Abstract
Background: Recently, there has been a growing interest in applying immune checkpoint blockers (ICBs), so far used to treat cancer, to patients with bacterial sepsis. We aimed to develop a method for predicting the personal benefit of potential treatments for sepsis, and to apply it to therapy by meropenem, an antibiotic drug, and nivolumab, a programmed cell death-1 (PD-1) pathway inhibitor.Methods: We defined an optimization problem as a concise framework of treatment aims and formulated a fitness function for grading sepsis treatments according to their success in accomplishing the pre-defined aims. We developed a mathematical model for the interactions between the pathogen, the cellular immune system and the drugs, whose simulations under diverse combined meropenem and nivolumab schedules, and calculation of the fitness function for each schedule served to plot the fitness landscapes for each set of treatments and personal patient parameters.Results: Results show that treatment by meropenem and nivolumab has maximum benefit if the interval between the onset of the two drugs does not exceed a dose-dependent threshold, beyond which the benefit drops sharply. However, a second nivolumab application, within 7–10 days after the first, can extinguish a pathogen which the first nivolumab application failed to remove. The utility of increasing nivolumab total dose above 6 mg/kg is contingent on the patient's personal immune attributes, notably, the reinvigoration rate of exhausted CTLs and the overall suppression rates of functional CTLs. A baseline pathogen load, higher than 5,000 CFU/μL, precludes successful nivolumab and meropenem combination therapy, whereas when the initial load is lower than 3,000 CFU/μL, meropenem monotherapy suffices for removing the pathogen.Discussion: Our study shows that early administration of nivolumab, 6 mg/kg, in combination with antibiotics, can alleviate bacterial sepsis in cases where antibiotics alone are insufficient and the initial pathogen load is not too high. The study pinpoints the role of precision medicine in sepsis, suggesting that personalized therapy by ICBs can improve pathogen elimination and dampen immunosuppression. Our results highlight the importance in using reliable markers for classifying patients according to their predicted response and provides a valuable tool in personalizing the drug regimens for patients with sepsis.
Highlights
Bacterial sepsis is a severe life-threatening systemic dysregulated pro-and anti-inflammatory response to infection, often resulting in tissue damage, multiple organ dysfunction, and death [1]
Nivolumab We modeled nivolumab, a programmed cell death1 (PD-1) pathway inhibitor hitherto used in oncology, as the representative immune checkpoint blockers (ICBs), exerting its effect on the reinvigoration rate of exhausted cytotoxic T lymphocytes (CTLs) (Figure 1)
We evaluated the benefit of a sepsis treatment by the antibiotic drug meropenem, combined with the ICB drug nivolumab, for patients who vary in personal parameters of adaptive immunity, or in initial pathogen load
Summary
Bacterial sepsis is a severe life-threatening systemic dysregulated pro-and anti-inflammatory response to infection, often resulting in tissue damage, multiple organ dysfunction, and death [1]. Efforts were made to avoid hyper-inflammation, which characterizes the early stage of this disorder, by administering anti-inflammatory agents, including toll-like receptor (TLR) antagonists, anti-cytokine therapies, and corticosteroids [3]. These have often failed in relieving the septic condition [9]. Patients who endure the initial phase of hyper-inflammation frequently enter a second, lengthier phase of immunosuppression, characterized by immune cell depletion and changes in receptor expression patterns, usually resulting in the acquisition of nosocomial infections, and often death [10, 11]. We aimed to develop a method for predicting the personal benefit of potential treatments for sepsis, and to apply it to therapy by meropenem, an antibiotic drug, and nivolumab, a programmed cell death-1 (PD-1) pathway inhibitor
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