Discerning the effect of pharmacological exposures on intestinal bacterial communities in cancer patients is challenging. Here, we deconvoluted the relationship between drug exposures and changes in ...microbial composition by developing and applying a new computational method, PARADIGM (parameters associated with dynamics of gut microbiota), to a large set of longitudinal fecal microbiome profiles with detailed medication-administration records from patients undergoing allogeneic hematopoietic cell transplantation. We observed that several non-antibiotic drugs, including laxatives, antiemetics, and opioids, are associated with increased Enterococcus relative abundance and decreased alpha diversity. Shotgun metagenomic sequencing further demonstrated subspecies competition, leading to increased dominant-strain genetic convergence during allo-HCT that is significantly associated with antibiotic exposures. We integrated drug-microbiome associations to predict clinical outcomes in two validation cohorts on the basis of drug exposures alone, suggesting that this approach can generate biologically and clinically relevant insights into how pharmacological exposures can perturb or preserve microbiota composition.
The application of a computational method called PARADIGM to a large dataset of cancer patients’ longitudinal fecal specimens and detailed daily medication records reveals associations between drug exposures and the intestinal microbiota that recapitulate in vitro findings and are also predictive of clinical outcomes.
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•A computational method identifies medication-microbiome associations•Applied to the dataset of cancer patients’ fecal microbiome profiles and medication records•In silico results recapitulate in vitro measurements of anti-bacterial activities•Medication-bacteria associations are predictive of patient clinical outcomes
The application of a computational method called PARADIGM to a large dataset of cancer patients’ longitudinal fecal specimens and detailed daily medication records reveals associations between drug exposures and the intestinal microbiota that recapitulate in vitro findings and are also predictive of clinical outcomes.
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Background: Clinical and preclinical experiments suggest that the gut microbiome can affect outcome in cancer patients treated with immune checkpoint inhibitors (ICI). Most data to ...date has been in melanoma, so the relationship of the gut microbiome with treatment outcome in other cancers is poorly understood. Here, we evaluated the microbiome composition in correlation to ICI response in patients with metastatic lung, urothelial, or renal cancer, as well as metastatic melanoma. Methods: Fecal microbiome samples were obtained from patients with metastatic melanoma, lung, urothelial, or renal cancer immediately before ICI therapy was initiated. Bacterial genomic DNA was isolated and profiled by whole metagenome sequencing. Sequence data were analyzed using a custom implementation of MetaPhlAn2. Response to ICI was defined as partial or complete response or remaining on therapy for more than 6 months. Results: Samples were prospectively collected from 94 patients, including metastatic melanoma (n = 17), lung (n = 44), urothelial (n = 23), or renal cancer (n = 10). Treatment included anti-PD(L)1 monotherapy (n = 51), anti-PD1 + anti-CTLA4 combination therapy (n = 17), or a combination of anti-PD1 and chemotherapy (n = 26). Clinical response was observed in 58% of patients, including partial or complete response (45%) and on treatment for more than 6 months (55%, with 31% on treatment for more than 1 year). Although the variance in the composition of pretreatment microbiome samples did not explain response alone (R vs NR, PERMANOVA, p = 0.273), a significant portion of the variance in microbiome composition was explained by the interaction of cancer type and outcome (PERMANOVA, p = 0.014), suggesting a cancer-specific microbiome relationship. Notably, there was some similarity in the signature of NR across three cancer types (lung, urothelial and melanoma). One sample in this NR cluster was from a patient whose metastatic NSCLC was nonresponsive to pembrolizumab and carboplatin/pemetrexed. This microbiome sample was evaluated in vivo using subcutaneous MC38 and CT26 tumor models in germ-free mice. In contrast to mice colonized with stool from a healthy donor, mice colonized with stool from this patient yielded a nonresponsive result upon treatment with anti-PD1 or anti-PD-L1 in combination with anti-CTLA4. Conclusions: Analysis of the fecal microbiome composition from patients with metastatic lung, urothelial, renal cancer, and melanoma identified a cancer-specific signature of R and NR to ICI. Across three cancer types, a consistent signature of NR was identified and corroborated experimentally in preclinical models.
We previously described clinically relevant reductions in fecal microbiota diversity in patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). Recipients of high-dose ...chemotherapy and autologous HCT (auto-HCT) incur similar antibiotic exposures and nutritional alterations. To characterize the fecal microbiota in the auto-HCT population, we analyzed 1161 fecal samples collected from 534 adult recipients of auto-HCT for lymphoma, myeloma, and amyloidosis in an observational study conducted at 2 transplantation centers in the United States. By using 16S ribosomal gene sequencing, we assessed fecal microbiota composition and diversity, as measured by the inverse Simpson index. At both centers, the diversity of early pretransplant fecal microbiota was lower in patients than in healthy controls and decreased further during the course of transplantation. Loss of diversity and domination by specific bacterial taxa occurred during auto-HCT in patterns similar to those with allo-HCT. Above-median fecal intestinal diversity in the periengraftment period was associated with decreased risk of death or progression (progression-free survival hazard ratio, 0.46; 95% confidence interval, 0.26-0.82; P = .008), adjusting for disease and disease status. This suggests that further investigation into the health of the intestinal microbiota in auto-HCT patients and posttransplant outcomes should be undertaken.
•Microbiota injury is observed in recipients of auto-HCT.•Lower periengraftment diversity in fecal samples is associated with worse overall and progression-free survival in auto-HCT patients.
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Colitis induced by treatment with immune-checkpoint inhibitors (ICI), termed irColitis, is a substantial cause of morbidity complicating cancer treatment. We hypothesized that abnormal fecal ...microbiome features would be present at the time of irColitis onset and that restoring the microbiome with fecal transplant from a healthy donor would mitigate disease severity. Herein, we present fecal microbiota profiles from 18 patients with irColitis from a single center, 5 of whom were treated with healthy-donor fecal microbial transplantation (FMT). Although fecal samples collected at onset of irColitis had comparable α-diversity to that of comparator groups with gastrointestinal symptoms, irColitis was characterized by fecal microbial dysbiosis. Abundances of Proteobacteria were associated with irColitis in multivariable analyses. Five patients with irColitis refractory to steroids and biologic anti-inflammatory agents received healthy-donor FMT, with initial clinical improvement in irColitis symptoms observed in four of five patients. Two subsequently exhibited recurrence of irColitis symptoms following courses of antibiotics. Both received a second "salvage" FMT that was, again, followed by clinical improvement of irColitis. In summary, we observed distinct microbial community changes that were present at the time of irColitis onset. FMT was followed by clinical improvements in several cases of steroid- and biologic-agent-refractory irColitis. Strategies to restore or prevent microbiome dysbiosis in the context of immunotherapy toxicities should be further explored in prospective clinical trials.
Researchers have attempted to link incidences of papillary thyroid cancer with radioiodine releases from nuclear power plants. Thyroid cancer detection rates are examined together with overall ...population exposure to ionizing radiation and actual radioiodine releases from the Indian Point Energy Center to determine if a causal relationship exists. A critical review of the statistical analyses used in previous papers is then presented.
Anti-CD19 chimeric antigen receptor (CAR) T cell therapy has led to unprecedented responses in patients with high-risk hematologic malignancies. However, up to 60% of patients still experience ...disease relapse and up to 80% of patients experience CAR-mediated toxicities, such as cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. We investigated the role of the intestinal microbiome on these outcomes in a multicenter study of patients with B cell lymphoma and leukemia. We found in a retrospective cohort (n = 228) that exposure to antibiotics, in particular piperacillin/tazobactam, meropenem and imipenem/cilastatin (P-I-M), in the 4 weeks before therapy was associated with worse survival and increased neurotoxicity. In stool samples from a prospective cohort of CAR T cell recipients (n = 48), the fecal microbiome was altered at baseline compared to healthy controls. Stool sample profiling by 16S ribosomal RNA and metagenomic shotgun sequencing revealed that clinical outcomes were associated with differences in specific bacterial taxa and metabolic pathways. Through both untargeted and hypothesis-driven analysis of 16S sequencing data, we identified species within the class Clostridia that were associated with day 100 complete response. We concluded that changes in the intestinal microbiome are associated with clinical outcomes after anti-CD19 CAR T cell therapy in patients with B cell malignancies.
Low intestinal microbial diversity is associated with poor outcomes after allogeneic hematopoietic cell transplantation (HCT). Using 16S rRNA sequencing of 2067 stool samples and flow cytometry data ...from 2370 peripheral blood samples drawn from 894 patients who underwent allogeneic HCT, we have linked features of the early post-HCT microbiome with subsequent immune cell recovery. We examined lymphocyte recovery and microbiota features in recipients of both unmodified and CD34-selected allografts. We observed that fecal microbial diversity was an independent predictor of CD4 T-cell count 3 months after HCT in recipients of a CD34-selected allograft, who are dependent on de novo lymphopoiesis for their immune recovery. In multivariate models using clinical factors and microbiota features, we consistently observed that increased fecal relative abundance of genus Staphylococcus during the early posttransplant period was associated with worse CD4 T-cell recovery. Our observations suggest that the intestinal bacteria, or the factors they produce, can affect early lymphopoiesis and the homeostasis of allograft-derived T cells after transplantation.
•Fecal microbial diversity is an independent predictor of CD4 T-cell count 3 months after HCT in recipients of CD34-selected allografts.•Increased fecal relative abundance of Staphylococcus in the early post-HCT period is independently associated with worse CD4 T-cell count.
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Studies of the relationship between the gastrointestinal microbiota and outcomes in allogeneic hematopoietic stem cell transplantation (allo-HCT) have thus far largely focused on early complications, ...predominantly infection and acute graft-versus-host disease (GVHD). We examined the potential relationship of the microbiome with chronic GVHD (cGVHD) by analyzing stool and plasma samples collected late after allo-HCT using a case-control study design. We found lower circulating concentrations of the microbe-derived short-chain fatty acids (SCFAs) propionate and butyrate in day 100 plasma samples from patients who developed cGVHD, compared with those who remained free of this complication, in the initial case-control cohort of transplant patients and in a further cross-sectional cohort from an independent transplant center. An additional cross-sectional patient cohort from a third transplant center was analyzed; however, serum (rather than plasma) was available, and the differences in SCFAs observed in the plasma samples were not recapitulated. In sum, our findings from the primary case-control cohort and 1 of 2 cross-sectional cohorts explored suggest that the gastrointestinal microbiome may exert immunomodulatory effects in allo-HCT patients at least in part due to control of systemic concentrations of microbe-derived SCFAs.
•The microbe-derived SCFAs butyrate and propionate in the systemic circulation are associated with protection from cGVHD.•cGVHD is associated with gastrointestinal dysbiosis late after HCT.
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•Use of the rhIL-22 dimer F-652 with systemic steroids appeared safe and was associated with a high response rate in newly diagnosed GI GVHD.•Patients responding after tissue-targeted therapy with ...F-652 and corticosteroids demonstrated an expansion of healthy commensal GI flora.
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Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic transplantation. In experimental models, interleukin-22 promotes epithelial regeneration and induces innate antimicrobial molecules. We conducted a multicenter single-arm phase 2 study evaluating the safety and efficacy of a novel recombinant human interleukin-22 dimer, F-652, used in combination with systemic corticosteroids for treatment of newly diagnosed lower gastrointestinal acute GVHD. The most common adverse events were cytopenias and electrolyte abnormalities, and there were no dose-limiting toxicities. Out of 27 patients, 19 (70%; 80% confidence interval, 56%-79%) achieved a day-28 treatment response, meeting the prespecified primary endpoint. Responders exhibited a distinct fecal microbiota composition characterized by expansion of commensal anaerobes, which correlated with increased overall microbial α-diversity, suggesting improvement of GVHD-associated dysbiosis. This work demonstrates a potential approach for combining immunosuppression with tissue-supportive strategies to enhance recovery of damaged mucosa and promote microbial health in patients with gastrointestinal GVHD. This trial was registered at www.clinicaltrials.gov as NCT02406651.
Acute lower gastrointestinal (GI) graft-versus-host disease (aGVHD) remains a leading cause of mortality and morbidity postallograft. Ponce et al report on the results of a multicenter single-arm, phase 2 study evaluating the safety and efficacy of a novel recombinant human interleukin-22 dimer in combination with systemic corticosteroids for newly diagnosed GI aGVHD. With no dose-limiting toxicity identified and a 70% day 28 response rate with associated expansion of healthy commensal GI flora, these data suggest acceptable safety and efficacy deserving of phase 3 evaluation.
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Background: Immune-related colitis (irColitis) is associated with significant morbidity and mortality among patients treated with immune checkpoint inhibition (ICI). The gut microbiota has been ...implicated in the pathophysiology of irColitis. We hypothesized that abnormal fecal microbiome features would be present at the time of irColitis onset, and that restoring the microbiome to a healthy state would mitigate disease severity. Methods: We present fecal microbiota profiles from N = 18 patients with irColitis and describe our clinical experience of N = 5 patients treated with healthy donor fecal microbial transplantation (FMT). Recipients of ICI between May 2019 and June 2021 at Memorial Sloan Kettering Cancer Center whose stool samples were investigated for diarrhea were included in our dataset (N = 100). N = 18 patients with a diagnosis of irColitis were identified. Patients that had other causes of diarrhea were classified as part of the “no-colitis” comparator group (N = 32). All patients with infectious causes of diarrhea ( C. difficile, other GI pathogen) were excluded from the analysis. Stool samples were profiled by whole metagenomic shotgun sequencing. FMT products from individual healthy donors were procured from the OpenBiome fecal bank and delivered via colonoscopy. Results: There was no difference in alpha diversity between the irColitis and no-colitis groups. Patients in the irColitis group had significantly higher relative abundance of Proteobacteria at the time of symptom onset compared to the no-colitis group (p = 0.04). Escherichia spp. and Klebsiella spp. were associated with irColitis, also described in multivariate analyses. Five patients with irColitis refractory to steroids and biologics received healthy-donor FMT, with initial clinical improvement in irColitis symptoms observed in four of five (80%) patients. Two out of five subsequently exhibited recurrence of irColitis symptoms following a course of antibiotics for pneumonia and urinary tract infection, respectively. Both received a second “salvage” FMT that was, again, followed by clinical improvement of irColitis. In these two cases, fecal profiles demonstrated dysbiotic shifts in the gut microbiome post-antibiotics characterized by Proteobacteria expansion, which was salvaged post salvage FMT, mirroring clinical resolution of irColitis symptoms. Conclusions: We observed that Proteobacteria expansion is characteristic of irColitis at time of symptom onset. FMT was followed by clinical improvements in several cases of refractory irColitis. Strategies to restore or prevent microbiome injury—with a particular focus on salvage FMT after antibiotic injury—in the context of immunotherapy toxicities could be further explored in prospective clinical trials.
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