Immune Pre-Training for TIMED Immune Checkpoint Inhibition to Enhance Response

Ziel

Immune checkpoint inhibition (ICI) has transformed cancer care by enabling immune cells to eliminate malignant cells. Although ICIs save hundreds of thousands of lives each year, more than two-thirds of the millions of patients treated annually fail to respond. Thus, strategies that increase the proportion of patients benefiting from ICI, while reducing unnecessary harm and costs, are urgently needed.
Based on emerging evidence, I propose that the timing of ICI administration is critical to allow more patients to respond. Clinical trials showed that patients who initiate ICI treatment in the morning exhibit higher response rates than those treated in the afternoon or evening, a finding supported by mechanistic studies in mice. Since ICIs have half-lives of several weeks, these effects cannot be attributed to pharmacokinetics. Our preliminary data in both humans and mice demonstrate that effective anti-tumor immune responses can be detected earlier than anticipated. Together, these observations suggest that ICI must be administered within a specific temporal window when the immune system is most responsive in order to directly trigger therapeutic activity. These insights have major implications not only for the clinical use of ICI but also for strategies that enhance their efficacy.
The TIMED-ICI project aims to (1) define and characterize early immune responses to enable rapid prediction of therapeutic outcomes, and (2) develop strategies to pre-train the immune system for enhanced responsiveness at the time of therapy, with a focus on the diet–microbiome–metabolite axis and on how concurrent chemotherapy may interfere with this process. Leveraging unique clinical cohorts of ICI-treated cancer patients, complemented by ex vivo human tumor models and mechanistic murine cancer models, TIMED-ICI will uncover the neglected early immune response to ICI and drive a paradigm shift in the treatment of cancer.

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