Modulation of Gut Microbiota to Enhance Effect of Checkpoint Inhibitor Immunotherapy.
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ABSTRACT:
SUBMITTER: Wu J
PROVIDER: S-EPMC8276067 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In the past decade, a growing set of immunotherapies including immune checkpoint blockade, chimeric antigen receptor T cells, and bispecific antibodies propelled the advancement of oncology therapeutics. Accumulating evidence demonstrates that immunotherapy could eliminate tumors better than traditional chemotherapy or radiotherapy with lower risk of adverse events in numerous cancer types. Unfortunately, a substantial proportion of patients eventually acquire resistance to immunotherapy. By analyzing the differences between immunotherapy-sensitive and immunotherapy-resistant populations, it was noticed that the composition of gut microbiota is closely related to treatment effect. Moreover, in xenograft models, interventional regulation of gut microbiota could effectively enhance efficacy and relieve resistance during immunotherapy. Thus, we believe that gut microbiota composition might be helpful to explain the heterogeneity of treatment effect, and manipulating gut microbiota could be a promising adjuvant treatment for cancer immunotherapy. In this mini review, we focus on the latest understanding of the cross-talk between gut microbiota and host immunity. Moreover, we highlight the role of gut microbiota in cancer immunotherapy including immune checkpoint inhibitor and adoptive cell transfer.
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Project description:BackgroundEvidence suggests that the human gut microbiota modulates the treatment response of immune checkpoint inhibitors (ICI) in cancer. Thus, finding predictive biomarkers in the fecal gut microbiota of patients who are less likely to respond to ICI would be valuable. This systematic review aimed to investigate the association between fecal gut microbiota composition and ICI-treatment response in patients with cancer.MethodsEMBASE, Medline, and Cochrane Library databases were searched using the "Participants, Interventions, Comparisons, and Outcomes" (PICO) process to locate studies including participants with solid cancers treated with ICI intervention. The comparator was the gut microbiota, and the outcomes were oncological outcomes such as response rates and progression-free survival. Study data were synthesized qualitatively in a systematic narrative synthesis, and the risk of bias in the studies was assessed.ResultsTwo reviewers screened 2092 abstracts independently, and 140 studies were read as full-text reports and assessed for eligibility. Eighteen studies were included with 775 patients with different types of solid cancers who received anti-PD-1, anti-PD-L1, or anti-CTLA-4 therapy. Distinct patterns were observed in the patients' fecal samples. Some bacterial species were reported to be present in responders and non-responders, while others were present only in one group. The most reported species associated with better prognosis were Faecalibacterium prausnitzii, Streptococcus parasanguinis, Bacteroides caccae, and Prevotella copri. In contrast, the most reported species associated with poor prognosis were Blautia obeum and Bacteroides ovatus.ConclusionDistinct microbiota features were associated with good and poor prognoses in ICI-treated patients with cancer.
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Project description:Beer is the most consumed alcoholic beverage worldwide. It is rich in nutrients, and with its microbial component it could play a role in gut microbiota modulation. Conflicting data are currently available regarding the consequences of alcohol and alcohol-containing beverages on dementia and age-associated disorders including Alzheimer's disease (AD), a neurodegeneration characterized by protein aggregation, inflammatory processes and alterations of components of the gut-brain axis. The effects of an unfiltered and unpasteurized craft beer on AD molecular hallmarks, levels of gut hormones and composition of micro/mycobiota were dissected using 3xTg-AD mice. In addition, to better assess the role of yeasts, beer was enriched with the same Saccharomyces cerevisiae strain used for brewing. The treatment with the yeast-enriched beer ameliorated cognition and favored the reduction of Aβ(1-42) and pro-inflammatory molecules, also contributing to an increase in the concentration of anti-inflammatory cytokines. A significant improvement in the richness and presence of beneficial taxa in the gut bacterial population of the 3xTg-AD animals was observed. In addition, the fungal order, Sordariomycetes, associated with gut inflammatory conditions, noticeably decreased with beer treatments. These data demonstrate, for the first time, the beneficial effects of a yeast-enriched beer on AD signs, suggesting gut microbiota modulation as a mechanism of action.
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Project description:Immune checkpoint inhibitor therapies such as ipilimumab, are increasingly being used as a treatment option for a variety of cancers, including metastatic melanoma and have demonstrated effectively a prolonged survival. These agents have an immunological mode of action that predisposes patients to a number of immune-related adverse events, colitis being one of the most commonly encountered complications. The pathogenesis for the development of colitis is unclear, and there is a growing consensus that the ecosystem of the gastrointestinal microbiota plays a significant role. Based on this suspected connection, studies are being carried out to explore the changes in the microbiota in patients on these medications who develop colitis. Conceivably, the modulation of the gut microbiota could offer a therapeutic benefit. Fecal microbiota transplantation is one therapeutic option that is currently being investigated, though there are still more data needed to evaluate its efficacy. In this review, we recapitulate the mechanisms of action of immune checkpoint inhibitors, their adverse events, with a focus on colitis and the role gut microbiota are suspected to play, and finally discuss the microbiota modulation therapies being investigated.
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Project description:Background Neoadjuvant checkpoint inhibition (CPI) has recently demonstrated impressive outcomes in patients with stage 3 cutaneous melanoma. However, the safety, efficacy, and outcome of neoadjuvant CPI in patients with mucosal melanoma (MM) are not well studied as MM is a rare melanoma subtype. CPI such as combination nivolumab and ipilimumab achieves response rates of 37-43% in unresectable or metastatic MM but there is limited data regarding the efficacy of these agents in the preoperative setting. We hypothesize that neoadjuvant CPI is a safe and feasible approach for patients with resectable MM. Method Under an institutionally approved protocol, we identified adult MM patients with resectable disease who received neoadjuvant anti-PD1 +/- anti-CTLA4 between 2015 to 2019 at our institution. Clinical information include age, gender, presence of nodal involvement or satellitosis, functional status, pre-treatment LDH, tumor mutation status, and treatment data was collected. Outcomes include event free survival (EFS), overall survival (OS), objective response rate (ORR), pathologic response rate (PRR), and grade ≥3 toxicities. Results We identified 36 patients. Median age was 62; 58% were female. Seventy-eight percent of patients received anti-PD1 + anti-CTLA4. Node positive disease or satellite lesions was present at the time of treatment initiation in 47% of patients. Primary sites of disease were anorectal (53%), urogenital (25%), head and neck (17%), and esophageal (6%). A minority of patients did not undergo surgery due to complete response (n=3, 8%) and disease progression (n=6, 17%), respectively. With a median follow up of 37.9 months, the median EFS was 9.2 months with 3-year EFS rate of 29%. Median OS had not been reached and 3-year OS rate was 55%. ORR was 47% and PRR was 35%. EFS was significantly higher for patients with objective response and for patients with pathologic response. OS was significantly higher for patients with pathologic response. Grade 3 toxicities were reported in 39% of patients. Conclusion Neoadjuvant CPI for resectable MM is a feasible approach with signs of efficacy and an acceptable safety profile. As there is currently no standard approach for resectable MM, this study supports further investigations using neoadjuvant therapy for these patients.
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Project description:The association of gut microbiota with gastrointestinal carcinogenesis has been heavily investigated since the recent advance in sequencing technology. Accumulating evidence has revealed the critical roles of commensal microbes in cancer progression. Given by its importance, emerging studies have focussed on targeting microbiota to ameliorate therapeutic effectiveness. It is now clear that the microbial community is closely related to the efficacy of chemotherapy, while the correlation of microbiota with immunotherapy is much less studied. Herein, we review the up-to-date findings on the influence of gut microbiota on three common immunotherapies including adoptive cell transfer, immune checkpoint blockade, and CpG-oligodeoxynucleotide therapy. We then explore three microbiota-targeted strategies that may improve treatment efficacy, involving dietary intervention, probiotics supplementation, and fecal microbiota transplantation.
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Project description:Alzheimer's disease (AD) is a progressive neurodegenerative disorder that eventually leads to dementia and death of the patient. Currently, no effective treatment is available that can slow or halt the progression of the disease. The gut microbiota can modulate the host immune system in the peripheral and central nervous system through the microbiota-gut-brain axis. Growing evidence indicates that gut microbiota dysbiosis plays an important role in the pathogenesis of AD, and modulation of the gut microbiota may represent a new avenue for treating AD. Immunotherapy targeting Aβ and tau has emerged as the most promising disease-modifying therapy for the treatment of AD. However, the underlying mechanism of AD immunotherapy is not known. Importantly, preclinical and clinical studies have highlighted that the gut microbiota exerts a major influence on the efficacy of cancer immunotherapy. However, the role of the gut microbiota in AD immunotherapy has not been explored. We found that immunotherapy targeting tau can modulate the gut microbiota in an AD mouse model. In this article, we focused on the crosstalk between the gut microbiota, immunity, and AD immunotherapy. We speculate that modulation of the gut microbiota induced by AD immunotherapy may partially underlie the efficacy of the treatment.
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