Neutrophil-to-Lymphocyte Ratio Predicts Development of Immune-Related Adverse Events and Outcomes from Immune Checkpoint Blockade: A Case-Control Study.
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SUBMITTER: Lee PY
PROVIDER: S-EPMC8001500 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:An elevated Neutrophil-to-lymphocyte ratio (NLR) is associated with worse outcomes in several malignancies. However, its role with contemporary immune checkpoint blockade (ICB) is unknown. We investigated the utility of NLR in metastatic renal cell carcinoma (mRCC) patients treated with PD-1/PD-L1 ICB. METHODS:We examined NLR at baseline and 6 (±2) weeks later in 142 patients treated between 2009 and 2017 at Dana-Farber Cancer Institute (Boston, USA). Landmark analysis at 6 weeks was conducted to explore the prognostic value of relative NLR change on overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Cox and logistic regression models allowed for adjustment of line of therapy, number of IMDC risk factors, histology and baseline NLR. RESULTS:Median follow up was 16.6 months (range: 0.7-67.8). Median duration on therapy was 5.1 months (<1-61.4). IMDC risk groups were: 18% favorable, 60% intermediate, 23% poor-risk. Forty-four percent were on first-line ICB and 56% on 2nd line or more. Median NLR was 3.9 (1.3-42.4) at baseline and 4.1 (1.1-96.4) at week 6. Patients with a higher baseline NLR showed a trend toward lower ORR, shorter PFS, and shorter OS. Higher NLR at 6 weeks was a significantly stronger predictor of all three outcomes than baseline NLR. Relative NLR change by ?25% from baseline to 6 weeks after ICB therapy was associated with reduced ORR and an independent prognostic factor for PFS (p?<?0.001) and OS (p?=?0.004), whereas a decrease in NLR by ?25% was associated with improved outcomes. CONCLUSIONS:Early decline and NLR at 6 weeks are associated with significantly improved outcomes in mRCC patients treated with ICB. The prognostic value of the readily-available NLR warrants larger, prospective validation.
| S-EPMC5776777 | biostudies-literature
Project description:BackgroundThe impact of the gut microbiome on the initiation and intensity of immune-related adverse events (irAEs) prompted by immune checkpoint inhibitors (ICIs) is widely acknowledged. Nevertheless, there is inconsistency in the gut microbial associations with irAEs reported across various studies.MethodsWe performed a comprehensive analysis leveraging a dataset that included published microbiome data (n = 317) and in-house generated data from 16S rRNA and shotgun metagenome samples of irAEs (n = 115). We utilized a machine learning-based approach, specifically the Random Forest (RF) algorithm, to construct a microbiome-based classifier capable of distinguishing between non-irAEs and irAEs. Additionally, we conducted a comprehensive analysis, integrating transcriptome and metagenome profiling, to explore potential underlying mechanisms.ResultsWe identified specific microbial species capable of distinguishing between patients experiencing irAEs and non-irAEs. The RF classifier, developed using 14 microbial features, demonstrated robust discriminatory power between non-irAEs and irAEs (AUC = 0.88). Moreover, the predictive score from our classifier exhibited significant discriminative capability for identifying non-irAEs in two independent cohorts. Our functional analysis revealed that the altered microbiome in non-irAEs was characterized by an increased menaquinone biosynthesis, accompanied by elevated expression of rate-limiting enzymes menH and menC. Targeted metabolomics analysis further highlighted a notably higher abundance of menaquinone in the serum of patients who did not develop irAEs compared to the irAEs group.ConclusionsOur study underscores the potential of microbial biomarkers for predicting the onset of irAEs and highlights menaquinone, a metabolite derived from the microbiome community, as a possible selective therapeutic agent for modulating the occurrence of irAEs.
| S-EPMC10799412 | biostudies-literature
Project description:Immunotherapy with monoclonal antibodies targeting immune checkpoint molecules, including programmed death-1 (PD-1), PD ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen (CTLA)-4, has become prominent in the treatment of many types of cancer. However, a significant number of patients treated with immune checkpoint inhibitors (ICIs) develop immune-related adverse events (irAEs). irAEs can affect any organ system, and although most are clinically manageable, irAEs can result in mortality or long-term morbidity. Factors that can predict irAEs remain elusive. Understanding the etiology of ICI-induced irAEs and ways to limit these adverse events are needed. In this review, we provide basic science and clinical insights on the mechanisms responsible for ICI efficacy and ICI-induced irAEs. We further provide insights into approaches that may uncouple irAEs from the ability of ICIs to kill tumor cells.
| S-EPMC7554032 | biostudies-literature
Project description:Immune related adverse events (irAEs) after immune checkpoint blockade (ICB) therapy occur in a significant proportion of cancer patients. To date, the circulating mediators of ICB-irAEs remain poorly understood. Using non-targeted mass spectrometry, here we identify the circulating bio-active lipid linoleoyl-lysophosphatidylcholine (LPC 18:2) as a modulator of ICB-irAEs. In three independent human studies of ICB treatment for solid tumor, loss of circulating LPC 18:2 preceded the development of severe irAEs across multiple organ systems. In both healthy humans and severe ICB-irAE patients, low LPC 18:2 was found to correlate with high blood neutrophilia. Reduced LPC 18:2 biosynthesis was confirmed in preclinical ICB-irAE models, and LPC 18:2 supplementation in vivo suppressed neutrophilia and tissue inflammation without impacting ICB anti-tumor response. Results indicate that circulating LPC 18:2 suppresses human ICB-irAEs, and LPC 18:2 supplementation may improve ICB outcomes by preventing severe inflammation while maintaining anti-tumor immunity.
| S-EPMC11326322 | biostudies-literature
Project description:Background Myocarditis attributable to immune checkpoint inhibitor (ICI) therapy is a potentially fatal immune-related adverse event. Limited data have suggested an association between baseline and on-treatment absolute lymphocyte count (ALC) and neutrophil/lymphocyte ratio (NLR) and the development of other immune-related adverse events; there are no data characterizing the role of ALC and NLR in ICI-associated myocarditis. Methods and Results This was a case control study of 55 patients with ICI myocarditis and 55 controls without any post-ICI immune-related adverse events. We leveraged clinical testing, where patients underwent routine serial blood counts before and with each ICI cycle to compare the baseline and change in ALC and NLR between cases and controls. The association between the change in these parameters with clinical variables and major adverse cardiac events was also tested. In cases, there was a statistically significant decrease in ALC with myocarditis from baseline (1.6 thousands per cubic milliliter (K/?L); interquartile range, 1.1-1.9 K/?L) to admission (1.1 K/?L; interquartile range, 0.7-1.3 K/?L; P<0.001). Similarly, there was an increase in NLR from baseline (3.5; interquartile range, 2.3-5.4) to admission (6.6; interquartile range, 4.5-14.1; P<0.001). There was no statistically significant change in controls. In follow-up, there were 20 events; larger decreases in ALC (44.6% versus 18.2%; P<0.001) or increases in NLR (156.5% versus 65.1%; P=0.019) were associated with major adverse cardiac events. Conclusions A reduction in ALC and an increase in NLR was seen with ICI myocarditis. A greater decrease in ALC or increase in NLR was associated with subsequent major adverse cardiac events.
| S-EPMC7763791 | biostudies-literature
Project description:The efficacy of current treatment regimens for pancreatic cancer (PC) remains unsatisfactory. In recent years, immune checkpoint blockade (ICB) therapy has shown promising anti-tumor outcomes in many malignancies, including PC. Inexpensive and readily available biomarkers which predict therapeutic responses and prognosis are in critical need. Systemic immune-inflammation index (SII) and neutrophil-lymphocyte ratio (NLR) are emerging predictors for prognosis of various tumors. We aim to investigate the prognostic significance of baseline SII, NLR, and their changes in PC patients treated with ICB. Our retrospective analysis included PC patients treated with ICB therapy in the Chinese PLA General Hospital. All demographic, biological, and clinical data were extracted from medical records. Relative changes of SII after two doses of ICB were defined as ΔSII% and calculated as (SIIafter 2 doses-SIIbaseline)/SIIbaseline, and so was the case for ΔNLR%. Overall survival (OS) and progression-free survival (PFS) were compared using Kaplan-Meier curves. The prognostic significance of baseline SII, NLR, and their changes was assessed in univariate and multivariate analyses using the Cox proportional hazard regression model. In total, 122 patients with PC treated with ICB were included in the present analysis. Elevated baseline SII (HR=3.28; 95% CI:1.98-5.27; P=0.03) and ΔNLR% (HR=2.21; 95% CI:1.03-4.74; P=0.04) were significantly correlated with an increased risk of death. For PC patients receiving ICB combined with chemotherapies or radiotherapies as the first-line treatment, increased baseline SII was a negative predictor for both OS (HR=8.06; 95% CI:1.71-37.86; P=0.01) and PFS (HR=2.84; 95%CI:1.37-10.38; P=0.04). Our study reveals the prognostic value of baseline SII and NLR changes in PC patients receiving ICB therapy. The clinical utility of these prognostic biomarkers needs to be further studied in prospective studies.
| S-EPMC7943876 | biostudies-literature
Project description:The association of chronic inflammatory markers with the clinical outcome after endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm (AAA) was investigated. We included 230 patients, treated electively with EVAR. The values of neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) were measured pre- and postoperatively. Any major adverse cardiovascular event (MACE) and acute kidney injury (AKI) were recorded. Adverse events occurred in 12 patients (5.2%). Seven patients suffered from MACE and five from AKI. Median NLR and PLR values were significantly increased after the procedure (NLR: from 3.34 to 8.64, p < 0.001 and PLR: from 11.37 to 17.21, p < 0.001). None of the patients or procedure characteristics were associated with the occurrence of either a MACE or AKI. Receiver operating characteristic curve analysis showed that postoperative NLR and PLR were strongly associated with AKI. A threshold postoperative NLR value of 9.9 was associated with the occurrence of AKI, with a sensitivity of 80% and specificity of 81%. A threshold postoperative PLR value of 22.8 was associated with the occurrence of AKI, with a sensitivity of 80% and specificity of 83%. Postoperative NLR and PLR have been associated with the occurrence of AKI after EVAR for AAA.
| S-EPMC7961355 | biostudies-literature
Project description:Three checkpoint inhibitor drugs have been approved by the US Food and Drug Administration for use in specific types of cancers. While the results are promising, severe immunotherapy-related adverse events (irAEs) have been reported.To conduct a systematic review of case reports describing the occurrence of irAEs in patients with cancer following checkpoint blockade therapy, primarily to identify potentially unrecognized or unusual clinical findings and toxicity.We searched Medline, EMBASE, Web of Science, PubMed ePubs, and Cochrane CENTRAL with no restriction through August 2015.Studies reporting cases of cancer develop irAEs following treatment with anti CTLA-4 (ipilimumab) or anti PD-1 (nivolumab or pembrolizumab) antibodies were included.We extracted data on patient characteristics, irAEs characteristics, how irAEs were managed, and their outcomes.191 publications met inclusion criteria, reporting on 251 cases. Most patients had metastatic melanoma (95.6%), and the majority were treated with ipilimumab (93.2%). Autoimmune colitis, hepatitis, endocrinopathies, and cutaneous irAEs were the most frequently reported irAEs in ipilimumab treated patients. A broad spectrum of toxicities were reported for almost every body system. Moreover, well-defined diseases such as sarcoidosis, polyarthritis, polymyalgia rheumatica/arteritis, lupus, celiac disease, dermatomyositis, and Vogt-Koyanagi-like syndrome were reported. The most frequent irAEs reported with anti-PD1 agents were dermatitis for pembrolizumab, and thyroid disease and pneumonitis for nivolumab. Complete resolution of adverse events occurred in most cases. However, persistent irAEs and death were reported, mainly in patients treated with ipilimumab.Our study is limited by information available in the original reports.Evidence from case reports shows that cancer patients develop irAEs following checkpoint blockade therapy, and can occasionally develop clearly defined autoimmune systemic diseases. While discontinuation of therapy and/or treatment can result in resolution of irAEs, long-term sequelae and death have been reported.
| S-EPMC4966895 | biostudies-literature
Project description:BackgroundImmune checkpoint blockade (ICB) brings hope to many late-stage cancer patients yet its marker for response remains elusive.MethodsWe developed a hypothesis that treatment-related adverse events (TrAEs) could predict objective response rate (ORR) to ICB. We plotted ORR against corresponding any and grade 3 to 5 (G3-5) TrAEs across a variety of cancer types by performing a meta-analysis using linear regression.ResultsWe identified 113 eligible studies encompassing 25 types of malignancies that were treated with ICB or ICB-based regimes. A significant linear correlation was observed for any and severe TrAEs, respectively. The correlation coefficient was 0.57 (r = 0.324) for any TrAE and 0.61 (r = 0.37) for G3-5 TrAE. For melanoma, the correlation coefficient was 0.81 (r = 0.57) for any TrAE and 0.65 (r = 0.42) for G3-5 TrAEs. For RCC, the correlation coefficient was 0.86 (r = 0.74) for any TrAE and 0.91 (r = 0.83) for G3-5 TrAE. For NSCLC, the correlation coefficient was 0.55 (r = 0.3) for any TrAE and 0.74 (r = 0.86) for G3-5 TrAE. For UC, the correlation coefficient was 0.47 (r = 0.68) for any TrAE and 0.27 (r = 0.52) for G3-5 TrAE, yet the correlation was insignificant for severe AEs.ConclusionOur findings suggest that over half of ICB responses could be reflected by any adverse events and ∼60% of responses could be reflected by severe AEs. Further validation is needed in individual trials.
| S-EPMC7489750 | biostudies-literature
Project description:Checkpoint inhibitors (CPIs) are monoclonal antibodies which, by disrupting interactions of immune checkpoint molecules with their ligands, block regulatory immune signals otherwise exploited by cancers. Despite revolutionary clinical benefits, CPI use is associated with an array of immune-related adverse events (irAEs) that mirror spontaneous autoreactivity. Severe irAEs necessitate pausing or stopping of CPI therapy and use of corticosteroids and/or other immunomodulatory interventions. Despite increasingly widespread CPI use, irAE pathobiology remains poorly understood; its elucidation may point to targeted mitigation strategies and uncover predictive biomarkers for irAE onset in patients, whilst casting new light on mechanisms of spontaneous immune-mediated disease. This review focuses on common CPI-induced irAEs of the gut, skin and synovial joints, and how these compare to immune-mediated diseases such as ulcerative colitis, vitiligo and inflammatory arthritis. We review current understanding of the immunological changes reported following CPI therapy at the level of peripheral blood and tissue. Many studies highlight dysregulation of cytokines in irAE-affected tissue, particularly IFNγ and TNF. IrAE-affected tissues are also predominantly infiltrated by T-cells, with low B-cell infiltration. Whilst there is variability between studies, patients treated with anti-programmed cell death-1 (PD-1)/PDL-1 therapies seem to exhibit CD8+ T-cell dominance, with CD4+ T-cells dominating in those treated with anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) monotherapy. Interestingly, CD8+CXCR3+ T-cells have been reported to be elevated in gastrointestinal, dermatological and musculoskeletal -irAE affected tissues. These findings may highlight potential opportunities for therapeutic development or re-deployment of existing therapies to prevent and/or improve the outcome of irAEs.
| S-EPMC9909476 | biostudies-literature