Analysis of Toxicity Profile and Predictors of Immune Checkpoint Inhibitor-Related Adverse Events

2020 ◽  
Author(s):  
Rilan Bai ◽  
Naifei Chen ◽  
Xiao Chen ◽  
Lingyu Li ◽  
Wei Song ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Area Under The Curve ◽  
Progression Free Survival ◽  
Toxicity Profile ◽  
Baseline Characteristics ◽  
Pan Cancer

Abstract Background and objectiveIn recent years, a wide variety of immune checkpoint inhibitors (ICIs) is emerging and has shown long-lasting and significant efficacy in the treatment of various malignant tumors. However, about 10% of patients experience serious and even life-threatening immune-related adverse events (irAEs). Fully understanding the characteristics of toxic effects and biomarkers to predict irAEs is, therefore, of great interest. We aimed to retrospectively analyze the toxicity profile and predictors of irAEs, as well as the correlation between irAEs and clinical efficacy in patients with advanced pan-cancer who were treated with multi-type ICIs in real-world.MethodsWe retrospectively analyzed data from 105 patients with advanced pan-cancer who were treated with multi-type ICIs in the First Hospital of Jilin University from Jan 1, 2016 to Aug 1, 2020. We used logistic regression analyses to investigate associations between irAEs and clinical baseline characteristics, blood count parameters, and biochemical indicators during the treatment. Receiver-operating characteristic (ROC) curve was used to determine a cutoff value for parameters and area under the curve (AUC). Kaplan–Meier and cox multivariate regression analysis were performed to estimate the relationship of baseline characteristics and irAEs with progression-free survival (PFS) and overall survival (OS).ResultsWe found that lower relative lymphocyte count (RLC) (cutoff=0.285*10^9/L), higher albumin (ALB) (cutoff=39.05g/L) and higher absolute eosinophil count (AEC) (cutoff=0.175*10^9/L) were significantly associated with the occurrence of any irAEs, of which a higher AEC (cutoff=0.205*10^9/L) was strongly associated with skin-related irAEs (HR=0.163, p=0.004); And a higher lactate dehydrogenase (LDH) level (cutoff=237.5U/L) was an independent predictor of serious irAEs (HR=0.199, p=0.022). In the analysis of immune cell subgroup, lower absolute CD8+CD28- T cell count (HR=0.806; 95%CI: 0.643-1.011; p=0.062), a regulatory T lymphocytes, was associated with the occurrence of irAEs, although the difference was not statistically significant; And a higher percentage of CD19+ B cells were associated with the occurrence of serious irAEs and irAEs of grade ≥2 (p＜0.05). In addition, our study showed that patients with any grade irAE had a significantly better PFS (8.37 vs.3.77 months, HR=2.02, p=0.0038) and OS (24.77 vs.13.83 months, HR=1.78, p=0.029).ConclusionsThis retrospective study reported the clinical profile data of irAEs of unselected patients in the real world, and explored some parameters that may all be conventional, potentially predictable markers of the occurrence, type, or grade of irAEs in clinical practice. Evidence of a correlation between safety and efficacy may contribute to fully assess the risk-benefit ratio for patients treated with ICIs.

scholarly journals Rheumatic Immune-Related Adverse Events—A Consequence of Immune Checkpoint Inhibitor Therapy

Biology ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 561
Author(s):  
Anca Bobircă ◽  
Florin Bobircă ◽  
Ioan Ancuta ◽  
Alesandra Florescu ◽  
Vlad Pădureanu ◽  
...  
Keyword(s):  
Immune System ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Multidisciplinary Approach ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Cancer Cell Growth ◽  
Inhibitory Mechanisms ◽  
Checkpoint Inhibitor Therapy

The advent of immunotherapy has changed the management and therapeutic methods for a variety of malignant tumors in the last decade. Unlike traditional cytotoxic chemotherapy, which works by interfering with cancer cell growth via various pathways and stages of the cell cycle, cancer immunotherapy uses the immune system to reduce malignant cells’ ability to escape the immune system and combat cell proliferation. The widespread use of immune checkpoint inhibitors (ICIs) over the past 10 years has presented valuable information on the profiles of toxic adverse effects. The attenuation of T-lymphocyte inhibitory mechanisms by ICIs results in immune system hyperactivation, which, as expected, is associated with various adverse events defined by inflammation. These adverse events, known as immune-related adverse events (ir-AEs), may affect any type of tissue throughout the human body, which includes the digestive tract, endocrine glands, liver and skin, with reports of cardiovascular, pulmonary and rheumatic ir-AEs as well. The adverse events that arise from ICI therapy are both novel and unique compared to those of the conventional treatment options. Thus, they require a multidisciplinary approach and continuous updates on the diagnostic approach and management.

scholarly journals SAT0540 ONE-YEAR OUTCOMES AFTER RHEUMATIC IMMUNE-RELATED ADVERSE EVENTS FROM CHECKPOINT INHIBITORS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1227.2-1227
Author(s):  
E. Berard ◽  
T. Barnetche ◽  
L. Rouxel ◽  
C. Dutriaux ◽  
L. Dousset ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Symptomatic Treatment ◽  
Musculoskeletal Symptoms ◽  
Day Range ◽  
One Year

Background:Description and initial management of rheumatic immune-related adverse-events (irAEs) from cancer immunotherapies have been reported by several groups but to date, few studies have evaluated the long-term outcomes and management of rheumatic irAEs (1).Objectives:To describe the long-term management and assess the one-year outcomes of patients who experienced rheumatic immune-related adverse events (irAEs) due to immune checkpoint inhibitors (ICI).Methods:This was a single-centre prospective observational study including patients referred for musculoskeletal symptoms while treated with ICI. After baseline rheumatological evaluation defining the clinical entity presented, follow-up visits were organised according to the type and severity of irAE. At one year, persistence of irAE, ongoing treatment, as well as cancer outcomes were assessed.Results:63 patients were included between September 2015 and June 2018. 24 patients (38%) presented with non-inflammatory musculoskeletal conditions managed with short-term symptomatic treatment and did not require specific follow-up. 39 patients (62%) experienced inflammatory manifestations, mimicking either rheumatoid arthritis (RA, n=19), polymyalgia rheumatica (PMR, n=16), psoriatic arthritis (PsA, n=3) and one flare of a preexisting axial spondyloarthritis. Overall, 32 patients (82%) received systemic glucocorticoids, with a median rheumatic dosage of 15mg/day (range: 5-60mg/day). None of the patients had to permanently discontinue ICI therapy for rheumatic irAE. 20 patients (67%) were still receiving glucocorticoids at one year, with a median dosage of 5mg/day (range: 2-20mg/day). Glucocorticoids were more frequently discontinued for patients with RA-like condition (44%) than PMR-like condition (23%), but no other predictive factor of glucocorticoids withdrawal could be identified. At one year, overall survival and progression-free survival were comparable between patients who were still receiving glucocorticoids for rheumatic irAE and patients who have discontinued. Eight patients required csDMARDs.Conclusion:At one year, a majority of patients required long-term low-dose glucocorticoids for chronic rheumatic irAE, which seems not altering oncological control.References:[1]Braaten TJ, Brahmer JR, Forde PM, et al. Immune checkpoint inhibitor-induced inflammatory arthritis persists after immunotherapy cessation. Ann Rheum Dis. 2019 Sep 20.Disclosure of Interests:None declared

Gastrointestinal Adverse Events Induced by Immune-Checkpoint Inhibitors

Digestion ◽  
2021 ◽  
pp. 1-9
Author(s):  
Shunichi Yanai ◽  
Yosuke Toya ◽  
Tamotsu Sugai ◽  
Takayuki Matsumoto
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Architectural Distortion ◽  
Management Guidelines ◽  
Crypt Abscess ◽  
Gastrointestinal Adverse Events ◽  
Histopathologic Findings

<b><i>Background:</i></b> As immune-checkpoint inhibitors (ICI) are becoming standard therapies for malignant tumors, increasing attention has been paid to their associated immune-related adverse events (irAEs). The gastrointestinal tract is the major site of irAEs, and it has recently become evident that the large bowel is the most frequently affected region. The aim of this narrative review was to clarify the endoscopic and histopathologic findings of and treatments for ICI-induced colitis. <b><i>Summary:</i></b> Endoscopic findings of ICI-induced colitis include a reddish, edematous mucosa with increased mucous exudate, loss of normal vascularity, and a granular mucosa with or without mucosal breaks. Histopathologic findings of ICI-induced colitis are expansion of the lamina propria, intraepithelial infiltration of neutrophils, crypt architectural distortion, neutrophilic crypt abscess, and prominent apoptosis. The clinical, endoscopic, and histopathologic severity of ICI-induced colitis is diverse, but colonoscopy together with biopsy is necessary for diagnosis. While a certain proportion of patients with ICI-induced colitis have an intractable clinical course, management guidelines are based on retrospective analyses. Prospective studies are needed to assess the efficacy of various medications, including immunosuppressive regimens. <b><i>Key Messages:</i></b> Colonoscopy with biopsy is the gold standard for the diagnosis of ICI-induced colitis. Endoscopists should be aware of the clinical features and pathophysiology of ICI-induced colitis for prompt diagnosis and treatment planning.

Immune-related adverse events associated with immune-checkpoint inhibitors therapy in Mexican patients: Experience at a single center.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14580-e14580
Author(s):  
Iván Romarico Romarico Gonzalez Espinoza ◽  
Neil Cortés Escobar ◽  
Mariana Chiquillo-Domínguez ◽  
Gabriela Juárez Salazar ◽  
Julio Cesar Garibay Diaz ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Chemotherapeutic Agents ◽  
Real World Data ◽  
Non Melanoma Skin Cancer ◽  
Grade 3 ◽  
Patients Experience

e14580 Background: The use of immune-checkpoint inhibitors (ICIs) for solid malignancies is rapidly rising, and many new agents and treatment combinations are in development. However, ICIs have a unique side-effect profile of immune-related adverse events (irAEs) compared with chemotherapeutic agents or targeted therapies. The aim of this work was to describe the irAEs in diverse types of malignant tumors using real-world data. Methods: This is a retrospective and descriptive study of patients with diverse types of advanced malignancies treated with immunotherapy at Centro Oncológico Integral of the Hospital Ángeles in Puebla, México; during the period 2016-2020. Data about the primary neoplasm, ICIs, irAEs, organ system affected, grade and treatment was collected. Clinical and laboratory parameters were obtained by reviewing medical records. Results: A total of 117 patients were included, median age of 65 years, of which 63.2% were male and 36.8% were female. The most frequent neoplasms treated with ICIs were: lung (27.4%), kidney (16.2%), melanoma (12.8%), hepatocellular (9.4%), breast (8.5%), non-melanoma skin cancer (6.0%), mesothelioma (4.3%) and other tumors (15.3%). 39.3% of the patients had no metastases, 41.9% had metastases to at least 1 or 2 sites, and 18.8% to 3 or more sites. The types of ICIs were: nivolumab (35.0%), pembrolizumab (28.2%), atezolizumab (23.9%), ipilimumab + nivolumab (12.0%) and durvalumab (0.9%). The most frequent irAEs were: gastrointestinal (61.5%), neurologic (46.2%), pulmonary (38.5%), metabolic (32.5%) and hematologic (29.1%). 39.3% of the irAEs were reported as grade 1, 31.6% as grade 2, 14.5% as grade 3 and 2.6% as grade 4. Conclusions: Our work shows the incidence of irAEs in a poorly studied population and provides new data that complement that reported by other works, however, further prospective studies are necessary.[Table: see text]

scholarly journals Immune checkpoint inhibitors, endocrine adverse events, and outcomes of melanoma

2022 ◽  
Author(s):  
Hanna Karhapää ◽  
Siru Mäkelä ◽  
Hanna Laurén ◽  
Marjut Jaakkola ◽  
Camilla Schalin-Jäntti ◽  
...  
Keyword(s):  
Adverse Events ◽  
Treatment Outcomes ◽  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Autoimmune Diabetes ◽  
Progression Free Survival ◽  
Electronic Patient Records ◽  
Melanoma Patients

Objective: Immune checkpoint inhibitors (ICI) can cause endocrine adverse events. However, endocrine AEs could be related to better treatment outcomes. Our aim was to investigate whether this holds true in a real-world setting of metastatic melanoma patients. Design: A retrospective single-institution study. Methods: We included 140 consecutive metastatic melanoma patients treated with ICI between January 2012 and May 2019. We assessed endocrine toxicity and best possible treatment outcomes from electronic patient records, including laboratory parameters, and radiological images. Results: Of the treated patients, 21 patients (15%) were treated with ipilimumab, 46 (33%) with nivolumab, 67 (48%) with pembrolizumab, and six (4%) with combination therapy (ipilimumab + nivolumab). Endocrine AEs appeared in 29% (41/140) patients. Three patients had two different endocrine AEs. Thyroid disorders were the most common: 26% (36/140), followed by hypophysitis: 4% (5/140). Three subjects (2%, 3/140) were diagnosed with autoimmune diabetes. Three patients had to terminate treatment due to endocrine toxicity. Radiological manifestations of endocrine AEs were found in 16 patients (39%, 16/41). Endocrine toxicity was associated with significantly better treatment outcomes. Median progression-free survival (8.1 months, range 5.1 – 11.1 months vs. 2.7 months, range 2.4 – 3.0 months, P < 0.001), and median overall survival (47.5 months, range 15.5 – 79.5 months vs. 23.7 months, range 15.3 – 32.1 months, P = 0.035) were longer for patients experiencing endocrine AEs. Conclusions: The higher number of endocrine AEs suggest regular laboratory monitoring aids in AE detection. Endocrine AEs in metastatic melanoma may correlate with better treatment outcomes.

Assessment of hospitalization rates for immune-related adverse events with immune checkpoint inhibitors

2020 ◽  
pp. 107815522096890
Author(s):  
Laura Nice ◽  
Ryan Bycroft ◽  
Xiaoyong Wu ◽  
Shesh N Rai ◽  
Lindsay Figg ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Median Length ◽  
Number Of Patients ◽  
Grade 3 ◽  
The Impact

Introduction Immune checkpoint inhibitors (ICIs) have become the standard of care in many cancer types. As the number of patients receiving ICIs for various cancers continues to expand, patients and practitioners should be aware of potentially severe immune-related adverse events (irAEs). Despite reports of the incidence of grade 3/4 toxicities, the proportion of patients whose symptoms were clinically severe enough to warrant hospitalization for adverse event management is unknown. Methods This single center, retrospective, observational study was designed to determine the impact of irAEs on patients and the hospital. Patients who started ICIs from May 2016 through May 2019 for melanoma or lung cancer were included. The primary outcome was incidence of hospitalization for irAE. Secondary outcomes included median length of hospitalization, time to onset of irAE, rates of hospitalization for irAE per each checkpoint inhibitor regimen, organ system affected, progression free survival, and overall survival. Results Of 384 patients with melanoma or lung cancer, 27 (7%) were hospitalized at our institution for an irAE. The most common irAE leading to hospitalization was colitis for patients with melanoma and pneumonitis for patients with lung cancer. The median length of stay across all hospitalizations was 10 days. Twenty-five patients required the use of corticosteroids while hospitalized, while eight of these patients required second line irAE treatment. For the total patient population, 34.7% experienced a grade 1/2 irAE and 13.1% experienced a grade 3/4 irAE. Conclusion Our cohort of patients experienced similar rates irAEs as reported in clinical trials and published reports.

scholarly journals Results from a Meta-analysis of Combination of PD-1/PD-L1 and CTLA-4 Inhibitors in Malignant Cancer Patients: Does PD-L1 Matter?

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuqian Feng ◽  
Huimin Jin ◽  
Kaibo Guo ◽  
Yuying Xiang ◽  
Yiting Zhang ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Objective Response ◽  
Progression Free Survival ◽  
Combination Immunotherapy

Background: Combination therapy with immune checkpoint inhibitors (ICIs) has been widely used for clinical treatment in recent years, which has a better survival benefit. However, not all patients can derive clinical benefit from combination immunotherapy. Therefore, it is necessary to explore the biomarkers of combination immunotherapy.Methods: We retrieved articles from electronic databases including PubMed, EMBASE and Cochrane. The statistical analysis was performed using RevMan software. Progression free survival (PFS), overall survival (OS) and objective response rate (ORR) were the outcome indicators. In the unselect population, we compared combination therapy with other treatments. In addition, we also conducted subgroup analysis on PFS, OS and ORR according to PD-L1 status.Results: Seven studies were included in the analysis for a total of 3,515 cases. In the unselected population, we found that combination therapy has longer PFS, OS, and better ORR than other treatments for cancer patients. The longer PFS was showed in PD-L1 ≥ 5% cases (HR = 0.64, 95% CI: 0.56–0.76; p &lt; 0.001) than PD-L1 ≥ 1% cases (HR = 0.72, 95% CI: 0.66–0.79; p &lt; 0.001), while ORR and OS have not related to the status of PD-L1.Conclusion: This study supported the efficacy of combination therapy with immune checkpoint inhibitors (ICIs), and also showed that PFS in patients with malignant tumors is positively correlated with PD-L1 expression. Due to the limited number of trials included, more high-quality clinical randomized controlled trials should be conducted to confirm the review findings.

scholarly journals High TGF-β signature predicts immunotherapy resistance in gynecologic cancer patients treated with immune checkpoint inhibition

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Ying Ni ◽  
Ahmed Soliman ◽  
Amy Joehlin-Price ◽  
Peter G. Rose ◽  
Anda Vlad ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Signaling Pathway ◽  
Immune Checkpoint ◽  
T Regulatory Cells ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Gynecologic Cancer ◽  
Progression Free Survival ◽  
Gene Markers ◽  
Free Survival

AbstractVarious immune signatures predictive of resistance to immune checkpoint inhibitors (ICI) have been described in multiple solid cancers, but still under-investigated in gynecological (GYN) cancer. For 49 GYN cancer patients included in our study, without transcriptome signature, immune-related toxicity was the only clinical predictor of ICI treatment response (p = 0.008). The objective clinical response was the only predictor of progression-free survival (ICI-PFS, p = 0.0008) and overall survival (ICI-OS, p = 0.01). Commonly used ICI marker PD-L1 expression negatively correlated with progression-free survival (ICI-PFS) (p = 0.0019). We performed transcriptome and signaling pathway enrichment analyses based on ICI treatment responses and the survival outcome, and further estimated immune cell abundance using 547 gene markers. Our data revealed that TGF-β regulated signaling pathway was noted to play an important role in immunotherapy failure. Using our 6-genes TGF-β score, we observed longer ICI-PFS associated with lower TGF-β score (8.1 vs. 2.8 months, p = 0.046), which was especially more prominent in ovarian cancer (ICI-PFS 16.6 vs. 2.65 months, p = 0.0012). Further, abundant immunosuppressive cells like T-regulatory cells, eosinophils, and M2 macrophages were associated with shorter ICI-OS and correlated positively with CD274 and CTLA4 expressions. This study provides insight on the potential role of TGF-β in mediating immunotherapy resistance and cross-talking to immunosuppressive environment in GYN cancer. The TGF-β score, if validated in a larger cohort, can identify patients who likely to fail ICI and benefit from targeting this pathway to enhance the response to ICI.

scholarly journals Pan-Cancer Analysis of FURIN as a Potential Prognostic and Immunological Biomarker

2021 ◽  
Vol 8 ◽  
Author(s):  
Bolun Zhou ◽  
Shugeng Gao
Keyword(s):  
Dna Methylation ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Strong Association ◽  
Strongly Correlated ◽  
Calcium Dependent ◽  
Free Interval ◽  
Tumor Mutational Burden ◽  
Pan Cancer

BackgroundFurin is a calcium-dependent protease that processes various precursor proteins through diverse secretory pathways. The deregulation of FURIN correlated with the prognosis of patients in numerous diseases. However, the role of FURIN in human pan-cancer is still largely unknown.MethodsMultiple bioinformatic methods were employed to comprehensively analyze the correlation of FURIN expression with prognosis, mismatch repair (MMR), microsatellite instability (MSI), tumor mutational burden (TMB), DNA methylation, tumor immune infiltration, and common immune checkpoint inhibitors (ICIs) from the public database, and aim to evaluate the potential prognostic value of FURIN across cancers.ResultsFURIN was aberrantly expressed and was strongly correlated with MMR, MSI, TMB, and DNA methylation in multiple types of cancer. Moreover, survival analysis across cancers revealed that FURIN expression was correlated with overall survival (OS) in four cancers, disease-specific survival (DSS) in five cancers, progression-free interval (PFI) in seven cancers, and disease-free interval (DFI) in two cancers. Also, FURIN expression was related to immune cell infiltration in 6 cancers and ImmuneScore/StromalScore in 10 cancers, respectively. In addition, FURIN expression also showed strong association between expression levels and immune checkpoint markers in three cancers.ConclusionFURIN can serve as a significant prognostic biomarker and correlate with tumor immunity in human pan-cancer.

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