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Here we explore the theoretical consequences of the existence of multiple states of immune cell exhaustion on response to checkpoint inhibition therapy. In particular, we consider the emerging understanding that T cells can exist in various states: fully functioning cytotoxic cells, reversibly exhausted cells with minimal cytotoxicity, and terminally exhausted cells. We hypothesize that inflammation augmented by drug activity triggers transitions between these phenotypes, which can lead to non-genetic resistance to checkpoint inhibitors. We introduce a conceptual mathematical model, coupled with a standard 2-compartment pharmacometric (PK) model, that incorporates these mechanisms. Simulations of the model reveal that, within this framework, the emergence of resistance to checkpoint inhibitors can be mitigated through altering the dose and the frequency of administration. Our analysis also reveals that standard PK metrics do not correlate with treatment outcome. However, we do find that levels of inflammation that we assume trigger the transition from the reversibly to terminally exhausted states play a critical role in therapeutic outcome. A simulation of a population that has different values of this transition threshold reveals that while the standard high-dose, low-frequency dosing strategy can be an effective therapeutic design for some, it is likely to fail a significant fraction of the population. Conversely, a metronomic-like strategy that distributes a fixed amount of drug over many doses given close together is predicted to be effective across the entire simulated population, even at a relatively low cumulative drug dose. We also demonstrate that these predictions hold if the transitions between different states of immune cell exhaustion are triggered by prolonged antigen exposure, an alternative mechanism that has been implicated in this process. Our theoretical analyses demonstrate the potential of mitigating resistance to checkpoint inhibitors via dose modulation.<\/jats:p>","DOI":"10.1038\/s41540-024-00336-6","type":"journal-article","created":{"date-parts":[[2024,2,9]],"date-time":"2024-02-09T08:02:35Z","timestamp":1707465755000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Mitigating non-genetic resistance to checkpoint inhibition based on multiple states of immune exhaustion"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1100-6806","authenticated-orcid":false,"given":"Irina","family":"Kareva","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5577-1676","authenticated-orcid":false,"given":"Jana L.","family":"Gevertz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,9]]},"reference":[{"key":"336_CR1","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1016\/j.ccell.2020.03.017","volume":"37","author":"AJ Schoenfeld","year":"2020","unstructured":"Schoenfeld, A. 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