Faecalibacterium prausnitzii strain EXL01 boosts efficacy of immune checkpoint inhibitors
Open accessAbstract
Gut microbiota impacts responses to immune checkpoint inhibitors (ICI). A high level of Faecalibacterium prausnitzii have been associated with a positive response to ICI in multiple cancer types. Here, based on fecal shotgun metagenomics data, we show in two independent cohorts of patients with non-small cell lung cancer and advanced melanoma that a high level of F. prausnitzii at baseline is positively associated with a better clinical response to ICI. In MCA205 tumor-bearing mice, administration of F. prausnitzii strain EXL01, already in clinical development for Inflammatory Bowel Disease, restores the anti-tumor response to ICI in the context of antibiotic-induced microbiota perturbation at clinical and tumor transcriptomics level. In vitro, EXL01 strain enhances T cell activation in the presence of ICI. Interestingly, oral administration of EXL01 strain did not induce any change in fecal microbiota diversity or composition, suggesting a direct effect on immune cells in the small intestine. F. prausnitzii strain EXL01 will be evaluated as an adjuvant to ICI in multiple cancers in the near future.
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Written from the paper’s full text.
TL;DR
In two independent patient cohorts, high baseline fecal *Faecalibacterium prausnitzii* was associated with better overall survival on immune checkpoint inhibitors, though the melanoma signal was restricted to one microbiota community type. In mice, oral *F. prausnitzii* strain EXL01 restored anti-PD-L1 efficacy after antibiotic-induced dysbiosis without altering fecal microbiota diversity/composition, and in vitro it enhanced dendritic cell and CD4+ T cell activation with anti-PD-L1.
Key findings
- In 337 patients with advanced NSCLC, higher baseline *F. prausnitzii* abundance was associated with better OS with a dose effect (p = .008); the predictive effect was lost in patients exposed to antibiotics within 2 months before ICI (p = .83) but remained in non-ABX-exposed patients (p = .031).
- In 165 pooled patients with advanced melanoma from 5 cohorts, OS differences were not significant across the whole population, but in the dominant community type (two-thirds of the cohort), higher *F. prausnitzii* was independently associated with better OS (HR = 0.44; 95% CI = 0.21–0.94; p = .03), while no signal was seen in the second community type (HR = 0.63; 95% CI = 0.19–2.02; p = .46).
- In MCA205 tumor-bearing mice, ABX treatment reduced anti-PD-L1 activity, and oral EXL01 restored anti-PD-L1 efficacy with greater reduction in mean tumor volume and increased survival; EXL01 did not change fecal microbiota diversity or composition, and *F. prausnitzii* was not detected in mouse feces.
- Tumor RNA sequencing showed 3,835 differentially expressed genes between vehicle and anti-PD-L1 alone, 3,313 between anti-PD-L1 alone and ABX + anti-PD-L1, and 4,468 between ABX + anti-PD-L1 and ABX + anti-PD-L1 + EXL01 (padj < 0.05); anti-PD-L1 alone and anti-PD-L1 + ABX + EXL01 clustered together by PCA (pairwise PERMANOVA: F = 1.1252, df = 1, p = .281).
Methods
- Reanalysis of fecal shotgun metagenomics from the Derosa et al. NSCLC cohort and the Lee et al. advanced melanoma cohort using MetaPhlAn 4; survival by Kaplan–Meier and log-rank; community types by Dirichlet multinomial mixture; Cox regression and MaAsLin2 with adjustment for age, gender, BMI, ABX treatment, and disease progression.
- MCA205 sarcoma mouse model in female C57Bl/6J mice: broad-spectrum ABX from Day 14 to 30, tumor inoculation at Day 0, anti-PD-L1 intraperitoneally on Days 6, 9, 12, and 15, and EXL01 by oral gavage from Day 6 at 10^10 total cell count per dose; fecal microbiota by 16S rRNA gene sequencing and tumor biopsies by RNA sequencing.
- In vitro mixed lymphocyte reaction using human HLA-mismatched monocyte-derived dendritic cells and CD4+ T cells from three independent healthy donor pairs, with EXL01 at MOI 1, 10, and 100 in the presence of nivolumab (1 μg/mL); cytokine quantification by HTRF and T cell proliferation by flow cytometry.
Limitations
- Stated: the precise mechanisms by which EXL01 boosts ICI remain unknown; EXL01 is extremely oxygen-sensitive and loses culturability after oxygen exposure, yet still shows biological effects, suggesting activity may not depend on metabolically active or culturable bacteria.
- Evident: the melanoma association was not significant in the whole pooled cohort and appeared only in one of two community types, so the clinical signal is context-dependent.
- Evident: the mechanistic and efficacy data come from a mouse sarcoma model and in vitro healthy-donor assays, and *F. prausnitzii* was not detected in mouse feces, so translation to patients and the role of the small intestine remain to be established.
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Claims the paper makes
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- Findingown data
In two independent cohorts of patients with NSCLC and advanced melanoma, high baseline F. prausnitzii is positively associated with better clinical response to ICI.
“Here, based on fecal shotgun metagenomics data, we show in two independent cohorts of patients with non-small cell lung cancer and advanced melanoma that a high level of F. prausnitzii at baseline is positively associated with a better clinical response to ICI.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Derosa et al.10 Derosa L, Routy B, Thomas AM, Iebba V, Zalcman G, Friard S, Mazieres J, Audigier-Valette C, Moro-Sibilot D, Goldwasser F, et al. Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer. Nat Med. 2022; 28(2): 315– 324. doi: 10.1038/s41591-021-01655-5. 35115705 PMC9330544
Not checked in the free run.
- cites Lee et al.27 Lee KA, Thomas AM, Bolte LA, Björk JR, de Ruijter LK, Armanini F, Asnicar F, Blanco-Miguez A, Board R, Calbet-Llopart N, et al. Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma. Nat Med. 2022; 28(3): 535– 544. doi: 10.1038/s41591-022-01695-5. 35228751 PMC8938272
Not checked in the free run.
- Findingown data
There were no differences in abundance of F. prausnitzii between the two communities.
“Also, there were no differences in the microbiota richness and diversity between the two communities (Supp. Figure S2b) nor in the abundance of F. prausnitzii (Supp. Figure S2c).”
Quote in the paperNot a substantial claim - Findingown data
Dirichlet Multinomial Mixtures identified two optimal community types in melanoma cohort.
“Using the Laplace approximation, we determined that the optimum number of clusters was two (Figure 2(b)).”
Quote in the paperNot a substantial claim - Findingown data
Oral administration of EXL01 strain does not induce change in fecal microbiota diversity or composition.
“Interestingly, oral administration of EXL01 strain did not induce any change in fecal microbiota diversity or composition, suggesting a direct effect on immune cells in the small intestine.”
- Also stated in: § F. prausnitzii EXL01 strain administration does not impact fecal microbiota composition and diversity · plain
“Likewise, the administration of E×L01 strain in combination with ABX and anti-PD-L1 treatment did not shift the microbial communities, with almost no taxonomic difference between the groups (Figure 4(c-d), Supp. Figure S3).”
Quote in the paperSubstantial claim - Also stated in: § F. prausnitzii EXL01 strain administration does not impact fecal microbiota composition and diversity · plain
- Findingown data
Multivariate Cox regression confirmed independent association between F. prausnitzii level and OS in first community type (HR=0.44; 95% CI=0.21-0.94; p=.03).
“Multivariate Cox regression analysis confirmed the independent association between F. prausnitzii level and OS in the first (HR = 0.44; 95% CI = 0.21–0.94; p = .03) but not in the second (HR = 0.63; 95% CI = 0.19–2.02; p = .46) community type (Figure 2(e)).”
Quote in the paperSubstantial claim
- Findingown data
Multivariate Cox regression did not confirm independent association between F. prausnitzii level and OS in second community type (HR=0.63; 95% CI=0.19-2.02; p=.46).
“Multivariate Cox regression analysis confirmed the independent association between F. prausnitzii level and OS in the first (HR = 0.44; 95% CI = 0.21–0.94; p = .03) but not in the second (HR = 0.63; 95% CI = 0.19–2.02; p = .46) community type (Figure 2(e)).”
Quote in the paperNot a substantial claim - Findingown data
There were no differences in microbiota richness and diversity between the two communities.
“Also, there were no differences in the microbiota richness and diversity between the two communities (Supp. Figure S2b) nor in the abundance of F. prausnitzii (Supp. Figure S2c).”
Quote in the paperNot a substantial claim - Findingown data
Predictive effect of F. prausnitzii on OS was observed in NSCLC patients with low (<50%) or no PD-L1 expression.
“The predictive effect of F. prausnitzii on OS was observed in patients with low (<50%) or no PD-L1 expression (Figure 1e, Supp. Figure S1e).”
Quote in the paperSubstantial claim - Findingown data
There was a trend toward higher OS in advanced melanoma patients with higher relative abundance of F. prausnitzii.
“The OS analyses on the whole population did not reveal any significant differences (the same results were observed when using the cut-offs of Figure 1a); however, there was a trend toward a higher OS in patients with higher relative abundance of F. prausnitzii (Figure 2(a)).”
Quote in the paperNot a substantial claim - Findingown data
In first community type (two-thirds of cohort), patients with higher F. prausnitzii had better OS than low.
“In the first community type (comprising two-thirds of the global cohort), patients with higher levels of F. prausnitzii had a better OS than those with a low F. prausnitzii level.”
Quote in the paperSubstantial claim - Findingown data
In ABX-exposed NSCLC patients, applying thresholds from non-ABX subgroup, high F. prausnitzii abundance predicted higher OS.
“Furthermore, we also observed that high F. prausnitzii abundance was predictive of a higher OS when we applied the thresholds defining F. prausnitzii abundance tertile from the non-ABX-exposed subgroup to the ABX-exposed one (Supp. Figure S1c)”
Quote in the paperSubstantial claim - Findingown data
In NSCLC patients not exposed to ABX, predictive effect of F. prausnitzii abundance on OS was present (p=.031).
“Upon analysis based on ABX exposure, the predictive effect of the abundance of F. prausnitzii was lost in a subgroup of patients exposed to ABX within 2 months prior to starting ICI treatment (p = .83, Figure 1b), in contrast to patients who did not receive ABX (p = .031, Figure 1(c)).”
Quote in the paperSubstantial claim - Findingown data
In NSCLC patients exposed to ABX within 2 months prior to ICI, predictive effect of F. prausnitzii abundance on OS was lost (p=.83).
“Upon analysis based on ABX exposure, the predictive effect of the abundance of F. prausnitzii was lost in a subgroup of patients exposed to ABX within 2 months prior to starting ICI treatment (p = .83, Figure 1b), in contrast to patients who did not receive ABX (p = .031, Figure 1(c)).”
Quote in the paperSubstantial claim - Findingown data
In second community type, no signal of association between F. prausnitzii and OS was observed.
“However, no such signal was observed in the second community type (Figure 2(d)).”
Quote in the paperSubstantial claim - Findingown data
In vitro, EXL01 strain enhances T cell activation in presence of ICI.
“In vitro, EXL01 strain enhances T cell activation in the presence of ICI.”
Quote in the paperSubstantial claim - Findingown data
In MCA205 tumor-bearing mice, administration of F. prausnitzii strain EXL01 restores anti-tumor response to ICI in context of antibiotic-induced microbiota perturbation.
“In MCA205 tumor-bearing mice, administration of F. prausnitzii strain EXL01, already in clinical development for Inflammatory Bowel Disease, restores the anti-tumor response to ICI in the context of antibiotic-induced microbiota perturbation at clinical and tumor transcriptomics level.”
- Also stated in: § F. prausnitzii EXL01 strain restores response to ICI in presence of antibiotic-induced gut microbiota perturbation · boosted
“In ABX-treated mice, oral administration of EXL01 strain restored the efficacy of anti-PD-L1 treatment as demonstrated by a greater reduction in mean tumor volume and increased survival compared to anti-PD-L1 alone (Figure 3(b-d)).”
Quote in the paperSubstantial claim - Also stated in: § F. prausnitzii EXL01 strain restores response to ICI in presence of antibiotic-induced gut microbiota perturbation · boosted
- Findingown data
In whole population of 165 advanced melanoma patients, OS analyses did not reveal significant differences by F. prausnitzii abundance.
“The OS analyses on the whole population did not reveal any significant differences (the same results were observed when using the cut-offs of Figure 1a); however, there was a trend toward a higher OS in patients with higher relative abundance of F. prausnitzii (Figure 2(a)).”
Quote in the paperNot a substantial claim - Findingown data
Multivariate analysis showed significant differences in composition between the two community types.
“The multivariate analysis in Figure 2(c) shows the most significant differences in terms of composition between the two community types.”
Quote in the paperNot a substantial claim - Findingnone given
F. prausnitzii EXL01 strain supplementation was not associated with a change in fecal microbiota composition or diversity.
“Interestingly, F. prausnitzii EXL01 strain supplementation was not associated with a change in fecal microbiota composition or diversity.”
Quote in the paperNot a substantial claim - Findingown data
In mice treated with ABX alone, alpha diversity decreased over time.
“In mice treated with ABX alone, alpha diversity decreased over time, whereas it increased in the group treated with anti-PD-L1 alone (Figure 4(a)).”
Quote in the paperSubstantial claim - Findingown data
In both in vitro and in vivo experiments, oxygen exposure leads to the loss of EXL01 culturability.
“In both in vitro and in vivo experiments, oxygen exposure leads to the loss of EXL01 culturability.”
Quote in the paperNot a substantial claim - Findingown data
F. prausnitzii was not detected at baseline or any other timepoint in mice feces in any studied group.
“Importantly, F. prausnitzii was detected neither at baseline, nor at any other timepoints in the mice feces in any of the studied groups.”
Quote in the paperSubstantial claim - Findingown data
In ABX-treated groups, relative abundance of many bacterial families increased while others decreased.
“In the ABX-treated groups, the relative abundance of many bacterial families increased, while others decreased (Figure 4b, Supp. Figure S3).”
Quote in the paperNot a substantial claim - Findingown data
EXL01 strain reduced the expression of the regulatory marker CD209 (DC-SIGN).
“Interestingly, EXL01 strain reduced the expression of the regulatory marker CD209 (DC-SIGN, Figure 6d).”
Quote in the paperNot a substantial claim - Findingown data
Principal component analysis of tumor biopsies collected 13 days post tumor inoculation showed clear clustering according to treatment groups (PERMANOVA: F = 3.2484, df = 3, p = .001).
“Principal component analysis (PCA) showed a clear clustering according to treatment groups (Figure 5(a), PERMANOVA: F = 3.2484, df = 3, p = .001).”
Quote in the paperSubstantial claim - Findingown data
Similar results to the IFN increase were observed for IL-2.
“Similar results were observed for IL-2 (Suppl Figure S4a).”
Quote in the paperNot a substantial claim - Findingown data
In mice treated with anti-PD-L1 alone, alpha diversity increased over time.
“In mice treated with ABX alone, alpha diversity decreased over time, whereas it increased in the group treated with anti-PD-L1 alone (Figure 4(a)).”
Quote in the paperNot a substantial claim - Findingown data
3,313 genes were differentially expressed between the group treated with anti-PD-L1 alone and the group treated with both ABX and anti-PD-L1 (padj < 0.05).
“A comparison between the group treated with anti-PD-L1 alone and the group treated with both ABX and anti-PD-L1 revealed that 3,313 genes were differentially expressed (padj <0.05, Figure 5(b)).”
Quote in the paperSubstantial claim - Findingown data
In the presence of anti-PD-L1, EXL01 strain increased the production of IFN by CD4+ T cells in a dose-dependent manner.
“In the presence of anti-PD-L1, EXL01 strain increased the production of the anti-tumorigenic cytokine IFN by CD4+ T cells in a dose-dependent manner (Figure 6a).”
Quote in the paperSubstantial claim - Findingown data
PCA analysis showed that mice treated with anti-PD-L1 alone and mice treated with anti-PD-L1, ABX and EXL01 strain clustered together (Pairwise PERMANOVA: F = 1.1252, df = 1, p = .281).
“Consistent with this result, PCA analysis showed that mice treated with anti-PD-L1 alone and by anti-PD-L1, ABX and EXL01 strain clustered together (Figure 5a, Pairwise PERMANOVA: F = 1.1252, df = 1, p = .281)”
Quote in the paperSubstantial claim - Findingown data
Administration of EXL01 in combination with ABX and anti-PD-L1 did not shift microbial communities, with almost no taxonomic difference between groups.
“Likewise, the administration of E×L01 strain in combination with ABX and anti-PD-L1 treatment did not shift the microbial communities, with almost no taxonomic difference between the groups (Figure 4(c-d), Supp. Figure S3).”
Quote in the paperSubstantial claim - Findingown data
3,835 genes were differentially expressed between the groups treated by vehicle and by anti-PD-L1 alone (padj < 0.05).
“Our analysis revealed that 3,835 genes were differentially expressed between the groups treated by vehicle and by anti-PD-L1 alone (padj <0.05, Figure 5(b)).”
Quote in the paperNot a substantial claim - Findingown data
Stimulation of monocyte-derived dendritic cells by EXL01 strain increased the surface expression of PD-L1, CD80, and CD1a in a dose-dependent manner.
“Stimulation of mDC by E×L01 strain increased the surface expression of the immune-checkpoint protein PD-L1 (Figure 6b) and of the activation markers CD80 (CD28 ligand, Figure 6c) and CD1a (Suppl Figure 4b) in a dose-dependent manner.”
Quote in the paperSubstantial claim - Findingown data
In mice treated with anti-PD-L1 alone, there were no major changes in bacterial communities over time.
“Compared to the effect of ABX, there were no major changes in the bacterial communities over time in the group treated with anti-PD-L1 alone, indicating that the anti-PD-L1 treatment did not have significant effect on fecal microbiota composition (Figure 4(c-d), Supp. Figure S3).”
Quote in the paperSubstantial claim - Findingcitation
High levels of F. prausnitzii in the intestinal microbiota were positively correlated with a better response to ICI in two independent cohorts of non-small cell lung cancer and advanced melanoma.
“In the current study, we showed that high levels of F. prausnitzii in the intestinal microbiota were positively correlated with a better response to ICI in two independent cohorts of non-small cell lung cancer10 or advanced melanoma.25”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [10] Derosa L, Routy B, Thomas AM, Iebba V, Zalcman G, Friard S, Mazieres J, Audigier-Valette C, Moro-Sibilot D, Goldwasser F, et al. Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer. Nat Med. 2022; 28(2): 315– 324. doi: 10.1038/s41591-021-01655-5. 35115705 PMC9330544 source
Not checked in the free run.
- cites [25] Lee N, Zakka LR, Mihm MC, Schatton T. Tumour-infiltrating lymphocytes in melanoma prognosis and cancer immunotherapy. Pathology. 2016; 48(2): 177– 187. doi: 10.1016/j.pathol.2015.12.006. 27020390 source
Not checked in the free run.
- Findingreasoning
No induction of the maturation markers CD83 and CD86 was observed after stimulation of mDC with EXL01 strain.
“No induction of the maturation markers CD83 (Suppl Figure 4c) and CD86 (Suppl Figure 4d) was observed, most probably as mDC were matured by LPS before stimulation with EXL01 strain.”
Quote in the paperNot a substantial claim - Premisecitation
A high level of F. prausnitzii is associated with a positive response to ICI in multiple cancer types.
“A high level of Faecalibacterium prausnitzii have been associated with a positive response to ICI in multiple cancer types.”
- Also stated in: § Introduction · hedged
“There is thus increasing evidence to suggest that the abundance of F. prausnitzii in the gut may impact clinical response to ICI across multiple cancers.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [4] Chaput N, Lepage P, Coutzac C, Soularue E, Le Roux K, Monot C, Boselli L, Routier E, Cassard L, Collins M, et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol. 2017; 28(6): 1368– 1379. doi: 10.1093/annonc/mdx108. 28368458 source
Not checked in the free run.
- cites [6] Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, et al. Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science. 2018; 359(6371): 97– 103. doi: 10.1126/science.aan4236. 29097493 PMC5827966 source
Not checked in the free run.
- cites [9] Spencer CN, McQuade JL, Gopalakrishnan V, McCulloch JA, Vetizou M, Cogdill AP, Khan MAW, Zhang X, White MG, Peterson CB, et al. Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response. Science. 2021; 374(6575): 1632– 1640. doi: 10.1126/science.aaz7015. 34941392 PMC8970537 source
Not checked in the free run.
- Also stated in: § Introduction · hedged
- Premisecitation
Gut microbiota impacts responses to immune checkpoint inhibitors (ICI).
“Gut microbiota impacts responses to immune checkpoint inhibitors (ICI).”
- Also stated in: § Introduction · plain
“The gut microbiota plays a key role in shaping the immune response, and is a major tumor-extrinsic regulator of responses to immunotherapy.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [2] Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, et al. Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science. 2018; 359(6371): 91– 97. doi: 10.1126/science.aan3706. 29097494 source
Not checked in the free run.
- cites [3] Derosa L, Hellmann MD, Spaziano M, Halpenny D, Fidelle M, Rizvi H, Long N, Plodkowski AJ, Arbour KC, Chaft JE, 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. Annals of Oncology. 2018; 29(6): 1437– 1444. doi: 10.1093/annonc/mdy103. 29617710 PMC6354674 source
Not checked in the free run.
- Also stated in: § Introduction · plain
- Interpretationown data
Despite ABX-induced microbiota perturbations, NSCLC patients harboring high F. prausnitzii levels exhibit positive response to ICI.
“suggesting that despite ABX-induced microbiota perturbations, patients harboring high F. prausnitzii levels exhibit a positive response to ICI.”
Quote in the paperSubstantial claim - Premisecitation
Multiple studies reported significant differences in microbial diversity and composition between responding and non-responding melanoma, NSCLC, and RCC patients treated with anti-PD-1 alone or with anti-CTLA-4.
“Multiple studies have reported significant differences in microbial diversity and composition between responding and non-responding melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) patients treated with anti-PD-1 alone or in combination with anti-CTLA-4 agents (ipilimumab).2,4-8”
Quote in the paperSubstantial claim0 of 6 sources checked- cites [2] Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, et al. Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science. 2018; 359(6371): 91– 97. doi: 10.1126/science.aan3706. 29097494 source
Not checked in the free run.
- cites [4] Chaput N, Lepage P, Coutzac C, Soularue E, Le Roux K, Monot C, Boselli L, Routier E, Cassard L, Collins M, et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol. 2017; 28(6): 1368– 1379. doi: 10.1093/annonc/mdx108. 28368458 source
Not checked in the free run.
- cites [5] Frankel AE, Coughlin LA, Kim J, Froehlich TW, Xie Y, Frenkel EP, Koh AY. Metagenomic shotgun sequencing and unbiased metabolomic profiling identify specific human gut microbiota and metabolites associated with immune checkpoint therapy efficacy in melanoma patients. Neoplasia. 2017; 19(10): 848– 855. doi: 10.1016/j.neo.2017.08.004. 28923537 PMC5602478 source
Not checked in the free run.
- cites [6] Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, et al. Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science. 2018; 359(6371): 97– 103. doi: 10.1126/science.aan4236. 29097493 PMC5827966 source
Not checked in the free run.
- cites [7] Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre M-L, Luke JJ, Gajewski TF. The commensal microbiome is associated with anti–PD-1 efficacy in metastatic melanoma patients. Science. 2018; 359(6371): 104– 108. doi: 10.1126/science.aao3290. 29302014 PMC6707353 source
Not checked in the free run.
- cites [8] Derosa L, Routy B, Fidelle M, Iebba V, Alla L, Pasolli E, Segata N, Desnoyer A, Pietrantonio F, Ferrere G, et al. Gut bacteria composition drives primary resistance to cancer immunotherapy in renal cell carcinoma patients. Eur Urol. 2020; 78(2): 195– 206. doi: 10.1016/j.eururo.2020.04.044. 32376136 source
Not checked in the free run.
- Premisecitation
In humans, early ABX exposure is associated with decreased immunotherapy efficacy in multiple cancer types.
“In humans, early ABX exposure (prior to or early during ICI therapy) has been associated with decreased immunotherapy efficacy in multiple cancers types.2,3”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [2] Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, et al. Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science. 2018; 359(6371): 91– 97. doi: 10.1126/science.aan3706. 29097494 source
Not checked in the free run.
- cites [3] Derosa L, Hellmann MD, Spaziano M, Halpenny D, Fidelle M, Rizvi H, Long N, Plodkowski AJ, Arbour KC, Chaft JE, 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. Annals of Oncology. 2018; 29(6): 1437– 1444. doi: 10.1093/annonc/mdy103. 29617710 PMC6354674 source
Not checked in the free run.
- Interpretationcitation
Increasing evidence suggests abundance of F. prausnitzii in gut may impact clinical response to ICI across multiple cancers.
“There is thus increasing evidence to suggest that the abundance of F. prausnitzii in the gut may impact clinical response to ICI across multiple cancers.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [4] Chaput N, Lepage P, Coutzac C, Soularue E, Le Roux K, Monot C, Boselli L, Routier E, Cassard L, Collins M, et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol. 2017; 28(6): 1368– 1379. doi: 10.1093/annonc/mdx108. 28368458 source
Not checked in the free run.
- cites [6] Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, et al. Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science. 2018; 359(6371): 97– 103. doi: 10.1126/science.aan4236. 29097493 PMC5827966 source
Not checked in the free run.
- cites [9] Spencer CN, McQuade JL, Gopalakrishnan V, McCulloch JA, Vetizou M, Cogdill AP, Khan MAW, Zhang X, White MG, Peterson CB, et al. Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response. Science. 2021; 374(6575): 1632– 1640. doi: 10.1126/science.aaz7015. 34941392 PMC8970537 source
Not checked in the free run.
- Premisecitation
Deep shotgun metagenomics in 2 cohorts of rare cancers confirmed cross-cancer validity of strain-response signatures dependent on ICI treatment rather than cancer type.
“Another study performed deep shotgun metagenomics sequencing in 2 cohorts of patients with diverse rare cancers treated with combination ICI.16 Comforted by a meta-analysis of gut metagenomes from 6 additional comparable studies, they confirmed the cross-cancer (and cross-country) validity of strain – response signatures which were dependent on the ICI treatment rather than on the cancer type.16”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [16] Gunjur A, Shao Y, Rozday T, Klein O, Mu A, Haak BW, Markman B, Kee D, Carlino MS, Underhill C, et al. A gut microbial signature for combination immune checkpoint blockade across cancer types. Nat Med. 2024 Mar 1; 30(3): 797– 809. doi: 10.1038/s41591-024-02823-z. 38429524 PMC10957475 source
Not checked in the free run.
- Premisecitation
In 43 metastatic melanoma patients treated with anti-PD-1, high F. prausnitzii relative abundance was the strongest signal of response to ICI.
“Simultaneously, a second study on 43 patients with metastatic melanoma treated with anti-PD-1 agents showed the same results, with high F. prausnitzii relative abundance reported as the strongest signal of response to ICI.6”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6] Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, et al. Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science. 2018; 359(6371): 97– 103. doi: 10.1126/science.aan4236. 29097493 PMC5827966 source
Not checked in the free run.
- Premisecitation
In melanoma patients treated with dendritic cell immunotherapy, F. prausnitzii was main beneficial taxon for no recurrence at 2 years.
“They show that different microbes were associated with prognosis, with F. prausnitzii standing out as the main beneficial taxon for no recurrence at 2 year in the patients receiving the DC treatment.17”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [17] Alves Costa Silva C, Piccinno G, Suissa D, Bourgin M, Schreibelt G, Durand S, Birebent R, Fidelle M, Sow C, Aprahamian F, et al. Influence of microbiota-associated metabolic reprogramming on clinical outcome in patients with melanoma from the randomized adjuvant dendritic cell-based MIND-DC trial. Nat Commun. 2024; 15(1): 1633. doi: 10.1038/s41467-024-45357-1. 38395948 PMC10891084 source
Not checked in the free run.
- Premisecitation
In that context, positive response to ICI was associated with higher F. prausnitzii levels.
“Interestingly, the positive response to ICI in this context was also associated with higher F. prausnitzii levels.6”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6] Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, et al. Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science. 2018; 359(6371): 97– 103. doi: 10.1126/science.aan4236. 29097493 PMC5827966 source
Not checked in the free run.
- Interpretationown data
Loss of predictive effect of F. prausnitzii on OS in ABX-exposed patients suggests microbiota directly influences activity of ICI.
“The loss of the predictive effect of F. prausnitzii on OS in patients exposed to ABX-induced microbiota perturbations suggests that the microbiota directly influences the activity of ICI.”
Quote in the paperSubstantial claim - Premisecitation
In 26 metastatic melanoma patients treated with anti-CTLA-4, baseline gut microbiota enriched with Faecalibacterium species was associated with improved PFS and OS.
“A first study of 26 patients with metastatic melanoma treated with anti-CTLA-4 agents suggested that patients with baseline gut microbiota enriched with Faecalibacterium species (and other members of the Firmicutes phylum) had improved PFS and OS compared to patients who were not enriched.4”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [4] Chaput N, Lepage P, Coutzac C, Soularue E, Le Roux K, Monot C, Boselli L, Routier E, Cassard L, Collins M, et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol. 2017; 28(6): 1368– 1379. doi: 10.1093/annonc/mdx108. 28368458 source
Not checked in the free run.
- Premisecitation
Mice colonized with microbiota from ICI responders had better response to ICI in melanoma model than those colonized with non-responders.
“A causality link was then established by showing that mice colonized with microbiota from human patients that responded to ICI had a better response to ICI in a melanoma model than their counterparts colonized with the microbiota from non-responders.6”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6] Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, et al. Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science. 2018; 359(6371): 97– 103. doi: 10.1126/science.aan4236. 29097493 PMC5827966 source
Not checked in the free run.
- Premisecitation
Meta-analysis found high abundance of Faecalibacterium genus was strongest signal associated with response to ICI using anti-PD-1 or anti-CTLA-4.
“A meta-analysis found that high abundance of Faecalibacterium genus was the strongest signal associated with response to ICI, using either anti-PD-1 or anti-CTLA-4 antibodies.5–7,12,13”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [5] Frankel AE, Coughlin LA, Kim J, Froehlich TW, Xie Y, Frenkel EP, Koh AY. Metagenomic shotgun sequencing and unbiased metabolomic profiling identify specific human gut microbiota and metabolites associated with immune checkpoint therapy efficacy in melanoma patients. Neoplasia. 2017; 19(10): 848– 855. doi: 10.1016/j.neo.2017.08.004. 28923537 PMC5602478 source
Not checked in the free run.
- cites [6] Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, et al. Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science. 2018; 359(6371): 97– 103. doi: 10.1126/science.aan4236. 29097493 PMC5827966 source
Not checked in the free run.
- cites [7] Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre M-L, Luke JJ, Gajewski TF. The commensal microbiome is associated with anti–PD-1 efficacy in metastatic melanoma patients. Science. 2018; 359(6371): 104– 108. doi: 10.1126/science.aao3290. 29302014 PMC6707353 source
Not checked in the free run.
- cites [12] Limeta A, Ji B, Levin M, Gatto F, Nielsen J. Meta-analysis of the gut microbiota in predicting response to cancer immunotherapy in metastatic melanoma. JCI Insight. 2020; 5(23): e140940. doi: 10.1172/jci.insight.140940. 33268597 PMC7714408 source
Not checked in the free run.
- cites [13] Peters BA, Wilson M, Moran U, Pavlick A, Izsak A, Wechter T, Weber JS, Osman I, Ahn J. Relating the gut metagenome and metatranscriptome to immunotherapy responses in melanoma patients. Genome Med. 2019; 11(1): 61. doi: 10.1186/s13073-019-0672-4. 31597568 PMC6785875 source
Not checked in the free run.
- Interpretationreasoning
The ABX-induced microbiota alteration resembles the type of alteration cancer patients may experience in clinical practice.
“Of note, the chosen ABX cocktail alters the mouse microbiota structure without eliminating it completely (discussed in Figure 4), thus resembling the type of microbiota alteration cancer patients may experience in clinical practice.”
Quote in the paperSubstantial claim - Premisecitation
Clinical trials suggested that FMT can rescue the efficacy of ICI in non-responders, notably in patients with advanced melanoma refractory to treatment with PD-1 inhibitors, with a response rate of 30-40%.
“Recently, clinical trials suggested that FMT can rescue the efficacy of ICI in non-responders, notably in patients with advanced melanoma refractory to treatment with PD-1 inhibitors, with a response rate of 30–40%.18,19”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [18] Baruch EN, Youngster I, Ben-Betzalel G, Ortenberg R, Lahat A, Katz L, Adler K, Dick-Necula D, Raskin S, Bloch N, et al. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science. 2021; 371(6529): 602– 609. doi: 10.1126/science.abb5920. 33303685 source
Not checked in the free run.
- cites [19] Davar D, Dzutsev AK, McCulloch JA, Rodrigues RR, Chauvin J-M, Morrison RM, Deblasio RN, Menna C, Ding Q, Pagliano O, et al. Fecal microbiota transplant overcomes resistance to anti–PD-1 therapy in melanoma patients. Science. 2021; 371(6529): 595– 602. doi: 10.1126/science.abf3363. 33542131 PMC8097968 source
Not checked in the free run.
- Interpretationown data
EXL01 strain restored the anti-tumor transcriptomic response to ICI in the context of ABX-induced gut microbiota perturbation.
“providing further evidence that EXL01 strain restored the anti-tumor transcriptomic response to ICI.”
- Also stated in: § F. prausnitzii EXL01 strain administration restores normal response to ICI at the tumor gene expression level in gut microbiota perturbation context · plain
“F. prausnitzii EXL01 strain administration restores normal response to ICI at the tumor gene expression level in gut microbiota perturbation context”
Quote in the paperSubstantial claim- Rests on an assumption: The ABX-induced loss of ICI response in the mouse model is mediated by gut microbiota perturbation rather than by direct effects of antibiotics.
- Also stated in: § F. prausnitzii EXL01 strain administration restores normal response to ICI at the tumor gene expression level in gut microbiota perturbation context · plain
- Premisecitation
Half of the patients, supplemented or not with CBM588, developed toxicity that was associated with an increased abundance of E. coli and Klebsiella spp.
“However, half of the patients, supplemented or not with CBM588, developed toxicity that was associated with an increased abundance of E. coli and Klebsiella spp.39”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] Dizman N, Meza L, Bergerot P, Alcantara M, Dorff T, Lyou Y, Frankel P, Cui Y, Mira V, Llamas M, et al. Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial. Nat Med. 2022; 28(4): 704– 712. doi: 10.1038/s41591-022-01694-6. 35228755 PMC9018425 source
Not checked in the free run.
- Interpretationown data
In a mouse preclinical model of ICI treatment, F. prausnitzii EXL01 strain restores the response to ICI in the context of ABX-induced gut microbiota perturbation at both clinical and tumor transcriptomic levels.
“In a mouse preclinical model of ICI treatment, we demonstrated that F. prausnitzii EXL01 strain restores the response to ICI in the context of ABX-induced gut microbiota perturbation at both clinical and tumor transcriptomic levels.”
Quote in the paperSubstantial claim- Rests on an assumption: Findings in mouse preclinical models and in vitro human cell assays predict the clinical efficacy of EXL01 as an adjuvant to ICI in patients.
- Rests on an assumption: The ABX-induced loss of ICI response in the mouse model is mediated by gut microbiota perturbation rather than by direct effects of antibiotics.
- Interpretationreasoning
These results suggest that F. prausnitzii EXL01 strain might act through direct interactions with host immune cells in the small intestine, although the precise mechanisms remain to be elucidated.
“These results suggest that F. prausnitzii EXL01 strain might act through direct interactions with host immune cells in the small intestine, although the precise mechanisms remain to be elucidated.”
Quote in the paperNot a substantial claim - Premisecitation
Similar results to those with EXL01 were observed with supplementation of a bifidogenic live bacterial product in renal carcinoma patients.
“Similar results were observed with the supplementation of a bifidogenic live bacterial product in renal carcinoma patients.39”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] Dizman N, Meza L, Bergerot P, Alcantara M, Dorff T, Lyou Y, Frankel P, Cui Y, Mira V, Llamas M, et al. Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial. Nat Med. 2022; 28(4): 704– 712. doi: 10.1038/s41591-022-01694-6. 35228755 PMC9018425 source
Not checked in the free run.
- Interpretationown data
In mice that received oral EXL01 strain, gene expression was restored, as demonstrated by 4,468 differentially expressed genes between the anti-PD-L1 plus ABX group and the anti-PD-L1 plus ABX plus EXL01 group (padj < 0.05).
“In mice that received oral EXL01 strain, gene expression was restored, as demonstrated by 4,468 differentially expressed genes between anti-PD-L1 and ABX treatment group and the group that received anti-PD-L1, ABX and EXL01 strain (padj <0.05, Figure 5b).”
Quote in the paperSubstantial claim- Rests on an assumption: The ABX-induced loss of ICI response in the mouse model is mediated by gut microbiota perturbation rather than by direct effects of antibiotics.
- Interpretationown data
Anti-PD-L1 treatment did not have significant effect on fecal microbiota composition.
“Compared to the effect of ABX, there were no major changes in the bacterial communities over time in the group treated with anti-PD-L1 alone, indicating that the anti-PD-L1 treatment did not have significant effect on fecal microbiota composition (Figure 4(c-d), Supp. Figure S3).”
Quote in the paperSubstantial claim - Interpretationown data
In vitro, F. prausnitzii EXL01 strain directly interacts with host immune cells, through activation of both dendritic cells and CD4+ T cells in the presence of ICI.
“In vitro, we demonstrate direct interactions between F. prausnitzii EXL01 strain and host immune cells, through activation of both DC and CD4+ T cells in the presence of ICI.”
Quote in the paperSubstantial claim - Interpretationown data
ABX blocked the ability of anti-PD-L1 to modulate cancer cell proliferation, as suggested by upregulation of cell proliferation-related pathways in ABX-treated mice.
“Genes involved in cell proliferation-related pathways were upregulated in ABX-treated mice, suggesting that ABX blocked the ability of anti-PD-L1 to modulate cancer cell proliferation (Figure 5(b-e)).”
Quote in the paperSubstantial claim - Interpretationown data
Changes in fecal microbiota composition over time were primarily due to addition of ABX rather than anti-PD-L1 and EXL01 treatment.
“These analyses demonstrated that changes in fecal microbiota composition over time were primarily due to the addition of ABX rather than anti-PD-L1 and E×L01 strain treatment, suggesting that E×L01 strain modulation of ICI activity is not a result of changes in the composition or diversity of the fecal microbiome.”
Quote in the paperSubstantial claim - Interpretationown data
EXL01 strain alone is able to restore anti-tumor effect of anti-PD-L1 in context of gut microbiota perturbation.
“EXL01 strain alone is thus able to restore the anti-tumor effect of anti-PD-L1 treatment in the context of gut microbiota perturbation.”
Quote in the paperSubstantial claim - Premisecitation
In patients with cancer, specific taxa, including F. prausnitzii, A. muciniphila and Bifidobacteria, have been associated with improved clinical responses to ICI.
“In patients with cancer, specific taxa, including F. prausnitzii, A. muciniphila and Bifidobacteria, have been associated with improved clinical responses to ICI.2,6,7”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [2] Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, et al. Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science. 2018; 359(6371): 91– 97. doi: 10.1126/science.aan3706. 29097494 source
Not checked in the free run.
- cites [6] Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, et al. Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science. 2018; 359(6371): 97– 103. doi: 10.1126/science.aan4236. 29097493 PMC5827966 source
Not checked in the free run.
- cites [7] Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre M-L, Luke JJ, Gajewski TF. The commensal microbiome is associated with anti–PD-1 efficacy in metastatic melanoma patients. Science. 2018; 359(6371): 104– 108. doi: 10.1126/science.aao3290. 29302014 PMC6707353 source
Not checked in the free run.
- Interpretationcitation
Efficacy of ICI is microbiota-dependent.
“In accordance with previously published data,2 ABX treatment significantly reduced the activity of anti-PD-L1, as illustrated by a greater tumor growth and reduced survival, highlighting the microbiota-dependent efficacy of ICI (Figure 3(b-d)).”
Quote in the paperSubstantial claim - Interpretationown data
EXL01 strain modulation of ICI activity is not a result of changes in composition or diversity of fecal microbiome.
“These analyses demonstrated that changes in fecal microbiota composition over time were primarily due to the addition of ABX rather than anti-PD-L1 and E×L01 strain treatment, suggesting that E×L01 strain modulation of ICI activity is not a result of changes in the composition or diversity of the fecal microbiome.”
Quote in the paperSubstantial claim
- May combine two claims. 24
- Classified as probably not a substantial claim. 22
May combine two claims.
Findingown dataNSCLC patients exposed to ABX had lower relative abundance of F. prausnitzii and less rich/diverse microbiota.
“Patients exposed to ABX had a lower relative abundance of F. prausnitzii, and a less rich and diverse microbiota (Supp. Figure S1a,b).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn non-ABX-treated MCA205 tumor-bearing mice, anti-PD-L1 significantly reduced tumor volume and increased survival vs vehicle.
“As expected, in non-ABX-treated mice, anti-PD-L1 treatment significantly reduced tumor volume and increased survival compared to the vehicle group (Figure 3(b-d)).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn 337 NSCLC patients, higher F. prausnitzii abundance was associated with better OS, with dose effect (p=.008).
“Higher F. prausnitzii abundance was associated with better OS, with a dose effect (p = .008, Figure 1(a-d)).”
Quote in the paperSubstantial claimMay combine two claims.
FindingcitationABX treatment significantly reduced activity of anti-PD-L1 in MCA205 tumor-bearing mice, with greater tumor growth and reduced survival.
“In accordance with previously published data,2 ABX treatment significantly reduced the activity of anti-PD-L1, as illustrated by a greater tumor growth and reduced survival, highlighting the microbiota-dependent efficacy of ICI (Figure 3(b-d)).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, et al. Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science. 2018; 359(6371): 91– 97. doi: 10.1126/science.aan3706. 29097494 source
Not checked in the free run.
May combine two claims.
Findingown dataClustering was not dependent on original five cohorts; patients from several cohorts distributed in two clusters.
“Of note, the clustering was not only dependent on the original five cohorts as patients from several cohorts (Manchester, Leeds, PRIMM.NL, PRIMM.UK) were distributed in the two community clusters (Supp. Figure S2a).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataTreatment with anti-PD-L1 led to an upregulation of genes associated with immune response and a downregulation of genes involved in cell proliferation.
“Treatment with anti-PD-L1 led to an upregulation of genes associated with immune response and a downregulation of genes involved in cell proliferation (Figure 5(b-e)).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn ABX-treated MCA205 tumor-bearing mice, oral EXL01 restored efficacy of anti-PD-L1, with greater reduction in mean tumor volume and increased survival vs anti-PD-L1 alone.
“In ABX-treated mice, oral administration of EXL01 strain restored the efficacy of anti-PD-L1 treatment as demonstrated by a greater reduction in mean tumor volume and increased survival compared to anti-PD-L1 alone (Figure 3(b-d)).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe chosen ABX cocktail alters mouse microbiota structure without eliminating it completely.
“Of note, the chosen ABX cocktail alters the mouse microbiota structure without eliminating it completely (discussed in Figure 4), thus resembling the type of microbiota alteration cancer patients may experience in clinical practice.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
InterpretationreasoningF. prausnitzii is a strong candidate for development of live biotherapeutic products.
“F. prausnitzii is thus identified as a strong candidate for the development of live biotherapeutic products (LBP), a new type of biological product containing live microorganisms and applicable to the prevention or treatment of human diseases.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationThe two cohorts were expanded with 38 patients and results confirmed in 293 additional melanoma patients.
“These two cohorts were then further expanded with 38 patients and the results were confirmed in 293 additional melanoma patients.9,11”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [9] Spencer CN, McQuade JL, Gopalakrishnan V, McCulloch JA, Vetizou M, Cogdill AP, Khan MAW, Zhang X, White MG, Peterson CB, et al. Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response. Science. 2021; 374(6575): 1632– 1640. doi: 10.1126/science.aaz7015. 34941392 PMC8970537 source
Not checked in the free run.
- cites [11] Coutzac C, Jouniaux J-M, Paci A, Schmidt J, Mallardo D, Seck A, Asvatourian V, Cassard L, Saulnier P, Lacroix L, et al. Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer. Nat Commun. 2020; 11(1): 2168. doi: 10.1038/s41467-020-16079-x. 32358520 PMC7195489 source
Not checked in the free run.
May combine two claims.
PremisecitationEarly ABX exposure impairs therapeutic effect of ICI in sarcoma and melanoma-bearing mice, with increased tumor size and reduced OS.
“Early studies reported that antibiotics (ABX) impair the therapeutic effect of ICI (anti-PD-1 alone or combined with anti-CTLA-4 antibodies) in sarcoma and melanoma-bearing mice with increased tumor size and reduced overall survival (OS).2”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, et al. Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science. 2018; 359(6371): 91– 97. doi: 10.1126/science.aan3706. 29097494 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPD-L1 expression is predictive of positive response to ICI in NSCLC.
“To evaluate the potential interaction with PD-L1 expression, which is predictive of a positive response to ICI in NSCLC,30 we further separated the cohort into three tertiles according to PD-L1 expression levels (0, 1–49% and ≥50%).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, et al. Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. N Engl J Med. 2012; 366(26): 2443– 2454. doi: 10.1056/NEJMoa1200690. 22658127 PMC3544539 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationSome link was found between FMT efficacy and F. prausnitzii level.
“Interestingly, some link was found between FMT efficacy and F. prausnitzii level.19”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [19] Davar D, Dzutsev AK, McCulloch JA, Rodrigues RR, Chauvin J-M, Morrison RM, Deblasio RN, Menna C, Ding Q, Pagliano O, et al. Fecal microbiota transplant overcomes resistance to anti–PD-1 therapy in melanoma patients. Science. 2021; 371(6529): 595– 602. doi: 10.1126/science.abf3363. 33542131 PMC8097968 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationICI are proven effective in several solid and hematologic cancers.
“Immune checkpoint inhibitors (ICI) such as antibodies targeting CTLA-4, PD-1 and its ligand (PD-L1), are proven effective in several solid and hematologic cancers.1”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018; 359(6382): 1350– 12. doi: 10.1126/science.aar4060. 29567705 PMC7391259 source
Not checked in the free run.
May combine two claims.
PremisecitationBaseline enrichment of F. prausnitzii in stools predicts response to ICI in hepatocellular carcinoma and NSCLC.
“Baseline enrichment of F. prausnitzii in stools was found as a predictor of response to ICI in hepatocellular carcinoma14 and in NSCLC.15”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [14] Li L, Ye J. Characterization of gut microbiota in patients with primary hepatocellular carcinoma received immune checkpoint inhibitors: a Chinese population-based study. Medicine (Baltimore). 2020; 99(37): e21788. doi: 10.1097/MD.0000000000021788. 32925716 PMC7489660 source
Not checked in the free run.
- cites [15] Newsome RC, Gharaibeh RZ, Pierce CM, da Silva WV, Paul S, Hogue SR, Yu Q, Antonia S, Conejo-Garcia JR, Robinson LA, et al. Interaction of bacterial genera associated with therapeutic response to immune checkpoint PD-1 blockade in a United States cohort. Genome Med. 2022; 14(1): 35. doi: 10.1186/s13073-022-01037-7. 35346337 PMC8961902 source
Not checked in the free run.
May combine two claims.
PremisecitationF. prausnitzii exhibits immunomodulatory effects; high level associated with health, low with disease including IBD and cancer.
“Indeed, F. prausnitzii exhibits immunomodulatory effects, and a high level of F. prausnitzii is associated with health, whereas low level is associated with disease, notably Inflammatory Bowel Disease (IBD)22,23 and cancer.24”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [22] Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermúdez-Humarán LG, Gratadoux J-J, Blugeon S, Bridonneau C, Furet J-P, Corthier G, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci USA. 2008; 105(43): 16731– 16736. doi: 10.1073/pnas.0804812105. 18936492 PMC2575488 source
Not checked in the free run.
- cites [23] Touch S, Godefroy E, Rolhion N, Danne C, Oeuvray C, Straube M, Galbert C, Brot L, Alonso Salgueiro I, Chadi S, et al. Human CD4+CD8α+ Tregs induced by Faecalibacterium prausnitzii protect against intestinal inflammation. JCI Insight. 2022; 7(12): e154722. doi: 10.1172/jci.insight.154722. 35536673 PMC9309064 source
Not checked in the free run.
- cites [24] Dikeocha IJ, Al-Kabsi AM, Chiu H-T, Alshawsh MA. Faecalibacterium prausnitzii Ameliorates Colorectal Tumorigenesis and Suppresses Proliferation of HCT116 Colorectal Cancer Cells. Biomedicines. 2022; 10(5): 1128. doi: 10.3390/biomedicines10051128. 35625865 PMC9138996 source
Not checked in the free run.
May combine two claims.
InterpretationcitationNew results in two independent cohorts, together with previous studies, confirm high baseline F. prausnitzii abundance is predictive of positive response to ICI in multiple cancer types.
“These new results in two independent cohorts, together with previous studies,4,6,9,11,12,14,15 confirm that a high abundance of F. prausnitzii in stools at baseline is predictive of a positive response to ICI in multiple cancer types.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [4] Chaput N, Lepage P, Coutzac C, Soularue E, Le Roux K, Monot C, Boselli L, Routier E, Cassard L, Collins M, et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol. 2017; 28(6): 1368– 1379. doi: 10.1093/annonc/mdx108. 28368458 source
Not checked in the free run.
- cites [6] Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, et al. Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science. 2018; 359(6371): 97– 103. doi: 10.1126/science.aan4236. 29097493 PMC5827966 source
Not checked in the free run.
- cites [9] Spencer CN, McQuade JL, Gopalakrishnan V, McCulloch JA, Vetizou M, Cogdill AP, Khan MAW, Zhang X, White MG, Peterson CB, et al. Dietary fiber and probiotics influence the gut microbiome and melanoma immunotherapy response. Science. 2021; 374(6575): 1632– 1640. doi: 10.1126/science.aaz7015. 34941392 PMC8970537 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationF. prausnitzii is the most abundant species in human intestinal microbiota of healthy adults, representing around 5% of total fecal microbiota.
“F. prausnitzii, a member of the Firmicutes phylum, is the most abundant species in the human intestinal microbiota of healthy adults, representing around 5% of the total fecal microbiota.20–22”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [20] Hold GL, Schwiertz A, Aminov RI, Blaut M, Flint HJ. Oligonucleotide probes that detect quantitatively significant groups of butyrate-producing bacteria in human feces. Appl Environ Microbiol. 2003; 69(7): 4320– 4324. doi: 10.1128/AEM.69.7.4320-4324.2003. 12839823 PMC165216 source
Not checked in the free run.
- cites [21] Lopez-Siles M, Martinez-Medina M, Surís-Valls R, Aldeguer X, Sabat-Mir M, Duncan SH, Flint HJ, Garcia-Gil LJ. Changes in the abundance of Faecalibacterium prausnitzii phylogroups I and II in the intestinal mucosa of inflammatory bowel disease and patients with colorectal cancer. Inflamm Bowel Dis. 2016; 22(1): 28– 41. doi: 10.1097/MIB.0000000000000590. 26595550 source
Not checked in the free run.
- cites [22] Sokol H, Pigneur B, Watterlot L, Lakhdari O, Bermúdez-Humarán LG, Gratadoux J-J, Blugeon S, Bridonneau C, Furet J-P, Corthier G, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci USA. 2008; 105(43): 16731– 16736. doi: 10.1073/pnas.0804812105. 18936492 PMC2575488 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDerosa et al. showed fecal Akkermansia muciniphila levels correlated with ICI clinical success in NSCLC patients.
“Derosa et al.10 showed that levels of fecal Akkermansia muciniphila correlated with ICI clinical success in patients NSCLC treated with ICI.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Derosa et al.10 Derosa L, Routy B, Thomas AM, Iebba V, Zalcman G, Friard S, Mazieres J, Audigier-Valette C, Moro-Sibilot D, Goldwasser F, et al. Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer. Nat Med. 2022; 28(2): 315– 324. doi: 10.1038/s41591-021-01655-5. 35115705 PMC9330544
Not checked in the free run.
May combine two claims.
Interpretationown dataEXL01 strain modulates ICI activity via direct effect on immune cells in small intestine, not via changes in fecal microbiota composition/diversity.
“suggesting a direct effect on immune cells in the small intestine.”
- Also stated in: § F. prausnitzii EXL01 strain administration does not impact fecal microbiota composition and diversity · hedged
“suggesting that E×L01 strain modulation of ICI activity is not a result of changes in the composition or diversity of the fecal microbiome.”
Quote in the paperSubstantial claim- Rests on an assumption: Fecal microbiota composition and diversity reflect the relevant microbial environment (e.g., small intestine) for EXL01's effect on immune cells.
- Also stated in: § F. prausnitzii EXL01 strain administration does not impact fecal microbiota composition and diversity · hedged
Classified as probably not a substantial claim.
Study design and conductnone givenMice were randomized based on tumor volume and allocated to vehicle and anti-PD-L1 ±EXL01-treated groups.
“On Day 5 post-tumor inoculation, mice were randomized based on tumor volume and allocated to vehicle and anti-PD-L1 ±EXL01-treated groups.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationA high relative abundance of A. muciniphila coincided with ABX use (20% of cases) and presence of the genus Clostridium, both associated with resistance to ICI.
“Such a high relative abundance of A. muciniphila coincided with ABX use (20% of cases) and presence of the genus Clostridium, both associated with resistance to ICI.10”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] Derosa L, Routy B, Thomas AM, Iebba V, Zalcman G, Friard S, Mazieres J, Audigier-Valette C, Moro-Sibilot D, Goldwasser F, et al. Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer. Nat Med. 2022; 28(2): 315– 324. doi: 10.1038/s41591-021-01655-5. 35115705 PMC9330544 source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationThe intestinal microbiota is essential to host physiology and is established as a key modulator in immune responses.
“The intestinal microbiota is essential to the host physiology and is now established as a key modulator in immune responses.31”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [31] Zheng D, Liwinski T, Elinav E. Interaction between microbiota and immunity in health and disease. Cell Res. 2020; 30(6): 492– 506. doi: 10.1038/s41422-020-0332-7. 32433595 PMC7264227 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationBifidobacterium spp. increased with CBM588 therapy, specifically in responders.
“Interestingly, Bifidobacterium spp. increased with CBM588 therapy, specifically in responders.39”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] Dizman N, Meza L, Bergerot P, Alcantara M, Dorff T, Lyou Y, Frankel P, Cui Y, Mira V, Llamas M, et al. Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial. Nat Med. 2022; 28(4): 704– 712. doi: 10.1038/s41591-022-01694-6. 35228755 PMC9018425 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationF. prausnitzii colonization abrogates ICI-induced colitis and improves ICI antitumor activity in two mouse cancer models.
“Interestingly, F. prausnitzii colonization has also been shown to abrogate ICI-induced colitis and improve ICI antitumor activity in two mouse cancer models.41”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [41] Gao Y, Xu P, Sun D, Jiang Y, Lin X-L, Han T, Yu J, Sheng C, Chen H, Hong J, et al. Faecalibacterium prausnitzii abrogates intestinal toxicity and promotes tumor immunity to increase the efficacy of dual CTLA4 and PD-1 checkpoint blockade. Cancer Res. 2023; 83(22): 3710– 3725. doi: 10.1158/0008-5472.CAN-23-0605. 37602831 source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductcitationMice were randomized to receive a broad-spectrum ABX combination.
“mice were randomized to receive a broad-spectrum ABX combination from Day 14 to 30”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Routy et al.2 Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, et al. Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science. 2018; 359(6371): 91– 97. doi: 10.1126/science.aan3706. 29097494
Not checked in the free run.
May combine two claims.
InterpretationreasoningDespite oxygen exposure and loss of culturability, EXL01 still exhibits potent biological effects, suggesting that the biological activity of EXL01 does not necessarily depend on metabolically active or culturable bacteria.
“However, despite this, the bacterium still exhibits potent biological effects, suggesting that the biological activity of EXL01 does not necessarily depend on metabolically active or culturable bacteria.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHigher A. muciniphila level (above 4.8% abundance) in NSCLC patients is associated with poor survival rates.
“However, higher A. muciniphila level (above 4.8% abundance) in NSCLC patients is surprisingly associated with poor survival rates.10”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [10] Derosa L, Routy B, Thomas AM, Iebba V, Zalcman G, Friard S, Mazieres J, Audigier-Valette C, Moro-Sibilot D, Goldwasser F, et al. Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer. Nat Med. 2022; 28(2): 315– 324. doi: 10.1038/s41591-021-01655-5. 35115705 PMC9330544 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataMultivariable association between microbial community abundance and community type was examined with MaAsLin2 taking into account potential confounding factors (age, gender, BMI, treatment with ABX and disease progression).
“Multivariable association between microbial community abundance and community type was examined with MaAsLin2 (version 1.4.0)29 taking into account potential confounding factors (age, gender, BMI, treatment with ABX and disease progression).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [29] Mallick H, Rahnavard A, McIver LJ, Ma S, Zhang Y, Nguyen LH, Tickle TL, Weingart G, Ren B, Schwager EH, et al. Multivariable association discovery in population-scale meta-omics studies Coelho LP, editor. PLOS Comput Biol. 2021; 17(11): e1009442. doi: 10.1371/journal.pcbi.1009442. 34784344 PMC8714082 source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductown dataMLR assay used PBMCs from three independent healthy donor pairs.
“The co-culture of human HLA-mismatched mDC and CD4+ T cells was performed using PBMCs from three independent healthy donor pairs, with mDC and CD4+ T cells of each pair isolated from different donors.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationA. muciniphila and F. prausnitzii are among the few human microbiota-derived species positively associated with health and therapeutic potential, notably in metabolic syndrome and inflammatory bowel diseases, and are strong candidates for the development of live biotherapeutic products.
“A. muciniphila and F. prausnitzii are among the few human microbiota-derived species that have been positively associated with health and therapeutic potential, notably in metabolic syndrome and inflammatory bowel diseases, and are thus strong candidates for the development of LBP.36,37”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [36] O’Toole PW, Marchesi JR, Hill C. Next-generation probiotics: the spectrum from probiotics to live biotherapeutics. Nat Microbiol. 2017; 2(5): 17057. doi: 10.1038/nmicrobiol.2017.57. 28440276 source
Not checked in the free run.
- cites [37] Martín R, Langella P. Emerging health concepts in the probiotics field: streamlining the definitions. Front Microbiol. 2019; 10: 1047. doi: 10.3389/fmicb.2019.01047. 31164874 PMC6536656 source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductown dataCox regression models adjusted for other clinical data.
“Cox regression models were performed to determine hazard ratios and 95% confidence intervals for overall survival, adjusting for other clinical data using the R Survival package (version 3.2–10).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataEXL01 strain enhances ICI activity by activating both dendritic cells and T cells in the presence of anti-PD-L1.
“Thus, EXL01 strain enhances ICI activity by activating both dendritic cells (DC) and T cells in the presence of anti-PD-L1.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAnother study linked toxicity with dual CTLA-4 and PD-1 inhibition to an increased abundance of Bacteroides intestinalis in the stool of patients with melanoma.
“Another study linked toxicity with dual CTLA-4 and PD-1 inhibition to an increased abundance of Bacteroides intestinalis in the stool of patients with melanoma.40”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [40] Andrews MC, Duong CPM, Gopalakrishnan V, Iebba V, Chen W-S, Derosa L, Khan MAW, Cogdill AP, White MG, Wong MC, et al. Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade. Nat Med. 2021; 27(8): 1432– 1441. doi: 10.1038/s41591-021-01406-6. 34239137 PMC11107795 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationA. muciniphila is positively associated with anti-PD-1 antibody response in NSCLC patients, and its baseline level in stool has been shown to predict this enhanced response.
“A. muciniphila is positively associated with anti-PD-1 antibodies response in NSCLC patients,2,38 and its baseline level in stool has been shown to predict this enhanced response.10”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [2] Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, et al. Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science. 2018; 359(6371): 91– 97. doi: 10.1126/science.aan3706. 29097494 source
Not checked in the free run.
- cites [38] Jin Y, Dong H, Xia L, Yang Y, Zhu Y, Shen Y, Zheng H, Yao C, Wang Y, Lu S. The diversity of gut microbiome is associated with favorable responses to anti–programmed death 1 immunotherapy in Chinese patients with NSCLC. J Thorac Oncol. 2019; 14(8): 1378– 1389. doi: 10.1016/j.jtho.2019.04.007. 31026576 source
Not checked in the free run.
- cites [10] Derosa L, Routy B, Thomas AM, Iebba V, Zalcman G, Friard S, Mazieres J, Audigier-Valette C, Moro-Sibilot D, Goldwasser F, et al. Intestinal Akkermansia muciniphila predicts clinical response to PD-1 blockade in patients with advanced non-small-cell lung cancer. Nat Med. 2022; 28(2): 315– 324. doi: 10.1038/s41591-021-01655-5. 35115705 PMC9330544 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationFMT is generally recognized as safe, with no or limited side effects, but unexpected toxicity has been reported, including ESBL-producing Escherichia coli bacteremia in two patients who received FMT.
“Although FMT is generally recognized as safe, with no or limited side effects,33 unexpected toxicity has been reported, e.g., extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli bacteremia in two patients who received FMT.34”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [33] Merrick B, Allen L, Masirah M, Zain N, Forbes B, Shawcross DL, Goldenberg SD. Regulation, risk and safety of faecal microbiota transplant. Infect Prev Pract. 2020; 2(3): 100069. doi: 10.1016/j.infpip.2020.100069. 34316559 PMC7280140 source
Not checked in the free run.
- cites [34] DeFilipp Z, Bloom PP, Torres Soto M, Mansour MK, Sater MRA, Huntley MH, Turbett S, Chung RT, Chen Y-B, Hohmann EL. Drug-resistant E. coli bacteremia transmitted by fecal microbiota transplant. N Engl J Med. 2019; 381(21): 2043– 2050. doi: 10.1056/NEJMoa1910437. 31665575 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationThe gut microbiota has been involved in response to cancer treatments, and in particular to immunotherapy.
“In this context, the gut microbiota has been involved in response to cancer treatments, and in particular to immunotherapy.2,6,7,32”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [2] Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, et al. Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science. 2018; 359(6371): 91– 97. doi: 10.1126/science.aan3706. 29097494 source
Not checked in the free run.
- cites [6] Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, et al. Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science. 2018; 359(6371): 97– 103. doi: 10.1126/science.aan4236. 29097493 PMC5827966 source
Not checked in the free run.
- cites [7] Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre M-L, Luke JJ, Gajewski TF. The commensal microbiome is associated with anti–PD-1 efficacy in metastatic melanoma patients. Science. 2018; 359(6371): 104– 108. doi: 10.1126/science.aao3290. 29302014 PMC6707353 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSupplementation of Bifidobacterium spp. CBM588 significantly improved PFS when added to dual CTLA-4 and PD-1 inhibition in patients with metastatic renal cell carcinoma.
“Recently, a small size randomized clinical trial suggested that supplementation of the Bifidobacterium spp. CBM588 significantly improved PFS when added to a dual CTLA-4 and PD-1 inhibition treatment in patients with metastatic renal cell carcinoma.39”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] Dizman N, Meza L, Bergerot P, Alcantara M, Dorff T, Lyou Y, Frankel P, Cui Y, Mira V, Llamas M, et al. Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial. Nat Med. 2022; 28(4): 704– 712. doi: 10.1038/s41591-022-01694-6. 35228755 PMC9018425 source
Not checked in the free run.
May combine two claims.
InterpretationreasoningF. prausnitzii EXL01 strain is well characterized, has immune-modulatory properties, can potentiate immunotherapy in preclinical studies, and is in clinical development for IBD (NCT05542355).
“Thus, the F. prausnitzii EXL01 strain, already in clinical development stage for IBD (NCT05542355), is an ideal candidate strain for the development of LBP in immune-oncology indications, as it is well characterized, with immune-modulatory properties and a striking ability to potentiate immunotherapy in preclinical studies.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites NCT05542355
Not checked in the free run.
- Rests on an assumption: Findings in mouse preclinical models and in vitro human cell assays predict the clinical efficacy of EXL01 as an adjuvant to ICI in patients.
The paper relies on this without support.
Fecal microbiota composition and diversity reflect the relevant microbial environment (e.g., small intestine) for EXL01's effect on immune cells.
“suggesting a direct effect on immune cells in the small intestine.”
The paper relies on this without support.
The MCA205 tumor-bearing mouse model with ABX-induced dysbiosis is predictive of human cancer patients' response to ICI and EXL01.
“In ABX-treated mice, oral administration of EXL01 strain restored the efficacy of anti-PD-L1 treatment as demonstrated by a greater reduction in mean tumor volume and increased survival compared to anti-PD-L1 alone (Figure 3(b-d)).”
The paper relies on this without support.
The in vitro MLR assay is a valid measure of T cell activation relevant to in vivo anti-tumor response.
“In vitro, EXL01 strain enhances T cell activation in the presence of ICI.”
The paper relies on this without support.
The mechanisms by which F. prausnitzii boosts the response to ICI remain unknown.
“However, those involved in boosting the response to ICI remain unknown.”
The paper relies on this without support.
Findings in mouse preclinical models and in vitro human cell assays predict the clinical efficacy of EXL01 as an adjuvant to ICI in patients.
“Thus, the F. prausnitzii EXL01 strain, already in clinical development stage for IBD (NCT05542355), is an ideal candidate strain for the development of LBP in immune-oncology indications, as it is well characterized, with immune-modulatory properties and a striking ability to potentiate immunotherapy in preclinical studies.”
The paper relies on this without support.
The ABX-induced loss of ICI response in the mouse model is mediated by gut microbiota perturbation rather than by direct effects of antibiotics.
“In a mouse preclinical model of ICI treatment, we demonstrated that F. prausnitzii EXL01 strain restores the response to ICI in the context of ABX-induced gut microbiota perturbation at both clinical and tumor transcriptomic levels.”
Claims other papers make about this one
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Several Faecalibacterium prausnitzii SGBs are linked to favorable prognosis in multiple cancer types.
“Various F. prausnitzii SGBs are associated with favorable prognosis in patients diagnosed with several cancer types 23,24,56”
From Impact of the ONCOBIOME network in cancer microbiome research (2025) · cites this paper as [56]
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“2,6,7 A. muciniphila is positively associated with anti-PD-1 antibodies response in NSCLC patients, 2,38 and its baseline level in stool has been shown to predict this enhanced response.”
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- Authors
- Bredon, M., Danne, C., Pham, H. P., Ruffié, P., Bessede, A., Rolhion, N., Creusot, L., Brot, L., Alonso, I., Langella, P., Derosa, L., Cortot, A. B., Routy, B., Zitvogel, L., Segata, N., & Sokol, H.
- Affiliations
- Inserm (FR)
- Parean Biotechnologies, Saint-Malo, France
- Exeliom Biosciences, Dijon, France
- Explicyte Immuno-Oncology, Bordeaux, France
- Gastroenterology Department, Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, Saint-Antoine Hospital, Paris, France
- AgroParisTech (FR)
- Université Paris-Saclay (FR)
- Centre National de la Recherche Scientifique (FR)
- Centre Hospitalier de l’Université de Montréal (CA)
- University of Trento (IT)
- Corresponding author
- Sokol, Harry
- ORCID
- Venue
- OncoImmunology
- Publisher
- Informa UK Limited
- Published
- 2024-07
- Volume
- 13
- Issue
- 1
- Pages
- 2374954-2374954
- ISSN
- 2162-4011 (ISSN-L)
- 2162-402X
- PMC
- PMC11218805
- OpenAlex
- W4400205565
- Semantic Scholar
- 5c8220f3086f1b044ae25fe462c722be3cb2b6e5
- Cited by
- 74
- References
- 43
- Citations by year
- 2026: 36 · 2025: 29 · 2024: 9
- FWCI
- 12.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- OncoImmunology (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by-nc)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Institutional Research Information System (Università degli Studi di Trento) (submittedVersion, cc-by-nc)
- Funders
- Sorbonne university and Exeliom Biosciences
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Cancer Research and Treatments
- Keywords
- Faecalibacterium prausnitzii, immune checkpoint inhibitors, gut microbiota, non-small cell lung cancer, melanoma, T cell activation, cancer transcriptomics, cancer immunotherapy response
- MeSH terms
- Gastrointestinal Microbiome, Faecalibacterium prausnitzii, Immune Checkpoint Inhibitors, Animals, Carcinoma, Non-Small-Cell Lung, Feces, Female, Humans, Lung Neoplasms, Male, Melanoma, Mice, Inbred C57BL, Cell Line, Tumor, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-07.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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