Antibiotics and proton pump inhibitors suppress the efficacy of immunotherapy against non-small cell lung cancer.
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ABSTRACT:
SUBMITTER: Diao X
PROVIDER: S-EPMC7327691 | biostudies-literature | 2020 Jul
REPOSITORIES: biostudies-literature
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Antibiotics and proton pump inhibitors suppress the efficacy of immunotherapy against non-small cell lung cancer.
Thoracic cancer 20200506 7
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Project description:BackgroundThe use of antibiotics (ATB) and proton-pump inhibitors (PPI) alters the composition and diversity of the gut microbiota, which can influence the immune system, consequently interfering with response to anti-PD1 immune checkpoint inhibitors (ICI). We assessed the impact of ATB and/or PPI use on the efficacy and safety of ICI.MethodsTwo hundred twelve patients treated with anti-PD1 ICI for non-small cell lung carcinoma, melanoma, upper airway & digestive tract carcinoma or renal cell carcinoma were retrospectively included. Patients having received ATB within 60 days before ICI initiation were included in the ATB+ group. Patients having received PPI within 30 days before ICI initiation were included in the PPI+ group. Four groups were thus considered: ATB-/PPI-, ATB+/PPI-, ATB-/PPI+, ATB+/PPI+. Response rate was assessed by RECIST v1.1. Overall survival (OS), progression-free survival (PFS) and adverse events, recorded using Common Terminology Criteria for Adverse Events Version 5, were compared using inverse probability of treatment weighting to account for selection bias.ResultsPFS at 6 months was 56.7 %, 95%CI (49.6%; 63.2%) and 47.2 %, 95%CI (39.8%;54.1%) at 12 months. OS was 81.6%, 95%CI (75.6%; 86.2%) at 6 months, and 69.4%, 95%CI (61.9%;75.7%) at 12 months. Compared to ATB-/PPI- group, PFS was lower for the ATB+/PPI- group [Hazard ratio (HR) 1.90, 95%CI (1.41;2.57)] and the ATB-/PPI+ group [HR 1.51, 95%CI (1.11;2.05)], and lowest in the ATB+/PPI+ group [HR 3.65, 95%CI (2.75;4.84)]. For OS, the use of ATB alone or PPI alone or in combination was a risk factor for death, with each increasing HR values by a similar magnitude, and the combination of ATB and PPI did not increase risk further. AEs were observed in 78 cases (36.8%) with no significant impact of ATB or PPI use.ConclusionsThis study reveals that ATB and/or PPI use can alter response to anti-PD1 ICI, and the prognosis of cancer patients. The microbiota mechanisms involved in the response to ICI should be investigated to optimize patient management.
| S-EPMC8578856 | biostudies-literature
Project description:IntroductionImmune checkpoint inhibitors (ICI) is a rapidly evolving treatment modality for stage IV non-small cell lung cancer (NSCLC). Concomitant proton pump inhibitor (PPI) use can potentially reduce the clinical efficacy of ICIs; however, the consensus in recent literature has been conflicting. This study aims to analyze overall survival (OS) and progression-free survival (PFS) outcomes in patients with NSCLC on ICI and concomitant PPI therapy.MethodsA literature search was done in 3 databases (Pubmed/Medline, Embase, and Cochrane Central). All studies meeting the inclusion criteria assessing the impact of PPIs on the efficacy of ICI in NSCLC patients were systematically identified. A random-effects network meta-analysis evaluated OS and PFS in the two arms.ResultsFour studies with 2,940 patients are included in our analysis. ICI usage alone was associated with significantly better OS [HR = 1.46, 95% CI = 1.27-1.67, P < 0.00001] and PFS [HR = 1.31, 95% CI = 1.17-1.47, P < 0.00001] when compared to concomitant PPI and ICI therapy.ConclusionThe concomitant use of PPIs during ICI therapy significantly worsens clinical outcomes with shorter OS and increased risk of disease progression in patients with NSCLC.
| S-EPMC9119820 | biostudies-literature
Project description:BackgroundImmune checkpoint inhibitors (ICIs) have recently represented a breakthrough in urothelial carcinoma (UC). Proton pump inhibitors (PPIs) are routinely used for extended time periods in UC patients, with these agents having potentially and frequently undervalued effects on ICIs efficacy.MethodsWe performed a meta-analysis aimed at investigating the impact of concomitant PPI administration on progression-free survival (PFS) and overall survival (OS) among patients receiving immunotherapy for metastatic UC.ResultsTwo studies encompassing a total of 1015 patients were included. The pooled Hazard Ratios (HRs) for OS and PFS were 1.55 (95% CI, 1.31-1.84) and 1.43 (95% CI, 1.23-1.66), respectively, suggesting that the administration of PPIs was negatively associated with PFS and with OS in UC patients treated with ICIs.ConclusionsThe current meta-analysis represents the first study to provide a systematic evaluation of the impact of concomitant PPI use in UC patients treated with ICIs. Further studies are warranted on this topic to clarify the relationship between gut microbiome, antiacid exposure, and cancer immunotherapy. In the current era of medical oncology, progress in this setting will require the collaboration of basic science and clinical research to optimize systemic treatment and to improve the outcomes of UC patients receiving ICIs.
| S-EPMC9145929 | biostudies-literature
Project description:ObjectiveTo evaluate the effects of the concomitant use of proton pump inhibitors (PPIs) and/or antibiotics (Abs) on oncological outcomes in patients with advanced urothelial carcinoma.Patients and methodsWe retrospectively evaluated 155 patients with advanced urothelial carcinoma who were treated with immune checkpoint inhibitors (ICIs) between August 2015 and April 2021. The concomitant use of PPI or Abs was defined as any PPI or Abs administered within 30 days before ICI initiation and during ICI therapy. The primary outcomes were the effect of PPI and/or Abs use on the objective response rate (ORR) and immune-related adverse events (irAEs). The secondary outcomes were the effects of PPI and/or Abs use on progression-free survival (PFS) and overall survival (OS) after ICI therapy analyzed using the inverse probability of treatment weighting-adjusted Cox regression analysis.ResultsOf the 155 patients enrolled in the study, 99 (64%) were PPI users and 56 (36%) Abs users. PPI users were associated with a significantly poorer ORR than non-PPI users (41% vs. 20%, respectively), whereas Abs use was not significantly associated with changes in ORR. The rate of irAEs was not significantly associated with the use of PPIs or Abs. Multivariate inverse probability of treatment weighting-adjusted Cox regression analysis revealed significantly poorer PFS and OS in PPI users than in non-PPI users, whereas Abs use was not associated with poorer outcomes.ConclusionThe concomitant use of PPI may adversely affect oncological outcomes in patients with locally advanced or metastatic urothelial carcinoma treated with ICI therapy.
| S-EPMC8988833 | biostudies-literature
Project description:BackgroundProton pump inhibitors (PPIs) are commonly used concomitant to cancer treatment and they induce gut microbiota changes. It is increasingly apparent that gut dysbiosis can reduce the effectiveness of immune checkpoint inhibitors (ICI). However, little is known about PPI effects on outcomes with ICIs, particularly in combination, ICI approaches.MethodsPost hoc, Cox proportional hazard analysis of phase III trial, IMpower150 was conducted to assess the association between PPI use and overall survival (OS) and progression-free survival (PFS) in chemotherapy-naive, metastatic non-squamous non-small cell lung cancer participants randomised atezolizumab plus carboplatin plus paclitaxel (ACP), bevacizumab plus carboplatin plus paclitaxel (BCP), or atezolizumab plus BCP (ABCP). PPI use was defined as any PPI administration between 30 days prior and 30 days after treatment initiation.ResultsOf 1202 participants, 441 (37%) received a PPI. PPI use was independently associated with worse OS (n = 748; hazard ratio (HR) [95% confidence interval (CI)] = 1.53 [1.21-1.95], P < 0.001) and PFS (1.34 [1.12-1.61], P = 0.002) in the pooled atezolizumab arms (ACP plus ABCP). This association was not apparent for BCP (n = 368; OS 1.01 [0.73-1.39], P = 0.969; PFS 0.97 [0.76-1.25], P = 0.827). The observed OS treatment effect (HR 95% CI) of the atezolizumab (ACP plus ABCP) arms vs BCP was 1.03 (0.77-1.36) for PPI users compared to 0.68 (0.54-0.86) for non-users (P [interaction] = 0.028). A similar association was noted for ABCP vs BCP (PPI users 0.96 [0.68-1.35]; PPI non-users 0.66 [0.50-0.87]; P [interaction] = 0.095).ConclusionsPPI use was a negative prognostic marker in patients treated with ACP or ABCP, but not BCP. The analysis suggests that PPIs negatively influence the magnitude of ICI efficacy.
| S-EPMC8727569 | biostudies-literature
Project description:The incidence of resistant Candida isolates, especially Candida albicans, has increased continuously. To overcome the resistance, research on antifungal agent sensitizers has attracted considerable attention. Omeprazole and lansoprazole were found to inhibit the growth of sensitive C. albicans and hyphae formation in a high dose, respectively. This study aimed to determine the interactions of common clinically proton pump inhibitors (PPIs) and fluconazole both in vitro and in vivo and to further explore the possible mechanisms. In vitro, the tested PPIs all acted synergistically with fluconazole against both resistant C. albicans planktonic cells and biofilms preformed for ≤12 h with the minimum inhibitory concentration of fluconazole decreased from >512 μg/mL to 1-4 μg/mL. In vivo, PPIs plus fluconazole prolonged the survival rate of infected Galleria mellonella larvae by two-fold compared with that for the fluconazole monotherapy group and significantly reduced the tissue damage of infected larvae. Mechanism studies showed that PPIs significantly suppressed efflux pump activity, which is the common resistance mechanism of C. albicans, and significantly inhibited the virulence factors: phospholipase activity and morphology switching. These findings will provide new insights into antifungal agent discovery and potential approaches for the treatment of candidiasis caused by resistant C. albicans.
| S-EPMC6965112 | biostudies-literature
Project description:Small molecules that directly target MYC and are also well tolerated in vivo will provide invaluable chemical probes and potential anti-cancer therapeutic agents. We developed a series of small-molecule MYC inhibitors that engage MYC inside cells, disrupt MYC/MAX dimers, and impair MYC-driven gene expression. The compounds enhance MYC phosphorylation on threonine-58, consequently increasing proteasome-mediated MYC degradation. The initial lead, MYC inhibitor 361 (MYCi361), suppressed in vivo tumor growth in mice, increased tumor immune cell infiltration, upregulated PD-L1 on tumors, and sensitized tumors to anti-PD1 immunotherapy. However, 361 demonstrated a narrow therapeutic index. An improved analog, MYCi975 showed better tolerability. These findings suggest the potential of small-molecule MYC inhibitors as chemical probes and possible anti-cancer therapeutic agents.
| S-EPMC6939458 | biostudies-literature
Project description:BackgroundAntibiotics and proton pump inhibitors (PPI) are recognized risk factors for acquisition and recurrence of Clostridioides difficile infection (CDI), yet combined effects remain unclear.ObjectivesTo assess the short- and long-term effects of antibiotics and PPIs on CDI risk and recurrence.MethodsPopulation-based study including all 43 152 patients diagnosed with CDI in Sweden (2006-2019), and 355 172 matched population controls without CDI. The impact of antibiotics and PPIs on CDI risk and recurrence was explored for recent (0-30 days) and preceding (31-180 days) use prior to their first CDI diagnosis, using multivariable conditional logistic regression presented as odds ratios (ORs) and 95% confidence interval, adjusted for demographics, comorbidities and other drugs.ResultsCompared to controls, the combined effect of recent PPIs and antibiotics [ORAB+PPI = 17.51 (17.48-17.53)] on CDI risk was stronger than the individual effects [ORAB = 15.37 (14.83-15.93); ORPPI = 2.65 (2.54-2.76)]. Results were less pronounced for exposure during the preceding months. Dose-response analyses showed increasing exposure correlated with CDI risk [recent use: ORAB = 6.32 (6.15-6.49); ORPPI = 1.65 (1.62-1.68) per prescription increase].Compared to individuals without recurrence (rCDI), recent [ORAB = 1.30 (1.23-1.38)] and preceding [ORAB = 1.23 (1.16-1.31); ORPPI = 1.12 (1.03-1.21)] use also affected the risk of recurrence yet without significant interaction between both. Recent macrolides/lincosamides/streptogramins; other antibacterials including nitroimidazole derivates; non-penicillin beta lactams and quinolones showed the strongest association with CDI risk and recurrence, particularly for recent use. PPI use, both recent and preceding, further increased the CDI risk associated with almost all antibiotic classes.ConclusionRecent and less recent use of PPIs and systemic antibiotics was associated with an increased risk of CDI, particularly in combination.
| S-EPMC10904719 | biostudies-literature
Project description:RationaleProton pump inhibitors (PPIs) are popular drugs for gastroesophageal reflux, which are now available for long-term use without medical supervision. Recent reports suggest that PPI use is associated with cardiovascular, renal, and neurological morbidity.ObjectiveTo study the long-term effect of PPIs on endothelial dysfunction and senescence and investigate the mechanism involved in PPI-induced vascular dysfunction.Methods and resultsChronic exposure to PPIs impaired endothelial function and accelerated human endothelial senescence by reducing telomere length.ConclusionsOur data may provide a unifying mechanism for the association of PPI use with increased risk of cardiovascular, renal, and neurological morbidity and mortality.
| S-EPMC4902745 | biostudies-literature
Project description: Not available
| S-EPMC6485982 | biostudies-literature