Dose dependence of treatment-related adverse events for immune checkpoint inhibitor therapies: a model-based meta-analysis.
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ABSTRACT:
SUBMITTER: Shulgin B
PROVIDER: S-EPMC7466858 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Immune checkpoint inhibitors (ICIs), which target the programmed cell death receptor-1 and cytotoxic T lymphocyte-associated antigen-4 signaling pathways, represent remarkable breakthroughs in cancer treatment and have improved survival among patients with a variety of malignancies. However, the wide use of ICIs is associated with a spectrum of immune-related adverse events (irAEs) that can affect any organ system, and may sometimes be life threatening. Rheumatic irAEs are not an infrequent type of irAE. In this systematic review, we consider the clinical characteristics of rheumatic irAEs, including patients with pre-existing rheumatic diseases, and focus on the management of rheumatic irAEs.
| S-EPMC6938753 | biostudies-literature
Project description: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.
| S-EPMC8235766 | biostudies-literature
Project description:This study aimed to describe the landscape of Immune checkpoint inhibitors (ICIs)-related adverse events (AEs) in a predominantly Chinese cohort. We searched electronic datasets including PubMed, Web of Science and Embase to identify and recruit relevant trials up to September 2, 2019. Clinical trials focusing on ICIs in Chinese patients or a predominantly Chinese population were included. Incidences of treatment-related AEs (TRAEs) and immune-related AEs (irAEs) were pooled and compared. In total, we recruited 13 trials consisting of 1063 patients, with 922 (86.7%) receiving ICI monotherapy and 141 (13.3%) receiving combination of ICI with chemotherapy or anti-angiogenesis. The pooled incidence of any grade TRAEs, grade 1-2, grade 3-5 TRAEs, any grade irAEs, grade 1-2 irAEs and grade 3-5 irAEs in all 1063 patients were 84.1%, 63.3%, 20.9%, 43.3%, 40.0% and 3.0%, respectively. Moreover, 4.3% (44/1018) of patients experienced treatment discontinuation and only 8 (0.8%) patients experienced treatment-related death. Compared to ICI monotherapy, combination significantly increased grade 3-5 TRAEs (46.1% vs. 17.0%, P < 0.001) and grade 3-5 irAEs (7.1% vs. 2.0%, P = 0.015). By comparing the toxicity profiles between different ICIs, we found some drug-specific AEs such as reactive capillary haemangiomas for camrelizumab (58.6%), hyperglycemia for toripalimab (55.6%) and pyrexia for tislelizumab (54.3%). Additionally, nivolumab has the lowest incidence of any grade (64.1%) and grade 3-5 (11.8%) TRAEs. ICI-related AEs were generally mild and tolerable for a predominantly Chinese cohort. However, we should pay attention to the combination of ICI with chemotherapy as it could increase grade 3-5 TRAEs and irAEs.
| S-EPMC7511303 | biostudies-literature
Project description:ImportanceLimited information is available on the safety of a rechallenge with an immune checkpoint inhibitor (ICI) after an immune-related adverse event (irAE).ObjectiveTo identify the recurrence rate of the same irAE that prompted discontinuation of ICI therapy after an ICI rechallenge in patients with cancer and to identify the clinical features associated with such recurrences.Design, setting, and participantsThis observational, cross-sectional, pharmacovigilance cohort study examined individual case safety reports from the World Health Organization database VigiBase, which contains case reports from more than 130 countries. Case reports were extracted from database inception (1967) to September 1, 2019. All consecutive ICI cases with at least 1 associated irAE were included.Main outcomes and measuresThe primary outcome was the rate of recurrence of the initial irAE after an ICI rechallenge. Secondary outcomes included the factors associated with the recurrence after a rechallenge among informative rechallenges, the recurrence rate according to the ICI regimen (anti-programmed cell death 1 or anti-programmed cell death ligand 1 monotherapy, anti-cytotoxic T-lymphocyte antigen-4 monotherapy, or combination therapy), and the rate of occurrence of a different irAE after a rechallenge.ResultsA total of 24 079 irAE cases associated with at least 1 ICI were identified. Among the irAEs, 452 of 6123 irAEs associated with ICI rechallenges (7.4%) were informative rechallenges. One hundred thirty recurrences (28.8%; 95% CI, 24.8-33.1) of the initial irAE were observed. In a rechallenge, colitis (reporting odds ratio [OR], 1.77; 95% CI, 1.14-2.75; P = .01), hepatitis (reporting OR, 3.38; 95% CI, 1.31-8.74; P = .01), and pneumonitis (reporting OR, 2.26; 95% CI, 1.18-4.32; P = .01) were associated with a higher recurrence rate, whereas adrenal events were associated with a lower recurrence rate (reporting OR, 0.33; 95% CI, 0.13-0.86; P = .03) compared with other irAEs.Conclusions and relevanceThis cohort study found a 28.8% recurrence rate of the same irAE associated with the discontinuation of ICI therapy after a rechallenge with the same ICI. Resuming ICI therapy could be considered for select patients, with appropriate monitoring and use of standard treatment algorithms to identify and treat toxic effects.
| S-EPMC7163782 | biostudies-literature
Project description: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.
| S-EPMC7905347 | biostudies-literature
Project description:ObjectivesThe purpose of this study was to evaluate whether immune checkpoint inhibitors (ICIs) are associated with an increased risk of major adverse cardiovascular events (MACE) compared with non-ICI therapies in patients with lung cancer.BackgroundICIs activate the host immune system to target cancer cells. Though uncommon, cardiovascular immune-related adverse events can be life-threatening.MethodsA retrospective single-institution cohort study of 252 patients with pathologically confirmed lung cancer who received ICI or non-ICI therapy was analyzed. The primary endpoint was MACE, defined as a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure.ResultsDuring a median follow-up of 6 months, MACE occurred in 13.3% of ICI-treated patients, with a median time to event of 51 days, compared with 10.3% and 64 days in non-ICI patients. ICIs were not associated with MACE (hazard ratio [HR]: 1.18; 95% confidence interval [CI]: 0.57 to 2.43; p = 0.66) in a univariable Fine-Gray regression analysis incorporating noncardiovascular death as a competing risk. Multivariable regression analyses determined that patients treated with ICIs with elevated serum troponin I >0.01 ng/ml (HR: 7.27; 95% CI: 2.72 to 19.43; p < 0.001) and B-type natriuretic peptide (BNP) >100 pg/ml (HR: 2.65; 95% CI: 1.01 to 6.92; p = 0.047) had an increased risk of MACE. Patients pre-treated or receiving combined immunotherapy with ICIs and vascular endothelial growth factor inhibitors (VEGFIs) or tyrosine kinase inhibitors (TKIs) had an increased risk of MACE (HR: 2.15; 95% CI: 1.05 to 4.37; p = 0.04).ConclusionsICIs were not independently associated with an increased risk of MACE in patients with lung cancer, although power is an important limitation in these analyses. ICI-associated cardiotoxicity was associated with elevations in serum troponin and BNP, and combined immunotherapy with VEGFIs or TKIs. Future studies are needed to further define the role of cardiac biomarkers as a monitoring strategy with ICI therapy.
| S-EPMC8352266 | biostudies-literature
Project description:IntroductionImmune checkpoint inhibitors (ICIs) are effective in treating several cancers; however, acute kidney injury (AKI) can occur as part as an immune-related adverse event (iRAE). Biomarkers at the time of AKI diagnosis may help determine whether they are ICI- related and guide therapeutic strategies.MethodsIn this retrospective study, we reviewed patients with cancer treated with ICI therapy between 2014 and 2020 who developed AKI (defined as a ≥1.5-fold increase in serum creatinine [SCr]) that was attributed to ICI (ICI-AKI) and compared them with an adjudicated non-ICI-AKI group. Clinical and laboratory features, including SCr, serum C-reactive protein (CRP), and urine retinol binding protein/urine creatinine (uRBP/Cr) levels at AKI event were evaluated.ResultsThere were 37 patients with ICI-AKI and 13 non-ICI-AKI referents in the cohort for analysis. At time of AKI, SCr, CRP, and uRBP/Cr were significantly higher in the ICI-AKI compared with the non-ICI-AKI patients (median [interquartile range (IQR)] SCr 2.0 [1.7, 2.9] vs. 1.5 [1.3, 1.6] mg/dl, serum CRP 54.0 [33.7, 90.0] vs. 3.5 [3.0, 7.9] mg/l, and uRBP/Cr 1927 [1174, 46,522] vs. 233 [127, 989] μg/g Cr, respectively, P < 0.05 for all). Compared with the referent group, time from ICI initiation to AKI was shorter in the ICI-AKI patients. Among the ICI-AKI group, complete renal recovery occurred in 39% of patients by 3 months; rechallenge occurred in 16 (43%) of patients, of whom 3 (19%) had recurrence of AKI.ConclusionOur findings suggest that serum CRP and uRBP/Cr may help to differentiate AKI due to ICI from other causes.
| S-EPMC8071627 | biostudies-literature
Project description:BackgroundNeurological immune-related adverse events (irAE-n) are severe and potentially fatal toxicities of immune checkpoint inhibitors (ICI). To date, the clinical significance of neuronal autoantibodies in irAE-n is poorly understood. Here, we characterize neuronal autoantibody profiles in patients with irAE-n and compare these with ICI-treated cancer patients without irAE-n.MethodsIn this cohort study (DRKS00012668), we consecutively collected clinical data and serum samples of 29 cancer patients with irAE-n (n = 2 pre-ICI, n = 29 post-ICI) and 44 cancer control patients without irAE-n (n = 44 pre- and post-ICI). Using indirect immunofluorescence and immunoblot assays, serum samples were tested for a large panel of neuromuscular and brain-reactive autoantibodies.ResultsIrAE-n patients and controls received ICI treatment targeting programmed death protein (PD-)1 (61% and 62%), programmed death ligand (PD-L)1 (18% and 33%) or PD-1 and cytotoxic T-lymphocyte-associated protein (CTLA-)4 (21% and 5%). Most common malignancies were melanoma (both 55%) and lung cancer (11% and 14%). IrAE-n affected the peripheral nervous system (59%), the central nervous system (21%), or both (21%). Prevalence of neuromuscular autoantibodies was 63% in irAE-n patients, which was higher compared to ICI-treated cancer patients without irAE-n (7%, p <.0001). Brain-reactive autoantibodies targeting surface (anti-GABABR, -NMDAR, -myelin), intracellular (anti-GFAP, -Zic4, -septin complex), or unknown antigens were detected in 13 irAE-n patients (45%). In contrast, only 9 of 44 controls (20%) presented brain-reactive autoantibodies before ICI administration. However, seven controls developed de novo brain-reactive autoantibodies after ICI initiation, therefore, prevalence of brain-reactive autoantibodies was comparable between ICI-treated patients with and without irAE-n (p = .36). While there was no clear association between specific brain-reactive autoantibodies and clinical presentation, presence of at least one of six selected neuromuscular autoantibodies (anti-titin, anti-skeletal muscle, anti-heart muscle, anti-LRP4, anti-RyR, anti-AchR) had a sensitivity of 80% (95% CI 0.52-0.96) and a specificity of 88% (95% CI 0.76-0.95) for the diagnosis of myositis, myocarditis, or myasthenia gravis.ConclusionNeuromuscular autoantibodies may serve as a feasible marker to diagnose and potentially predict life-threatening ICI-induced neuromuscular disease. However, brain-reactive autoantibodies are common in both ICI-treated patients with and without irAE-n, hence, their pathogenic significance remains unclear.
| S-EPMC9945255 | biostudies-literature
Project description:More than 2000 immuno-oncology agents are being tested or are in use as a result of the cancer immunotherapy revolution. Manipulation of co-inhibitory receptors has achieved tumor eradication in a minority of patients, but widespread immune-related adverse events (irAEs) compromised tolerance to healthy self-tissues in the majority. We have proposed that a major mechanism of irAEs is similar to a graft-versus-malignancy effect of graft-versus-host disease. To verify our hypothesis, we retrieved post-marketing data of adverse events from the U.S. Food and Drug Administration Adverse Event Reporting System. A significant positive correlation was revealed in 7677 patients between the reporting odds ratio of irAEs during immune checkpoint inhibitor therapy and the corresponding tumor mutational burden across 19 cancer types. These results can be interpreted to mean that the ICI drugs unleashed T cells against "altered-self," self, and tumors resulting in better overall survival.
| S-EPMC7183506 | biostudies-literature
Project description:Immune checkpoint inhibitors represent a major breakthrough in cancer therapy. Immune-related adverse events (irAEs) may occur during treatment due to their unique mechanism of action. Management of irAEs is based on clinical experience because it is not easy to conduct prospective trials to evaluate the best treatment strategy. Using a combination of search terms in the PubMed and Embase databases, we reviewed all cases in the English language citing toxicities associated with either pembrolizumab, nivolumab, ipilimumab, atezolizumab, tremelimumab, durvalumab, avelumab or any combination of these agents published before 20 May 2019. A total of 128 reports with 239 cases were included in the study. Here, we summarize the spectrum of toxicities, safety in special patients, rechallenging after irAEs and agents used for treatment of irAEs in those reports.
| S-EPMC7049490 | biostudies-literature