Toxicity in the era of immune checkpoint inhibitor therapy

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Aug. 23, 2024

Immune checkpoint inhibitors (ICIs) reinvigorate anti-tumor immune responses by disrupting co-inhibitory molecules such as programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4). Although ICIs have had unprecedented success become the standard of care for many cancers, they are often accompanied off-target inflammation that can occur in any organ system. These related adverse events (irAEs) require steroid use and/or cessation ICI therapy, which both lead to cancer progression. irAEs common, detailed molecular mechanisms underlying their development still elusive. To further our understanding develop effective treatment options, there is pressing need preclinical models recapitulating clinical settings. In this review, we describe current implications ICI-induced skin toxicities, colitis, neurological endocrine pneumonitis, arthritis, myocarditis along with management.

Language: Английский

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Corticosteroids and other immunosuppressants for immune-related adverse events and checkpoint inhibitor effectiveness in melanoma

European Journal of Cancer, Journal Year: 2024, Volume and Issue: 207, P. 114172 - 114172

Published: June 15, 2024

Language: Английский

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Second-line therapies for steroid-refractory immune-related adverse events in patients treated with immune checkpoint inhibitors

European Journal of Cancer, Journal Year: 2024, Volume and Issue: 203, P. 114028 - 114028

Published: March 27, 2024

Immune checkpoint inhibitors (ICI) induce adverse events (irAEs) that do not respond to steroids, i.e. steroid-refractory (sr) irAEs, and irAEs in which steroids cannot be tapered, steroid-dependent (sd) about 10% of cases. An evidence-based analysis the effectiveness second-line immunosuppressive agents with regard irAE tumor control is lacking.

Language: Английский

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Immunologic Profiling of Immune-Related Cutaneous Adverse Events with Checkpoint Inhibitors Reveals Polarized Actionable Pathways

Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 30(13), P. 2822 - 2834

Published: April 23, 2024

Abstract Purpose: Immune-related cutaneous adverse events (ircAE) occur in ≥50% of patients treated with checkpoint inhibitors, but the underlying mechanisms for ircAEs are poorly understood. Experimental Design: Phenotyping/biomarker analyses were conducted 200 on inhibitors [139 and 61 without (control group)] to characterize their clinical presentation immunologic endotypes. Cytokines evaluated skin biopsies, tape strip extracts, plasma using real-time PCR Meso Scale Discovery multiplex cytokine assays. Results: Eight ircAE phenotypes identified: pruritus (26%), maculopapular rash (MPR; 21%), eczema (19%), lichenoid (11%), urticaria (8%), psoriasiform (6%), vitiligo (5%), bullous dermatitis (4%). All showed lymphocyte eosinophil infiltrates. Skin biopsy revealed highest increase IFNγ mRNA (P < 0.0001) 0.01) as compared ircAEs, whereas IL13 levels detected 0.0001, control). IL17A was selectively increased 0.001), 0.0001), 0.05), MPR 0.001) control. Distinct profiles confirmed plasma. Analysis determined skin/plasma IL4 pruritus, eczema, IL5 IL31 urticaria, mixed-cytokine pathways MPR. Broad inhibition via corticosteroids or type 2 cytokine–targeted resulted benefit these ircAEs. In contrast, significant upregulation 1/type 17 found psoriasiform, lichenoid, dermatitis, 1 activation vitiligo. Conclusions: endotypes suggest actionable targets precision medicine-based interventions.

Language: Английский

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Tebentafusp in Patients with Metastatic Uveal Melanoma: A Real-Life Retrospective Multicenter Study

Cancers, Journal Year: 2023, Volume and Issue: 15(13), P. 3430 - 3430

Published: June 30, 2023

Tebentafusp has recently been approved for the treatment of metastatic uveal melanoma (mUM) after proving to have survival benefits in a first-line setting.This retrospective, multicenter study analyzed outcomes and safety tebentafusp therapy 78 patients with mUM.Patients treated had median PFS 3 months (95% CI 2.7 3.3) OS 22 10.6 33.4). In contrast published Phase study, our cohort higher rate elevated LDH (65.4% vs. 35.7%) included prior systemic local ablative therapies. following ICI, there was trend longer (28 months, 95% 26.9 29.1) compared inverse sequence (24 13.0 35.0, p = 0.257). The most common treatment-related adverse events were cytokine release syndrome 71.2% skin toxicity 53.8% patients. Tumor lysis occurred one patient.Data from this real-life showed PFS/OS similar trial data. Treatment ICI followed by may result sequence.

Language: Английский

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G-CSF improving combined whole brain radiotherapy and immunotherapy prognosis of non-small cell lung cancer brain metastases

International Immunopharmacology, Journal Year: 2024, Volume and Issue: 130, P. 111705 - 111705

Published: Feb. 26, 2024

Language: Английский

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Real-World Impact of Low-Grade Toxicities to Adjuvant Pembrolizumab in Stage III Melanoma

JCO Oncology Practice, Journal Year: 2025, Volume and Issue: unknown

Published: March 28, 2025

PURPOSE Primary malignant melanoma is a curable disease, with surgical resection being the gold standard of treatment. For stage III melanoma, which poses high risk recurrence, adjuvant checkpoint inhibitors are used to reduce relapse. However, treatment carries immune-related adverse events that can significantly impact on quality life. Although grade 3 4 toxicities has been well characterized, lower-grade toxicity in this setting not as robustly discussed literature. METHODS We gathered retrospective data patients who underwent pembrolizumab between December 2019 and 2022 from two sites (Belfast City Hospital Royal Preston Hospital). This included information basis Common Terminology Criteria for Adverse Events grading (version 5), discontinuation, hospital admission, treatments, disease progression. RESULTS Data were collected 142 patients. 67 (47%) completed 1-year course pembrolizumab. Median recurrence-free survival was 36.2 months. One hundred (70%) experienced treatment-related toxicity, whom 72 (51%) had only low-grade (grade 1 2). In 15% hospitalized, 31% stopped because 33% required immunosuppression The rate early discontinuation higher among age 65 years or older compared younger than (66% v 38%, P < .001). CONCLUSION addition toxicities, there substantial burden undergoing melanoma. Clinicians should discuss its potentially significant prepare support them through these effects.

Language: Английский

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Precision Immunomodulation: Understanding and Harnessing Cytokine Pathways to Treat and Prevent Immune-Related Adverse Events (irAEs)

Best Practice & Research Clinical Haematology, Journal Year: 2025, Volume and Issue: unknown, P. 101625 - 101625

Published: April 1, 2025

Language: Английский

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Management of refractory checkpoint inhibitor-induced colitis

Expert Opinion on Drug Safety, Journal Year: 2025, Volume and Issue: unknown

Published: April 19, 2025

This review discusses the epidemiology, pathophysiology, and factors associated with refractory immune-mediated diarrhea colitis (r-IMDC), emphasizing tailored treatment strategies. The current literature on r-IMDC was reviewed using PubMed (2015-2025), focusing clinical trials, meta-analyses, case reports relevant to its management. Effectively managing is crucial for balancing toxicities antitumor response. Available second third-line management options cases must be carefully evaluated. Future perspectives include development of standardized protocols beyond second-line therapies predictive biomarkers enable personalized treatment.

Language: Английский

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Extracorporeal photopheresis vs. systemic immunosuppression for immune-related adverse events: Interim analysis of a prospective two-arm study

European Journal of Cancer, Journal Year: 2024, Volume and Issue: 212, P. 115049 - 115049

Published: Sept. 27, 2024

Language: Английский

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