Autoimmune Myocarditis, Old Dogs and New Tricks

Circulation Research, Journal Year: 2024, Volume and Issue: 134(12), P. 1767 - 1790

Published: June 6, 2024

Autoimmunity significantly contributes to the pathogenesis of myocarditis, underscored by its increased frequency in autoimmune diseases such as systemic lupus erythematosus and polymyositis. Even cases myocarditis caused viral infections, dysregulated immune responses contribute pathogenesis. However, whether triggered existing conditions or precise antigens immunologic pathways driving remain incompletely understood. The emergence associated with checkpoint inhibitor therapy, commonly used for treating cancer, has afforded an opportunity understand mechanisms autoreactive T cells specific cardiac myosin playing a pivotal role. Despite their self-antigen recognition, myosin-specific can be present healthy individuals due bypassing thymic selection stage. In recent studies, novel modalities suppressing activity pathogenic including have proven effective myocarditis. This review offers overview current understanding heart antigens, autoantibodies, underlying various forms along latest updates on clinical management prospects future research.

Language: Английский

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Risk of Serious Immune-Related Adverse Events with Various PD1 and PD-L1 Inhibitors: A Single-Institution, Real-Life, Comparative Study

Therapeutics and Clinical Risk Management, Journal Year: 2025, Volume and Issue: Volume 21, P. 273 - 282

Published: March 1, 2025

Immune checkpoint inhibitors (ICIs) are responsible for causing immune-related adverse events (irAEs). The frequency and severity of irAEs depend on various factors, but the role molecule used remains unclear. Our aim was to assess comparative safety profile different programmed cell death-1 (anti-PD1) death ligand-1 (anti-PD-L1) in a real-life setting. occurrence severe (grade ≥3) their characteristics were recorded all patients treated with anti-PD1 or anti-PD-L1, alone combination, at our center. Potential predictive factors irAEs, particularly concerning type molecule, identified by statistical analysis. Factors related overall survival also analyzed. A total 406 who received least one dose (68.5%) anti-PD-L1 (31.5%) included, among which 60% had lung cancer. ICIs 51%, 17.5%, 14.3%, 12.8%, 4.4% pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, respectively. Fifty-three (13%) experienced 3 4). While there no significant differences regard ICI categories (13.7% vs 11.7% anti-PD-L1; p = 0.5878), rates significantly between (29.6% 22.2% 13.8% 8.2% 5.8% durvalumab; < 0.0001). Multivariate analyses showed that treatments nivolumab low polymorphonuclear neutrophil level risk irAEs. early lower reported cancer progression greater toxic molecules (atezolizumab). This study highlights toxicity targeting PD1/PD-L1 axis use, as well identification possible biomarkers.

Language: Английский

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MIF and CD74 as Emerging Biomarkers for Immune Checkpoint Blockade Therapy

Cancers, Journal Year: 2024, Volume and Issue: 16(9), P. 1773 - 1773

Published: May 4, 2024

Immune checkpoint blockade (ICB) therapy is used to treat a wide range of cancers; however, some patients are at risk developing treatment resistance and/or immune-related adverse events (irAEs). Thus, there great need for the identification reliable predictive biomarkers response and toxicity. The cytokine MIF (macrophage migration inhibitory factor) its cognate receptor CD74 intimately connected with cancer progression have previously been proposed as prognostic patient outcome in various cancers, including solid tumors such malignant melanoma. Here, we assess their potential ICB irAE development. We provide brief overview function roles context autoimmune disease. also review evidence showing that may be use highlight careful consideration required when assessing serum levels biomarker due reported circadian expression human plasma. Finally, suggest future directions establishment development guide further research this field.

Language: Английский

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Fine-tuning tumor- and allo-immunity: advances in the use of immune checkpoint inhibitors in kidney transplant recipients

Clinical Kidney Journal, Journal Year: 2024, Volume and Issue: 17(4)

Published: March 8, 2024

Cancer is a common complication after kidney transplantation. Kidney transplant recipients (KTR) have 2- to 4-fold higher risk of developing cancer compared the general population and post-transplant malignancy third most cause death in KTR. Moreover, it well known that certain types are overrepresented transplantation, especially non-melanoma skin cancer. Immune checkpoint inhibitors (ICI) revolutionized treatment cancer, with remarkable survival benefit subgroup patients. ICI monoclonal antibodies block binding specific co-inhibitory signaling molecules. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), programmed cell protein 1 (PD-1), its ligand (PD-L1) main targets ICI. Solid organ (SOTR) been excluded from clinical trials owing concerns about tumor response, allo-immunity, rejection. Indeed, graft rejection has estimated as high 48% represents an emerging problem. The underlying mechanisms context poorly understood. search for restricted antitumoral responses without paramount importance. This review summarizes current knowledge use KTR, potential involved during treatment, biomarkers rejection, how deal practice.

Language: Английский

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Gender Difference in sidE eFfects of ImmuNotherapy: a possible clue to optimize cancEr tReatment (G-DEFINER): study protocol of an observational prospective multicenter study

Acta Oncologica, Journal Year: 2024, Volume and Issue: 63, P. 213 - 219

Published: April 21, 2024

Immune checkpoint inhibitors (ICIs) have significantly improved outcomes in various cancers. ICI treatment is associated with the incidence of immune-related adverse events (irAEs) which can affect any organ. Data on irAEs occurrence relation to sex- differentiation and their association gender-specific factors are limited.

Language: Английский

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Early Changes in LIPI Score Predict Immune-Related Adverse Events: A Propensity Score Matched Analysis in Advanced Non-Small Cell Lung Cancer Patients on Immune Checkpoint Blockade

Cancers, Journal Year: 2024, Volume and Issue: 16(2), P. 453 - 453

Published: Jan. 20, 2024

In advanced cancer patients undergoing immune checkpoint blockade, the burden of immune-related adverse events (irAEs) is high. The need for reliable biomarkers irAEs remains unfulfilled in this expanding therapeutic field. lung prognostic index (LIPI) a noninvasive measure systemic inflammation that has consistently shown correlation with survival various types when assessed at baseline. This study sought to determine whether early changes LIPI score could discriminate risk and different outcomes non-small cell (NSCLC) receiving PD-(L)1 blockade-based therapies. We included consecutive diagnosed metastatic NSCLC who received pembrolizumab, nivolumab, or atezolizumab as second-line therapy following platinum-based chemotherapy, first-line pembrolizumab either alone combination chemotherapy. relied on combined values derived neutrophil/lymphocyte ratio (dNLR) lactate dehydrogenase. Their assessment baseline after two cycles treatment allowed us categorize population into three subgroups good (LIPI-0), intermediate (LIPI-1), poor (LIPI-2) prognosis. Between April 2016 May 2023, we enrolled total 345 eligible patients, 165 (47.8%) 180 (52.2%) whom were treated first- our facility, respectively. After applying propensity matching, considered 83 relevant each cohort homogeneous distribution all characteristics across subgroups. There was noticeable change categories due significant decrease dNLR during treatment. Although no shifted worse prognosis category, 20 (24.1%) transitioned from LIPI-1 LIPI-0, 7 (8.4%) moved LIPI-2 (p < 0.001). Throughout median observation period 7.3 (IQR 3.9-15.1) months, 158 (63.5%) documented, 121 (48.6%) 39 (15.7%) experiencing mild moderate severe events, Multivariate logistic regression analysis showed classification while independent predictors irAEs. LIPI-0 group found have significantly increased odds Following follow-up 21.1 (95% CI 17.9-25.8) multivariable Cox model confirmed categorization any given time point covariate influence overall survival, irrespective line. These findings suggest reassessing help pinpoint particularly prone toxicities. Those maintain move category would be more likely develop continuous provides insights useful predicting benefit inhibitors.

Language: Английский

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Immunotherapy for Thymomas and Thymic Carcinomas: Current Status and Future Directions

Cancers, Journal Year: 2024, Volume and Issue: 16(7), P. 1369 - 1369

Published: March 30, 2024

Thymic epithelial tumors are a histologically diverse group of cancers arising from the compartment thymus. These characterized by low tumor mutation burden, lack actionable genomic changes, and, especially with thymomas, defects in immune tolerance. Surgery is mainstay management resectable disease, whereas advanced, unresectable treated platinum-based chemotherapy. Disease recurrence can occur months to years after frontline treatment. Although several options available for conventional treatment recurrent thymic tumors, response rates generally low, and treatment-related toxicity affect quality life. A subset patients benefit biologic therapies, but there remains an unmet need development new treatments. Immune checkpoint inhibitors safe, clinically active, have contributed improvement survival wide variety cancers. However, application these revolutionary treatments limited their use carcinoma because risk toxicity. In this paper, we review current uses immunotherapy highlight potential strategies improve safety broaden

Language: Английский

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From tumor to tolerance: A comprehensive review of immune checkpoint inhibitors and immune-related adverse events

Asia Pacific Allergy, Journal Year: 2024, Volume and Issue: 14(3), P. 124 - 138

Published: May 29, 2024

The advent of immune checkpoint inhibitors (ICIs) has revolutionized the treatment landscape for various malignancies by harnessing body’s system to target cancer cells. However, their widespread use unveiled a spectrum immune-related adverse events, highlighting critical balance between antitumor immunity and autoimmunity. This review article delves into molecular immunology ICIs, mapping journey from therapeutic action unintended induction events. We provide comprehensive overview all available including cytotoxic T-lymphocyte-associated protein 4, programmed cell death 1, death-ligand 1 inhibitors, emerging targets, discussing mechanisms action, clinical applications, underpinnings associated Special attention is given activation autoreactive T cells, B cytokine release, inflammatory cascade, which together contribute development Through lens, we explore manifestations events across organ systems, offering insights diagnosis, management, strategies mitigate these effects. underscores importance understanding delicate interplay enhancing responses minimizing aiming guide future research next-generation ICIs with improved drug safety profiles.

Language: Английский

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Stringent monitoring can decrease mortality of immune checkpoint inhibitor induced cardiotoxicity

Frontiers in Cardiovascular Medicine, Journal Year: 2024, Volume and Issue: 11

Published: June 10, 2024

Background Immune checkpoint inhibitor (ICI)-induced myocarditis is a rare immune-related adverse event (irAE) with fatality rate of 40%–46%. However, irMyocarditis can be asymptomatic. Thus, improved monitoring, detection and therapy are needed. This study aims to generate knowledge on pathogenesis assess outcomes in cancer centers intensified patient management. Methods Patients cardiac irAEs from the SERIO registry ( www.serio-registry.org ) were analyzed for demographics, ICI-related information (type ICI, line, combination other drugs, onset irAE, tumor response), examination results, irAE treatment outcome, as well oncological endpoints. Cardiac biopsies cases n = 12) by Nanostring compared healthy heart muscle 5) longitudinal blood sampling was performed immunophenotyping irMyocarditis-patients 4 baseline 8 during irAE) comparison patients without toxicity under ICI-therapy 7 ICI-therapy) using flow cytometry. Results A total 51 53 induced different ICIs (anti-PD1, anti-PD-L1, anti-CTLA4) included 12 3 countries. Altogether, 83.0% graded severe or life-threatening, 11.3% fatal (6/53). established consequent troponin work-up upon rise corticosteroids –if required–second-line mortality much lower than previously reported. The median time 36 days (range 4–1,074 days) after ICI initiation, whereas cardiotoxicities, e.g. asystolia myocardiopathy, occurred later. cytokine-mediated signaling pathway differentially regulated myocardial based enrichment Gene Ontology analysis. Additionally, peripheral mononuclear cell (PBMC) samples indicated ICI-driven enhanced CD4+ Treg cells reduced T cells. Immunophenotypes, particularly effector memory differed those ICI-treated side effects. LAG3 expression PD-L1 dendritic could serve predictive indicators development irMyocarditis. Conclusion Interestingly, our cohort shows very low irMyocarditis-patients. Our data indicate so far unknown local systemic immunological patterns cardiotoxicity.

Language: Английский

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Urine proteomics defines an immune checkpoint-associated nephritis signature

Journal for ImmunoTherapy of Cancer, Journal Year: 2025, Volume and Issue: 13(1), P. e010680 - e010680

Published: Jan. 1, 2025

Immune checkpoint inhibitor (ICI) therapy is a cornerstone treatment for many cancers, but it can induce severe immunotoxicity, including acute interstitial nephritis (AIN). Currently, kidney biopsy required to differentiate ICI-AIN from other causes of injury (AKI). However, this invasive approach lead morbidity, delayed glucocorticoid patients with AIN, and unnecessarily prolonged suspension ICI in non-AIN patients. Delayed or incorrect diagnosis particularly detrimental, as over 50% are at risk permanent renal damage. Thus, there an urgent need non-invasive biomarkers that rapidly accurately distinguish AKI. The urine plasma proteome contain actively secreted proteins provide real-time insights into dynamic physiological processes. identification effective disease using established technologies such proximity ligation assays (PLA) bead-based immunoassays challenging due their limited sensitivity loss precision multiplex analysis. To address this, we employed cutting-edge NUcleic acid Linked Immuno-Sandwich Assay (NULISA) technology measure protein expression samples AKI undergoing therapy. NULISA offers 10,000-fold greater than PLA, enabling quantification 200 inflammatory unprecedented precision. Our analysis revealed was more sensitive specific distinguishing cases. Pathway analyses highlighted the involvement JAK-STAT tumor necrosis factor (TNF) signaling pathogenesis. We identified several novel biomarkers, IL-5, Fas, TNFSF4, CD274, IL-20, TNFSF15, TSLP, TREM1 CCL1 while confirming previously reported markers CXCL9 TNF-α. Using statistical machine learning methods, constructed biomarker signature—IL-5+Fas—that achieved area under curve 0.94 diagnosing ICI-AIN. By leveraging high-sensitivity proteomics, developed strategy This will enable earlier intervention mitigate preservation antitumor efficacy patients, safe rechallenge treated

Language: Английский

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