scholarly journals Intestinal Microbiome Associated With Immune-Related Adverse Events for Patients Treated With Anti-PD-1 Inhibitors, a Real-World Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenhui Liu ◽  
Fang Ma ◽  
Bao Sun ◽  
Yiping Liu ◽  
Haoneng Tang ◽  
...  
Keyword(s):  
Adverse Events ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Intestinal Bacteria ◽  
Classification Model ◽  
Intestinal Microbiome ◽  
Fecal Samples ◽  
Microbial Biomarkers ◽  
Advanced Malignancies ◽  
Auc Value

AimImmune checkpoint inhibitors (ICIs) have updated the treatment landscape for patients with advanced malignancies, while their clinical prospect was hindered by severe immune-related adverse events (irAEs). The aim of this study was to research the association between gut microbiome diversity and the occurrence of ICI-induced irAEs.Patients and MethodWe prospectively obtained the baseline fecal samples and clinical data from patients treated with anti-PD-1 inhibitors as monotherapy or in combination with chemotherapy or antiangiogenesis regardless of treatment lines. The 16S rRNA V3-V4 sequencing was used to test the gene amplicons of fecal samples. The development of irAEs was evaluated and monitored from the beginning of therapy based on CTCAE V5.01.ResultsA total of 150 patients were included in the study and followed up for at least 6 months. A total of 90 (60%) patients developed at least one type of adverse effect, among which mild irAEs (grades 1–2) occurred in 65 patients (72.22%) and severe irAEs (grades 3–5) in 25 patients (27.78%). Patients with severe irAEs showed a visible higher abundance of Streptococcus, Paecalibacterium, and Stenotrophomonas, and patients with mild irAEs had a higher abundance of Faecalibacterium and unidentified_Lachnospiraceae. With the aid of a classification model constructed with 5 microbial biomarkers, patients without irAEs were successfully distinguished from those with severe irAEs (AUC value was 0.66).ConclusionCertain intestinal bacteria can effectively distinguish patients without irAEs from patients with severe irAEs and provide evidence of gut microbiota as an informative source for developing predictive biomarkers to predict the occurrence of irAEs.

scholarly journals Strategies for improving the management of immune-related adverse events

2020 ◽  
Vol 8 (2) ◽  
pp. e001754
Author(s):  
Aung Naing ◽  
Joud Hajjar ◽  
James L Gulley ◽  
Michael B Atkins ◽  
Gennaro Ciliberto ◽  
...  
Keyword(s):  
Side Effects ◽  
Adverse Events ◽  
Checkpoint Inhibitors ◽  
Digital Health ◽  
Immunosuppressive Agents ◽  
Significant Proportion ◽  
Cell Activity ◽  
Predictive Biomarkers ◽  
Chemotherapeutic Agents ◽  
Diagnostic Tools

With the advent of immunotherapeutic agents, durable and dramatic responses have been observed in several hard-to-treat malignancies, outlining a roadmap to conquering cancer. Immune checkpoint inhibitors (ICPi) are a class of immunotherapeutic agents that attack the tumor cells by reinvigorating the suppressed immune system. However, the unbridled T-cell activity disrupts the immune homeostasis and induces a unique spectrum of side effects called immune-related adverse events (irAEs) in a significant proportion of patients. These irAEs are distinct from the side effects produced by traditional chemotherapeutic agents. Although majority of irAEs are manageable with corticosteroids and other immunosuppressive agents, life-threatening and fatal events have been reported. In the absence of predictive biomarkers to identify patients at risk for irAEs and standardized approach to detect, report, and treat irAEs, management of irAEs has been challenging to the patients, caregivers and the healthcare providers alike. With increasing use of ICPis for treatment of various cancers, the incidence of irAEs will undoubtedly increase. There is a compelling need to develop measures to effectively manage irAEs, both in the community settings and in cancer centers alike. To this end, in this paper, we propose several strategies, such as providing patient education, harmonizing irAE management guidelines, standardizing reporting of irAEs, optimizing the choice of immunosuppressive agents, conducting preclinical, clinical and translational studies to better understand irAEs, including high-risk patients, incorporating diagnostic tools to personalize irAE management using wireless technology and digital health, providing a platform to hear the missing patient’s voice, and sharing evolving data to improve the management of irAEs.

Impact of radiotherapy on risk of adverse events in patients receiving immunotherapy: A U.S. Food and Drug Administration pooled analysis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3018-3018
Author(s):  
Mitchell Steven Anscher ◽  
Shaily Arora ◽  
Chana Weinstock ◽  
Rachael Lubitz ◽  
Anup Amatya ◽  
...  
Keyword(s):  
Adverse Events ◽  
Inflammatory Responses ◽  
Checkpoint Inhibitors ◽  
Pooled Analysis ◽  
Hematologic Toxicity ◽  
Pooled Data ◽  
Advanced Malignancies ◽  
Prospective Trials ◽  
Grade 3 ◽  
The Impact

3018 Background: Immune checkpoint inhibitors (ICIs) are widely used in the treatment of multiple advanced malignancies. Radiotherapy (RT) has been used in combination with ICIs to activate tumor-specific T cell responses, and RT also promotes non-specific acute and chronic inflammatory responses both locally and systemically. More than 50% of patients receive RT at some point during their course of cancer therapy, and relatively little information is available pertaining to the impact of RT, if any, on the risk of adverse events (AEs) in patients receiving ICIs. Methods: Pooled data from prospective trials of ICIs submitted to the FDA in initial or supplemental BLAs or NDAs through 12/2019 were included (N=66). Trials from applications that were withdrawn or not approved were not included. Patients were subdivided by whether or not radiotherapy was administered at any time during the course of their cancer treatment. AEs common to both ICI treatment and RT were identified to focus on the following reactions: neutropenia, thrombocytopenia, colitis, hepatitis, pneumonitis, and myocarditis. Descriptive statistics were used to examine AEs associated with the use of radiation and ICIs. Results: A total of 25,836 patients were identified, of which 9087 (35%) received RT and 16,749 (65%) did not. Radiation was associated with similar rates of AEs overall with numerically higher hematologic toxicities and pneumonitis and numerically lower colitis, hepatitis and myocarditis (Table). Patients receiving RT were more likely to experience Grade 3-5 hematologic toxicities compared to those not receiving RT. Conclusions: To our knowledge, this is the largest report of AE risk associated with the use of radiation and ICIs. Our results show that the incidence of hematologic toxicity and pneumonitis in patients receiving RT may be slightly higher. Analysis to determine comparability of baseline demographic characteristics, comprehensive AE profile, and timing of RT is underway. [Table: see text]

scholarly journals Biomarkers of Checkpoint Inhibitor Induced Immune-Related Adverse Events—A Comprehensive Review

2021 ◽  
Vol 10 ◽  
Author(s):  
Josefien W. Hommes ◽  
Rik J. Verheijden ◽  
Karijn P. M. Suijkerbuijk ◽  
Dörte Hamann
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Clinical Decision Making ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitor ◽  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Statistical Significance ◽  
Added Value ◽  
Microbial Biomarkers

Immune checkpoint inhibitors (ICIs) have substantially improved the prognosis of patients with different types of cancer. Through blockade of cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), negative feedback mechanisms of the immune system are inhibited, potentially resulting in very durable anti-tumor responses. Despite their promise, ICIs can also elicit auto-immune toxicities. These immune-related adverse events (irAEs) can be severe and sometimes even fatal. Therefore, being able to predict severe irAEs in patients would be of added value in clinical decision making. A search was performed using “adverse events”, “immune checkpoint inhibitor”, “biomarker”, and synonyms in PubMed, yielding 3580 search results. After screening title and abstract on the relevance to the review question, statistical significance of reported potential biomarkers, and evaluation of the remaining full papers, 35 articles were included. Five additional reports were obtained by means of citations and by using the similar article function on PubMed. The current knowledge is presented in comprehensive tables summarizing blood-based, immunogenetic and microbial biomarkers predicting irAEs prior to and during ICI therapy. Until now, no single biomarker has proven to be sufficiently predictive for irAE development. Recommendations for further research on this topic are presented.

Immunological and clinical profiles of patients with advanced or metastatic melanoma receiving immune checkpoint inhibitors to investigate potential biomarkers for immune-related adverse events.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14037-e14037
Author(s):  
Stephanie A. Berg ◽  
Michael Wesolowski ◽  
Brianna Burke ◽  
Courtney Regan Wagner ◽  
Joseph I Clark ◽  
...  
Keyword(s):  
T Cells ◽  
Adverse Events ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Molecular Mechanisms ◽  
Checkpoint Inhibitors ◽  
Rank Correlation ◽  
Predictive Biomarkers ◽  
Biological Variables

e14037 Background: Immune-related adverse events (irAEs) related to immune checkpoint inhibitors (ICIs) may target any organ and originate from autoreactive T cells injuring host tissues. There is a need to develop prognostic and predictive biomarkers to distinguish patients (pts) who will benefit from ICIs avoiding irAEs during treatment. We propose that irAEs are the result of many biological variables. We hypothesize that within each pts complex immunological profile, there may be patterns and associations which exist that represent a state of inflammation that is present prior to ICI therapy and hypothesize this could predict irAEs development. Methods: We created individual immunological profiles of 11 pts diagnosed with MM prior to receiving ICIs. Assays included: PBMC composition, circulating chemokines/cytokines, and IκB degradation status. CD4 and CD8 T cells were studied for their phenotype, activation status, proliferative capacity and cytolytic granules. Clinical data was collected on a larger MM pt cohort (n = 41) and descriptive statistics were utilized to characterize reported irAEs . Results: 110 input markers were utilized for immune signature analysis. 6 of the 11 pts reported grade 2+ irAEs after ICI therapy. The pro-inflammatory CCL13, CCL1, FLT-3, IL12p40, TRAIL, and granzyme b expressing CD4 T cells at steady state and after CD3 activation were significantly higher in pts with irAEs. Known inflammatory suspects (i.e., IL-2, IL-15, TNF-a or % CD8 T cells) were not associated with irAE development . A rank correlation test showed significant associations between the levels of these factors. irAEs were reported in 41% (n = 17) for our larger cohort, most frequently skin rash (7%), colitis (7%), hepatitis (7%) and thyroid dysfunction (4%). Conclusions: The immune signatures of pts with irAEs are highly heterogeneous and possess distinctive immunological patterns. Our results introduce possible molecular mechanisms that may aid understanding of irAE development, perhaps providing the basis for a new model prospectively testing these markers to risk stratify pts receiving ICIs.

scholarly journals Pan-Cancer Analysis Reveals Alternative Splicing Characteristics Associated With Immune-Related Adverse Events Elicited by Checkpoint Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiujing He ◽  
Jing Yu ◽  
Hubing Shi
Keyword(s):  
Alternative Splicing ◽  
Adverse Events ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Splicing Factors ◽  
Close Link ◽  
Cancer Types ◽  
Splicing Isoforms ◽  
L1 Protein ◽  
Pan Cancer

Immune-related adverse events (irAEs) can impair the effectiveness and safety of immune checkpoint inhibitors (ICIs) and restrict the clinical applications of ICIs in oncology. The predictive biomarkers of irAE are urgently required for early diagnosis and subsequent management. The exact mechanism underlying irAEs remains to be fully elucidated, and the availability of predictive biomarkers is limited. Herein, we performed data mining by combining pharmacovigilance data and pan-cancer transcriptomic information to illustrate the relationships between alternative splicing characteristics and irAE risk of ICIs. Four distinct classes of splicing characteristics considered were associated with splicing factors, neoantigens, splicing isoforms, and splicing levels. Correlation analysis confirmed that expression levels of splicing factors were predictive of irAE risk. Adding DHX16 expression to the bivariate PD-L1 protein expression-fPD1 model markedly enhanced the prediction for irAE. Furthermore, we identified 668 and 1,131 potential predictors based on the correlation of the incidence of irAEs with splicing frequency and isoform expression, respectively. The functional analysis revealed that alternative splicing might contribute to irAE pathogenesis via coordinating innate and adaptive immunity. Remarkably, autoimmune-related genes and autoantigens were preferentially over-represented in these predictors for irAE, suggesting a close link between autoimmunity and irAE occurrence. In addition, we established a trivariate model composed of CDC42EP3-206, TMEM138-211, and IRX3-202, that could better predict the risk of irAE across various cancer types, indicating a potential application as promising biomarkers for irAE. Our study not only highlights the clinical relevance of alternative splicing for irAE development during checkpoint immunotherapy but also sheds new light on the mechanisms underlying irAEs.

scholarly journals The Multiple Potential Biomarkers for Predicting Immunotherapy Response—Finding the Needle in the Haystack

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 277
Author(s):  
Tamiem Adam ◽  
Therese M. Becker ◽  
Wei Chua ◽  
Victoria Bray ◽  
Tara L. Roberts
Keyword(s):  
Immune Checkpoint Inhibitors ◽  
Mononuclear Cells ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Metal Chelators ◽  
Peripheral Blood Mononuclear ◽  
Mutational Burden ◽  
Advanced Malignancies ◽  
Circulating Tumour Dna ◽  
Potential Biomarkers

Immune checkpoint inhibitors (ICIs) are being increasingly utilised in a variety of advanced malignancies. Despite promising outcomes in certain patients, the majority will not derive benefit and are at risk of potentially serious immune-related adverse events (irAEs). The development of predictive biomarkers is therefore critical to personalise treatments and improve outcomes. A number of biomarkers have shown promising results, including from tumour (programmed cell death ligand 1 (PD-L1), tumour mutational burden (TMB), stimulator of interferon genes (STING) and apoptosis-associated speck-like protein containing a CARD (ASC)), from blood (peripheral blood mononuclear cells (PBMCs), circulating tumour DNA (ctDNA), exosomes, cytokines and metal chelators) and finally the microbiome.

scholarly journals Case Report: A Case of Sintilimab-Induced Cystitis/Ureteritis and Review of Sintilimab-Related Adverse Events

2021 ◽  
Vol 11 ◽  
Author(s):  
Lingfang Tu ◽  
Yuan Ye ◽  
Xiaoping Tang ◽  
Zhen Liang ◽  
Qihan You ◽  
...  
Keyword(s):  
Adverse Events ◽  
Blood Cells ◽  
Checkpoint Inhibitors ◽  
White Blood Cells ◽  
Driver Gene ◽  
Ct Urography ◽  
Advanced Malignancies ◽  
Computer Tomography Angiography ◽  
Stage Ivb ◽  
Symptoms And Signs

Immune checkpoint inhibitors (ICIs) have been proven to be beneficial in multiple advanced malignancies. However, the widespread use of ICIs also occurred with various immune-related adverse events (irAEs). Here, we first report a case of sintilimab-related cystitis/ureteritis. A 53-year-old man with driver gene-negative pulmonary adenocarcinoma (cT1cN3M1c, Stage IVB) was being treated with sintilimab in combination of paclitaxel-albumin and bevacizumab as second-line treatment. He was hospitalized for haematuria, pollakiuria, painful micturition and low back pain after three courses. Urinalysis showed red blood cells (RBCs) and white blood cells (WBCs) were obviously increased, and serum creatinine (sCr) level was also significantly elevated. Urine culture and cytology were both negative, and cystoscopy revealed diffused redness of bladder mucosa. Urinary ultrasonography showed mild hydronephrosis and dilated ureter. The patient was diagnosed as immunotherapy-related cystitis/ureteritis after a multidisciplinary team (MDT) meeting. Once the diagnosis was made, corticosteroid therapy was given, which rapidly resolved the patient’s symptoms and signs. Computer tomography angiography (CTA) and CT urography (CTU) was conducted after sCr level was back to normal and demonstrated ureter dilation and hydroureter. Once symptoms relieved, bladder biopsy was performed and confirmed the bladder inflammation. The patient was subsequently switched to maintenance dose of methylprednisolone and tapered gradually. Since sintilimab has been used in advanced malignancies, we first reported a rare case of sintilimab-induced cystitis/ureteritis and summarized sintilimab-related adverse events to improve the assessment and management of irAEs.

scholarly journals The Role of Cytokines in Predicting the Response and Adverse Events Related to Immune Checkpoint Inhibitors

2021 ◽  
Vol 12 ◽  
Author(s):  
Min Wang ◽  
Xiaoyang Zhai ◽  
Ji Li ◽  
Jingyuan Guan ◽  
Shuhui Xu ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Strategies ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Tnf Α ◽  
Wide Range

Recently, the overall survival (OS) and progression-free survival (PFS) of patients with advanced cancer has been significantly improved due to the application of immune checkpoint inhibitors (ICIs). Low response rate and high occurrence of immune-related adverse events (irAEs) make urgently need for ideal predictive biomarkers to identity efficient population and guide treatment strategies. Cytokines are small soluble proteins with a wide range of biological activity that are secreted by activated immune cells or tumor cells and act as a bridge between innate immunity, infection, inflammation and cancer. Cytokines can be detected in peripheral blood and suitable for dynamic detection. During the era of ICIs, many studies investigated the role of cytokines in prediction of the efficiency and toxicity of ICIs. Herein, we review the relevant studies on TNF-α, IFN-γ, IL-6, IL-8, TGF-β and other cytokines as biomarkers for predicting ICI-related reactions and adverse events, and explore the immunomodulatory mechanisms. Finally, the most important purpose of this review is to help identify predictors of ICI to screen patients who are most likely to benefit from immunotherapy.

scholarly journals A Rare Presentation of Checkpoint Inhibitor Induced Distal RTA

2021 ◽  
Vol 2021 ◽  
pp. 1-5
Author(s):  
Andrew V. Doodnauth ◽  
Miriam M. Klar ◽  
Zohra R. Malik ◽  
Krunal H. Patel ◽  
Samy I. McFarlane
Keyword(s):  
Adverse Events ◽  
Renal Tubular Acidosis ◽  
Checkpoint Inhibitors ◽  
Acute Interstitial Nephritis ◽  
Rare Presentation ◽  
New Era ◽  
Advanced Malignancies ◽  
Small Incidence ◽  
History Of ◽  
Renal Tubular

Immune checkpoint inhibitors have opened a new era in treating advanced malignancies, resulting in a rapid increase in utilization, given the remarkable clinical outcomes. The incidence of immune-related adverse events increased due to the immunologic effects of these therapeutic agents. However, immune-related renal adverse events remain low, representing only a small incidence of reported cases. Common renal toxicity described includes acute interstitial nephritis, minimal change disease, and immune complex glomerulonephritis. Renal tubular acidosis has occasionally been reported but is highly uncommon. This report presents a case of a 68-year-old woman with a known history of metastatic melanoma undergoing treatment with ipilimumab+nivolumab, who developed distal renal tubular acidosis requiring stress dose steroids and sodium bicarbonate for treatment. We describe the clinical characteristics, potential mechanisms, and management of this case, highlighting the need among clinicians utilizing immune check inhibitors to be aware of this immune-related disease entity.

scholarly journals Automated Identification of Patients with Immune-related Adverse Events from Clinical Notes using Word embedding and Machine Learning

2020 ◽  
Author(s):  
Samir Gupta ◽  
Anas Belouali ◽  
Neil J Shah ◽  
Michael B Atkins ◽  
Subha Madhavan
Keyword(s):  
Machine Learning ◽  
Adverse Events ◽  
Checkpoint Inhibitors ◽  
High Accuracy ◽  
Automated Identification ◽  
Real World Data ◽  
Clinical Notes ◽  
Safety Research ◽  
Advanced Malignancies ◽  
Treatment Safety

Immune Checkpoint Inhibitors (ICIs) have substantially improved survival in patients with advanced malignancies. However, ICIs are associated with a unique spectrum of side effects termed Immune-Related Adverse Events (irAEs). To ensure treatment safety, research efforts are needed to comprehensively detect and understand irAEs from real world data (RWD). The goal of this work is to evaluate a Machine Learning-based phenotyping approach that can identify patients with irAEs from a large volume of retrospective clinical notes representing RWD. Evaluation shows promising results with an average F1-score=0.75 and AUC-ROC=0.78. While the extraction of any available irAEs in charts achieves high accuracy, individual irAEs extraction has room for further improvement.

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