Comedications with Immune Checkpoint Inhibitors: Involvement of the Microbiota, Impact on Efficacy and Practical Implications

Abstract

Immune checkpoint inhibitors (ICIs) have been a major breakthrough in solid oncology over the past decade. The immune system and the gut microbiota are involved in their complex mechanisms of action. However, drug interactions have been suspected of disrupting the fine equilibrium necessary for optimal ICI efficacy. Thus, clinicians are facing a great deal of sometimes contradictory information on comedications with ICIs and must at times oppose conflicting objectives between oncological response and comorbidities or complications. We compiled in this review published data on the role of the microbiota in ICI efficacy and the impact of comedications. We found mostly concordant results on detrimental action of concurrent corticosteroids, antibiotics, and proton pump inhibitors. The timeframe seems to be an important variable each time to preserve an initial immune priming at ICIs initiation. Other molecules have been associated with improved or impaired ICIs outcomes in pre-clinical models with discordant conclusions in retrospective clinical studies. We gathered the results of the main studies concerning metformin, aspirin, and non-steroidal anti-inflammatory drugs, beta blockers, renin-angiotensin-aldosterone system inhibitors, opioids, and statins. In conclusion, one should always assess the necessity of concomitant treatment according to evidence-based recommendations and discuss the possibility of postponing ICI initiation or switching strategies to preserve the critical window.

Keywords: antibiotics; comedications; corticosteroids; immune checkpoint inhibitors; microbiota; proton pump inhibitors.

Figure 1

Schematic diagram summarizing the relation between the microbiota and the immune system (GMP: granulocyte and/or monocyte progenitor; TLR4: Toll-like receptor 4; NF-κB: nuclear factor kappa B; IL: interleukin; TNF: tumor necrosis factor; MMP: matrix metalloproteinases) [15,16,17].

Figure 2

Multiple interactions between drugs, cancer hallmarks and ICI efficacy (red/green: negative/positive impact on ICI efficacy, respectively; ICI: immune checkpoint inhibitor; GC: glucocorticoids; ATB: antibiotics; PPIs: proton pump inhibitors; NSAIDs: non-steroidal anti-inflammatory drugs and aspirin; ꞵB: beta blockers; RAASi: renin-angiotensin-aldosterone system inhibitors).