Modeling the effect of gut microbiome on therapeutic efficacy of immune checkpoint inhibitors against cancer

Abstract

Immune checkpoint inhibitors have been shown to be highly successful against some solid metastatic malignancies, but only for a subset of patients who show durable clinical responses. The overall patient response rate is limited due to the interpatient heterogeneity. Preclinical and clinical studies have recently shown that the therapeutic responses can be improved through the modulation of gut microbiome. However, the underlying mechanisms are not fully understood. In this paper, we explored the effect of favorable and unfavorable gut bacteria on the therapeutic efficacy of anti-PD-1 against cancer by modeling the tumor-immune-gut microbiome interactions, and further examined the predictive markers of responders and non-responders to anti-PD-1. The dynamics of the gut bacteria was fitted to the clinical data of melanoma patients, and virtual patients data were generated based on the clinical patient survival data. Our simulation results show that low initial growth rate and low level of favorable bacteria at the initiation of anti-PD-1 therapy are predictive of non-responders, while high level of favorable bacteria at the initiation of anti-PD-1 therapy is predictive of responders. Simulation results also confirmed that it is possible to promote patients’ response rate to anti-PD-1 by manipulating the gut bacteria composition of non-responders, whereby achieving long-term progression-free survival.