillance. Here we use a single-cell RNA sequencing approach and a genetic model of colorectal cancer to identify clock-dependent changes to the immune landscape that control the abundance of immunosuppressive cells and consequent suppression of cytotoxic CD8+ T cells. Of these immunosuppressive cell types, PD-L1-expressing myeloid-derived suppressor cells (MDSCs) peak in abundance in a rhythmic manner. Disruption of the epithelial cell clock regulates the secretion of cytokines that promote heightened inflammation, recruitment of neutrophils and the subsequent development of MDSCs. We also show that time-of-day anti-PD-L1 delivery is most effective when synchronized with the abundance of immunosuppressive MDSCs. Collectively, these data indicate that circadian gating of tumor immunosuppression informs the timing and efficacy of immune checkpoint inhibitors.},
language = {en},
number = {7},
urldate = {2025-10-29},
journal = {Nature Immunology},
publisher = {Nature Publishing Group},
author = {Fortin, Bridget M. and Pfeiffer, Shannon M. and Insua-Rodríguez, Jacob and Alshetaiwi, Hamad and Moshensky, Alexander and Song, Wei A. and Mahieu, Alisa L. and Chun, Sung Kook and Lewis, Amber N. and Hsu, Alex and Adam, Isam and Eng, Oliver S. and Pannunzio, Nicholas R. and Seldin, Marcus M. and Marazzi, Ivan and Marangoni, Francesco and Lawson, Devon A. and Kessenbrock, Kai and Masri, Selma},
month = jul,
year = {2024},
keywords = {Cancer immunotherapy, Immunosurveillance, Innate immune cells},
pages = {1257--1269},
}
@article{w,
title = {Dendritic cells direct circadian anti-tumour immune responses},
volume = {614},
issn = {0028-0836},
url = {https://pmc.ncbi.nlm.nih.gov/articles/PMC9891997/},
doi = {10.1038/s41586-022-05605-0},
abstract = {The process of cancer immunosurveillance is a mechanism of tumour suppression that can protect the host from cancer development throughout its lifetime,. However, it is unknown whether the effectiveness of cancer immunosurveillance fluctuates over a single day. Here we demonstrate that the initial time of day of tumour engraftment dictates the ensuing tumour size across mouse cancer models. Using immunodeficient mice as well as mice lacking lineage-specific circadian functions, we show that dendritic cells (DCs) and CD8+ T cells exert circadian anti-tumour functions that control melanoma volume. Specifically, we find that rhythmic trafficking of DCs to the tumour draining lymph node governs a circadian response of tumour-antigen-specific CD8+ T cells that is dependent on the circadian expression of the co-stimulatory molecule CD80. As a consequence, cancer immunotherapy is more effective when synchronized with DC functions, shows circadian outcomes in mice and suggests similar effects in humans. These data demonstrate that the circadian rhythms of anti-tumour immune components are not only critical for controlling tumour size but can also be of therapeutic relevance., Rhythmic trafficking of dendritic cells to the tumour draining lymph node governs a circadian response of tumour-antigen-specific CD8+ T cells that is dependent on the circadian expression of the co-stimulatory molecule CD80.},
number = {7946},
urldate = {2025-12-18},
journal = {Nature},
author = {Wang, Chen and Barnoud, Coline and Cenerenti, Mara and Sun, Mengzhu and Caffa, Irene and Kizil, Burak and Bill, Ruben and Liu, Yuanlong and Pick, Robert and Garnier, Laure and Gkountidi, Olga A. and Ince, Louise M. and Holtkamp, Stephan and Fournier, Nadine and Michielin, Olivier and Speiser, Daniel E. and Hugues, Stéphanie and Nencioni, Alessio and Pittet, Mikaël J. and Jandus, Camilla and Scheiermann, Christoph},
year = {2023},
pages = {136--143},
}
@article{b,
title = {Model‐{Based} {Population} {Pharmacokinetic} {Analysis} of {Nivolumab} in {Patients} {With} {Solid} {Tumors}},
volume = {6},
issn = {2163-8306},
url = {https://pmc.ncbi.nlm.nih.gov/articles/PMC5270302/},
doi = {10.1002/psp4.12143},
abstract = {Nivolumab is a fully human monoclonal antibody that inhibits programmed death‐1 activation. The clinical pharmacology profile of nivolumab was analyzed by a population pharmacokinetics model that assessed covariate effects on nivolumab concentrations in 1,895 patients who received 0.3–10.0 mg/kg nivolumab in 11 clinical trials. Nivolumab pharmacokinetics is linear with a time‐varying clearance. A full covariate model was developed to assess covariate effects on pharmacokinetic parameters. Nivolumab clearance and volume of distribution increase with body weight. The final model included the effects of baseline performance status (PS), baseline body weight, and baseline estimated glomerular filtration rate (eGFR), sex, and race on clearance, and effects of baseline body weight and sex on volume of distribution in the central compartment. Sex, PS, baseline eGFR, age, race, baseline lactate dehydrogenase, mild hepatic impairment, tumor type, tumor burden, and programmed death ligand‐1 expression had a significant but not clinically relevant ({\textless}20\%) effect on nivolumab clearance.},
number = {1},
urldate = {2026-03-09},
journal = {CPT: Pharmacometrics \& Systems Pharmacology},
author = {Bajaj, G and Wang, X and Agrawal, S and Gupta, M and Roy, A and Feng, Y},
month = jan,
year = {2017},
pages = {58--66},
}
