Inferring the role of the microbiome on survival in patients treated with immune checkpoint inhibitors: causal modeling, timing, and classes of concomitant medications

Abstract

Background: The microbiome has been shown to affect the response to Immune Checkpoint Inhibitors (ICIs) in a small number of cancers and in preclinical models. Here, we sought to broadly survey cancers to identify those in which the microbiome may play a prognostic role using retrospective analyses of patients with advanced cancer treated with ICIs. Methods: We conducted a retrospective analysis of 690 patients who received ICI therapy for advanced cancer. We used a literature review to define a causal model for the relationship between medications, the microbiome, and ICI response to guide the abstraction of electronic health records. Medications with precedent for changes to the microbiome included antibiotics, corticosteroids, proton pump inhibitors, histamine receptor blockers, non-steroid anti-inflammatories and statins. We tested the effect of medication timing on overall survival (OS) and evaluated the robustness of medication effects in each cancer. Finally, we compared the size of the effect observed for different classes of antibiotics to taxa that have been correlated to ICI response using a literature review of culturebased antibiotic susceptibilities.

Broad-Spectrum Antibiotic Regimen Affects Survival in Patients Receiving Nivolumab for Non-Small Cell Lung Cancer

“…Several studies have reported antibiotic use and its effects on the gut microbiome composition and the clinical impact of patients on ICIs [15,16]. Previously, the exposure period of eligible patients to systemic antibiotics was mostly from one to two months before or one month after initiation of ICIs [16,23]. When antibiotic-induced dysbiosis occurs, the intestinal microbiota composition may be disrupted for several weeks [24].…”

Impact of the corticosteroid indication and administration route on overall survival and the tumor response after immune checkpoint inhibitor initiation

“…The use of drugs inducing dysbiosis (which potentially decreases the effectiveness of ICIs) was also documented: antibiotics (ATBs), proton pump inhibitors (PPIs), drugs for gastrointestinal functional disorders (particularly phloroglucinol), anti-vitamin K (AVK) anticoagulants, antiarrhythmics, non-steroidal anti-inflammatory drugs (NSAIDs), cholecalciferol, metformin, opioids, statins, and levothyroxine. 20 With regard to ATBs and in particular: (a) the importance of the time needed for recovery of the gut microbiota after ATB discontinuation; 21 and (b) the difficulty setting an optimal time cut-off for determining whether or not ATB use influences the effectiveness of ICIs, 22 , 23 we included patients in the ATB group when the treatment was initiated during the 60 days preceding ICI initiation or the 60 days following ICI initiation. With regard to other drug classes and given the lack of data about the time needed for the gut microbiota to recover after discontinuation, patients were assigned to the corresponding drug class group when the treatment was received on ICI initiation or in the 60 days thereafter.…”

Association of baseline systemic corticosteroid use with overall survival and time to next treatment in patients receiving immune checkpoint inhibitor therapy in real-world US oncology practice for advanced non-small cell lung cancer, melanoma, or urothelial carcinoma

“…17,18 The mechanisms of PD-L1/PD-1 inhibitors counteract immune suppression in the tumor microenvironment by restoring antitumor activity of T cells; 19 immunosuppression from CSs administered prior to or at the start of CPI treatment, or "baseline" CS use (bCS), may counteract the CPI-driven antitumor immune response. [20][21][22] On the other hand, CSs used to manage immune-mediated adverse events later in the course of CPI treatment may not hinder its efficacy. 18,[23][24][25] In fact, differences in survival outcomes and peripheral blood immune cells associated with CSs may be limited to use within the first 28 days of CPI treatment.…”

“…18,[23][24][25] In fact, differences in survival outcomes and peripheral blood immune cells associated with CSs may be limited to use within the first 28 days of CPI treatment. 20,22 Patients receiving bCSs may be limited or excluded from participation in CPI clinical trials due to the potential impact on CPI efficacy; 20,21,26 therefore, clinical trials have not directly addressed the potential interactions between CSs and CPIs, which may vary by tumor site. 18,27,28 Real-world data can provide insight into CS use and impact on CPI effectiveness in clinical practice, particularly across multiple indications.…”