BackgroundImmune checkpoint inhibitors (ICIs) have considerably improved patient outcomes in various cancer types, but their efficacy remains poorly predictable among patients. The intestinal microbiome, whose balance and composition can be significantly altered by antibiotic use, has recently emerged as a factor that may modulate ICI efficacy. The objective of this systematic review and meta-analysis is to investigate the impact of antibiotics on the clinical outcomes of cancer patients treated with ICIs.MethodsPubMed and major oncology conference proceedings were systematically searched to identify all studies reporting associations between antibiotic use and at least one of the following endpoints: Overall Survival (OS), Progression-Free Survival (PFS), Objective Response Rate (ORR) and Progressive Disease (PD) Rate. Pooled Hazard Ratios (HRs) for OS and PFS, and pooled Odds Ratios (ORs) for ORR and PD were calculated. Subgroup analyses on survival outcomes were also performed to investigate the potential differential effect of antibiotics according to cancer types and antibiotic exposure time windows.Results107 articles reporting data for 123 independent cohorts were included, representing a total of 41,663 patients among whom 11,785 (28%) received antibiotics around ICI initiation. The pooled HRs for OS and PFS were respectively of 1.61 [95% Confidence Interval (CI) 1.48-1.76] and 1.45 [95% CI 1.32-1.60], confirming that antibiotic use was significantly associated with shorter survival. This negative association was observed consistently across all cancer types for OS and depending on the cancer type for PFS. The loss of survival was particularly strong when antibiotics were received shortly before or after ICI initiation. The pooled ORs for ORR and PD were respectively of 0.59 [95% CI 0.47-0.76] and 1.86 [95% CI 1.41-2.46], suggesting that antibiotic use was significantly associated with worse treatment-related outcomes.ConclusionAs it is not ethically feasible to conduct interventional, randomized, controlled trials in which antibiotics would be administered to cancer patients treated with ICIs to demonstrate their deleterious impact versus control, prospective observational studies and interventional trials involving microbiome modifiers are crucially needed to uncover the role of microbiome and improve patient outcomes. Such studies will reduce the existing publication bias by allowing analyses on more homogeneous populations, especially in terms of treatments received, which is not possible at this stage given the current state of the field. In the meantime, antibiotic prescription should be cautiously considered in cancer patients receiving ICIs.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42019145675.

BackgroundIn recent years, the gut microbiome has increasingly emerged as influencing the response to immune checkpoint inhibitors (ICIs).1–3 Antibiotic (ABX) exposure, that leads to microbiome dysbiosis, was further shown in numerous studies to adversely influence the clinical outcomes of cancer patients treated with ICIs, especially in non-small-cell lung cancer (NSCLC).4–6We published in 2020 a meta-analysis confirming that ABX use could hamper survival of NSCLC patients treated with ICIs.7 The present study aims at updating this prior work by incorporating studies published until July 2021 and by studying new clinical outcomes.MethodsPubMed and major oncology conferences’ proceedings were systematically searched to identify studies assessing the impact of ABX on the clinical outcomes of NSCLC patients treated with ICIs. Studies were included when reporting a hazard ratio (HR) or Kaplan–Meier curves for Overall Survival (OS) or Progression-Free Survival (PFS) based on antibiotic exposure, and/or data on treatment response such as Overall Response Rate (ORR) and Progressive Disease Rate (PD) according to antibiotic exposure. Pooled HRs for OS and PFS and Odds Ratios (OR) for ORR and PD were calculated, as well as HRs for OS and PFS according to different time windows of ABX exposure.ResultsOverall, 35 independent cohorts were included for a total of 12,235 patients. The pooled HRs for OS (12,235 patients) and PFS (5,356 patients) were 1.63 [95% Confidence Interval (CI) 1.37–1.94] and 1.49 [95% CI 1.26–1.76], respectively, confirming a significantly reduced survival in patients exposed to ABX. The subgroup analyses of OS and PFS based on the time window of ABX exposure (figures 1 and 2) suggest a harmful effect of ABX when taken around ICI initiation. The pooled OR for ORR (1,992 patients) and PD (1,272 patients) were 0.66 [95% CI 0.44–0.99] and 1.98 [95% CI 1.39–2.8], respectively, reflecting both a decreased odd of treatment response and an almost two-fold increased odd of cancer progression among ABX users (figures 3 and 4). These findings confirm the previously reported deleterious effect of ABX on all clinical outcomes (table 1).Abstract 278 Figure 1Forest plot of hazard ratios for overall survival of patients diagnosed with NSCLC and exposed to antibiotics versus not exposed to antibiotics, according to the time window of antibiotic exposureAbstract 278 Figure 2Forest plot of hazard ratios for progression-free survival of patients diagnosed with NSCLC and exposed to antibiotics versus not exposed to antibiotics, according to the time window of antibiotic exposureAbstract 278 Figure 3Forest plot of odds ratios for overall response rate of patients diagnosed with NSCLC and exposed to antibiotics versus not exposed to antibioticsAbstract 278 Figure 4Forest plot of odds ratios for progressive disease rate of patients diagnosed with NSCLC and exposed to antibiotics versus not exposed to antibioticsAbstract 278 Table 1Summary of the impact of antibiotic use on all clinical outcomesConclusionsAntibiotics were shown to impair clinical outcomes of NSCLC patients treated with ICIs in this study. Two (non mutually exclusive) mechanisms are increasingly discussed in the literature to explain the role of microbiome on immunotherapy response: the immunomodulatory effects of bacterial molecules,8 and antigenic mimicry between commensal bacteria and tumor antigens cross reactive for the same antigen specific T cells.9 10ReferencesGopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 5 January 2018;359(6371):97–103.Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 5 January 2018;359(6371):91–7. Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre M-L, et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 5 January 2018;359(6371):104–8. Derosa L, Hellmann MD, Spaziano M, Halpenny D, Fidelle M, Rizvi H, et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann Oncol Off J Eur Soc Med Oncol 1 June 2018;29(6):1437–44.Pinato DJ, Howlett S, Ottaviani D, Urus H, Patel A, Mineo T, et al. Association of prior antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer. JAMA Oncol 1 Décember 2019;5(12):1774–8.Rounis K, Makrakis D, Papadaki C, Monastirioti A, Vamvakas L, Kalbakis K, et al. Prediction of outcome in patients with non-small cell lung cancer treated with second line PD-1/PDL-1 inhibitors based on clinical parameters: results from a prospective, single institution study. PloS One 2021;16(6):e0252537.Lurienne L, Cervesi J, Duhalde L, de Gunzburg J, Andremont A, Zalcman G, et al. NSCLC immunotherapy efficacy and antibiotic use: a systematic review and meta-analysis. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer July 2020;15(7):1147–59.Sepich-Poore GD, Zitvogel L, Straussman R, Hasty J, Wargo JA, Knight R. The microbiome and human cancer. Science 26 March 2021;371(6536):eabc4552.Fluckiger A, Daillère R, Sassi M, Sixt BS, Liu P, Loos F, et al. Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage. Science 21 août 2020;369(6506):936–42.Bessell CA, Isser A, Havel JJ, Lee S, Bell DR, Hickey JW, et al. Commensal bacteria stimulate antitumor responses via T cell cross-reactivity. JCI Insight 23 avr 2020;5(8):135597.

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Background Antibiotics (ATB) induce intestinal dysbiosis and decrease the efficacy of immune checkpoint inhibitors (ICI). 1,2 DAV132 is an orally administered colon-targeted ATB adsorbent designed to prevent ATB-induced dysbiosis. 3 We investigated whether DAV132 co-administered with ATB could protect gut microbiota diversity and composition. Moreover, in murine avatar tumor model, we assessed anti-PD-1 efficacy through fecal microbiota transplantation (FMT) in germ-free (GF) or antibiotic-treated specific pathogen-free (SPF) mice. Methods Twenty-four human healthy volunteers (HV) were randomized to receive either ceftazidime-avibactam (CZA, 2g/ 0.5g q8h IV for 5 days) or CZA+DAV132 (12g PO tid for 7 days). CZA plasmatic and fecal pharmacodynamic levels were measured using HPLC-MS/MS. Microbiome was profiled with 16S and shotgun metagenomics at different timepoints. FMT in GF or ATB-treated SPF mice was performed using fecal samples from 3 HV and 2 HV respectively, in each group before (D1) or after 6 days (D6) of CZA+/-DAV132; subsequently mice were inoculated with MCA-205 tumor and treated intraperitoneally with anti-PD-1, 4 times every 3 days. Immunological population of tumor infiltrating lymphocytes were analyzed by flow cytometry. Results DAV132 did not impact plasmatic CZA concentrations, but significantly reduced ceftazidime concentration in feces compared to HV treated with CZA alone (p<0.001). DAV132 significantly prevented the reduction in microbiota alpha-diversity at D6 (p=0.0019) and was associated with a more rapid return to baseline microbiota composition (figure 1). Significantly more bacteria associated with better response to ICI were preserved in the DAV group compared to CZA, among which Faecalibacterium praunistzii and several Alistipes spp. FMT in GF mice transplanted with feces collected at D1 exhibited a significant anti-PD-1 activity. This anti-tumor response was inhibited in mice transplanted with D6 feces from any of the 3 CZA-treated HV. Conversely, the antitumor response was maintained in mice transplanted with D6 feces from any of the 3 HV treated with CZA + DAV132 (figure 2). Similar results were observed upon FMT using samples from HVs into ATB-treated SPF mice. Flow cytometry on tumor T cell infiltrates demonstrated that CZA decreased CD8 + T cell infiltration and CD8 + /Tregulatory ratio, compared to CZA + DAV132 treated HVs (figure 3). Conclusions DAV132 strongly prevented CZA-induced dysbiosis in HV without influencing plasmatic concentrations. In avatar mice FMT from HV treated with CZA+DAV132 was able to preserve anti-PD-1 cancer efficacy. These results provide rationale to launch clinical trials combining DAV132 in patients on ATB amenable to ICI.Ethics Approval All animal studies were approved by the Institutional Animal Care Committee (CIPA) and carried out in compliance with the Canadian Council on Animal Care guidelines (Ethics numbers: C18029BRs).

Background: Over the last decade, studies unraveled the cancer-immune dialogue in the setting of immune checkpoint inhibitors (ICI) and influenced by the gut microbiota. The first evidence of the key role of the microbiota in ICI modulation was observed during antibiotics (ATB) treatment, where altering the microbiota composition by ATB inhibited ICI responses. DAV132 (DAV) is an orally administered colon-targeted ATB adsorbent capsules designed to prevent ATB-induced dysbiosis. We investigated whether DAV co-administered with ATB could prevent ATB-related dysbiosis and ICI response. Methods: 72 human healthy volunteers (HV) were randomized to receive either IV ceftazidime-avibactam (CZA) or Piperacillin tazobactam (PTZ) alone or in combination with oral DAV. CZA and PTZ plasmatic and fecal pharmacodynamic levels were measured using HPLC-MS/MS. Microbiome was profiled with metagenomics at different timepoints. FMT experiments in germ-free mice were performed using fecal samples from HV from the trial, before (D1) or after 6 days (D6) of CZA or PTZ+/-DAV; subsequently mice were inoculated with MCA205 or B16 tumors and treated with anti-PD-1. Tumor infiltrating lymphocytes (TILs) were analyzed by flow cytometry. Results: DAV did not impact plasmatic CZA or PTZ concentrations, but significantly reduced ceftazidime and piperacillin concentrations in feces compared to ATB groups alone. DAV significantly prevented the reduction in microbiota alpha-diversity at D6 and was associated with a rapid return to baseline microbiota. 50 and 43 metagenomics species were preserved in the CZA+DAV vs CZA, or PTZ-DAV vs PTZ such as Faecalibacterium praunistzii, Alistipes Spp and Blautia obeum. FMT in germ-free mice using feces collected at D1 exhibited a significant anti-PD-1 activity. This anti-tumor response was inhibited in two tumors models in mice transplanted with D6 feces from patients in the CZA or PTZ alone groups. Conversely, the anti-tumor response was maintained in mice transplanted with D6 feces from HV treated with CZA+DAV or PTZ+DAV groups. Flow cytometry on TILs demonstrated that CZA decreased CD8+T cell and CD8+/Treg ratio compared to CZA+DAV. Conclusions: DAV prevented ATB-induced dysbiosis in HV treated with CZA or PTZ without influencing plasmatic concentrations. In avatar mice FMT from HV treated with CZA+DAV was able to preserve anti-PD-1 efficacy. These results provide rationale to launch clinical trials combining DAV in patients on ATB amenable to ICI. Citation Format: Meriem Messaoudene, Nathalie Saint-Lu, Frédérique Sablier-Gallis, Stéphanie Ferreira, Mayra Ponce, Clément Le Bescop, Thomas Loppinet, Tanguy Corbel, Céline Féger, Fabien Vitry, Antoine Andremont, Jean de Gunzburg, Bertrand Routy. Prevention of antibiotic-induced dysbiosis in human volunteers by DAV132 and preservation of responsiveness to anti-PD-1 demonstrated by transplantation of human feces into tumor-bearing mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5882.

2585 Background: In recent years, the gut microbiome has increasingly emerged as influencing the response to immune checkpoint inhibitors (ICIs) and antibiotic (ABX) exposure has repeatedly been shown to impair clinical outcomes of patients suffering from different cancer types and treated with ICIs. We published in 2020 a meta-analysis confirming that ABX use hampered survival of non-small cell lung cancer (NSCLC) patients treated with ICIs. The present study aims to determine whether ABX use also reduces survival of patients receiving ICIs for other cancers. Methods: PubMed and major oncology conferences’ proceedings were systematically searched to identify studies assessing the impact of ABX on the clinical outcomes of cancer patients treated with ICIs. Studies were included when reporting data on Overall Survival (OS), Progression-Free Survival (PFS), Overall Response Rate (ORR) and Progressive Disease Rate (PD), according to ABX exposure. Pooled Hazard Ratios (HRs) for OS and PFS and Odds Ratios (ORs) for ORR and PD were calculated, as well as HRs for OS and PFS according to different cancer types and different ABX exposure time windows (TWs). Results: Overall, 94 independent cohorts were included, representing 26,174 patients suffering from various types of cancer. The pooled HRs for PFS (61 cohorts, 13,224 patients) and OS (88 cohorts, 25,480 patients) were 1.47 [95% Confidence Interval (CI) 1.31-1.66] and 1.66 [95% CI 1.50-1.83], respectively, confirming a significant harmful impact of ABX on patient’ survival, observed across all cancer types (Table). The analyses of OS and PFS based on ABX exposure TWs suggested a stronger deleterious effect of ABX when taken around ICI treatment initiation. The response to treatment among ABX users was also impaired: the pooled ORs for ORR (30 cohorts, 4,590 patients) and PD (33 cohorts, 4,972 patients) were 0.55 [95% CI 0.39-0.77] and 1.97 [95% CI 1.48-2.64], respectively. Conclusions: ABX were shown to impair the clinical outcomes of cancer patients treated with ICIs, regardless of cancer type. [Table: see text]

BackgroundImmune checkpoint inhibitors (ICIs) have been shown to improve patients‘ clinical outcomes in a variety of cancers, but with variable efficacy. Prior research has also suggested that systemic antibiotic (ABX) exposure may impact the intestinal microbiota and result in suboptimal ICI treatment outcomes. Our team published a systematic review and meta-analysis showing that ABX use could indeed decrease the survival of patients diagnosed with non-small-cell lung cancer (NSCLC) and treated with ICIs.1 The present abstract aims at updating this meta-analysis by incorporating new studies that have been published in the period ranging from September 2019 to August 2020.MethodsMedline (through PubMed), the Cochrane Library and major oncology conferences proceedings were systematically searched to identify studies assessing the impact of ABX use on the clinical outcomes of NSCLC patients treated with ICIs. Studies were found eligible for inclusion when they mentioned a hazard ratio (HR) or Kaplan–Meier curves for overall survival (OS) or progression-free survival (PFS) based on antibiotic exposure. Pooled HRs for OS and PFS and HRs for OS and PFS according to different time windows for ABX exposure were calculated.Results6 eligible new studies were identified between September 2019 and August 2020 while 3 other studies were updated with new information. Altogether, 27 studies reported data for OS (6,436 patients, 826 of whom coming from new studies) and 24 for PFS (3,751 patients, 786 of whom coming from new studies). The pooled HR was 1.75 (95% confidence interval [CI]: 1.38–2.23) for OS and 1.57 (95% CI: 1.28–1.92) for PFS, confirming a significantly reduced survival in patients with NSCLC exposed to ABX. The detailed analysis in subgroups based on the time window of exposure (figure 1, figure 2) suggests that the deleterious effect of ABX is stronger when the exposition happens shortly before and after the initiation of the ICI treatment.Abstract 671 Figure 1Forest plot of hazard ratios for overall survival of patients diagnosed with NSCLC and exposed to antibiotics versus not exposed to antibiotics, according to the time window of antibiotic exposureAbstract 671 Figure 2Forest plot of hazard ratios for progression-free survival of patients diagnosed with NSCLC and exposed to antibiotics versus not exposed to antibiotics, according to the time window of antibiotic exposureConclusionsThe update of the meta-analysis confirms the previously reported deleterious effect of ABX on ICI treatment outcomes, taking into account the latest publications in the field. The topic deserves further research to uncover if the effect will stand with 1st line use of ICI together with chemotherapies and/or other approved combinations, elucidate the mechanisms at stake and improve care of patients.ReferencesLurienne L, Cervesi J, Duhalde L, de Gunzburg J, Andremont A, Zalcman G, et al. NSCLC immunotherapy efficacy and antibiotic use: a systematic review and meta-analysis. J Thorac Oncol 2020;15:1147–1159.