Best practices in the management of thyroid dysfunction induced by immune checkpoint inhibitors

European Thyroid Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Immune checkpoint inhibitors (ICIs) frequently cause immune-related adverse events (irAEs), with thyroid irAEs being the most common endocrine-related irAEs. The incidence of overt ranged 8.9–22.2% in real-world settings, typically triggered by antibodies against PD-1 and PD-L1 rarely anti-CTLA-4 alone. representative clinical course involves biphasic changes function, transient thyrotoxicosis subsequent persistent hypothyroidism. identified risk factors for include presence autoantibodies, uptake 18F-FDG-PET, prior use tyrosine kinase (TKIs), high BMI, TSH levels. There is evidence that are associated good prognosis, at least non-small cell lung cancer. Although features have been well clarified, management strategies require further refinement. Routine monitoring function every 4 to 6 weeks during ICI therapy recommended early detection While generally requires observation only, hypothyroidism should be promptly treated levothyroxine replacement. Continuation feasible patients irAEs, provided their overall health remains stable. However, these were largely based on experience monotherapy. As combination therapies developed as first-line treatments, antitumor agents may modify For example, cytotoxic can delay onset while TKIs often linked early-onset hypothyroidism, independent use. Given increasing diversity complexity cancer immunotherapy, it essential vigilantly screen

Language: Английский

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Characterization of immune checkpoint inhibitor‐induced cardiotoxicity reveals interleukin‐17A as a driver of cardiac dysfunction after anti‐PD‐1 treatment

British Journal of Pharmacology, Journal Year: 2022, Volume and Issue: 180(6), P. 740 - 761

Published: Nov. 10, 2022

Background and Purpose Immune checkpoint inhibitors (ICI), such as anti‐PD‐1 monoclonal antibodies, have revolutionized cancer therapy by enhancing the cytotoxic effects of T‐cells against tumours. However, enhanced T‐cell activity also may cause myocarditis cardiotoxicity. Our understanding mechanisms ICI‐induced cardiotoxicity is limited. Here, we aimed to investigate effect PD‐1 inhibition on cardiac function explore molecular Experimental Approach C57BL6/J BALB/c mice were treated with isotype control or antibody. Echocardiography was used assess function. Cardiac transcriptomic changes investigated bulk RNA sequencing. Inflammatory assessed qRT‐PCR immunohistochemistry in heart, thymus, spleen animals. In follow‐up experiments, anti‐CD4 anti‐IL‐17A antibodies along blockade C57BL/6J mice. Key Results Anti‐PD‐1 treatment led dysfunction left ventricular dilation mice, increased nitrosative stress. Only mild inflammation observed heart. resulted thymic inflammatory signalling, where Il17a most prominently. not evident, activation more balanced. Inhibition IL‐17A prevented anti‐PD‐1‐induced Comparing myocardial differentially regulated genes ( Dmd , Ass1 Chrm2 Nfkbia Stat3 Gsk3b Cxcl9 Fxyd2 Ldb3 ) revealed, related structure, inflammation. Conclusions induces IL‐17 signalling thymus. Pharmacological prevents dysfunction.

Language: Английский

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Checkpoint inhibitor immune-related adverse events: A focused review on autoantibodies and B cells as biomarkers, advancements and future possibilities

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 13

Published: Jan. 11, 2023

The use of immune checkpoint inhibitors (ICIs) has evolved rapidly with unprecedented treatment benefits being obtained for cancer patients, including improved patient survival. However, over half the patients experience related adverse events (irAEs) or toxicities, which can be fatal, affect quality life and potentially cause interruption cessation. Complications from these toxicities also long term irreversible organ damage other chronic health conditions. Toxicities occur in various systems, common observations skin, rheumatologic, gastrointestinal, hepatic, endocrine system lungs. These are not only challenging to manage but difficult detect during early stages treatment. Currently, no biomarker exists predict likely develop ICI therapy efforts identify robust biomarkers ongoing. B cells antibodies against autologous antigens (autoantibodies) have shown promise emerging as markers development irAEs patients. In this review, we discuss interplay between ICIs insights into underlying mechanisms irAEs, involvement humoral response, particularly by autoantibodies irAE development. We provide an appraisal progress, key empirical results advances cell autoantibody research predicting irAEs. conclude review outlining challenges steps required their potential clinical application future.

Language: Английский

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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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Immune-related events in individuals with solid tumors on immunotherapy associate with Th17 and Th2 signatures

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(20)

Published: Aug. 29, 2024

BACKGROUNDImmune-related adverse events (irAEs) and their associated morbidity/mortality are a key concern for patients receiving immune checkpoint inhibitors (ICIs). Prospective evaluation of the drivers irAEs in diverse pan-tumor cohort is needed to identify at greatest risk develop rational treatment interception strategies.METHODSIn an observational study, we prospectively collected blood samples performed regular clinical evaluations ICI therapy as standard care solid tumors. We in-parallel analysis cytokines by Luminex immunoassay circulating cells cytometry time-of-flight (CyTOF) baseline on investigate mechanisms irAEs.RESULTSWe enrolled 111 patients, whom 40.5% developed symptomatic irAE (grade ≥ 2). Development grade 2 was positively with use combination history autoimmune disorder. Early changes T helper 17 (Th17) (IL-6, IL-17f), type (IL-5, IL-13, IL-25), 1 (TNF-α) cytokine signatures congruent on-treatment expansions Th17 Th2 effector memory (Th2EM) cell populations peripheral were development ≥2 irAEs. IL-6 levels also inferior cancer-specific survival overall survival.CONCLUSIONSIn diverse, prospective cohort, skewing during early clinically relevant but not antitumor responses, providing possible targets monitoring therapeutic interventions.FUNDINGJohns Hopkins Bloomberg-Kimmel Institute Cancer Immunotherapy, NCI SPORE Gastrointestinal Cancers (P50 CA062924), grant (R50CA243627 LD), NIH Center Core Grant (P30 CA006973), Swim Across America (to MY), NIAMS (K23AR075872 LC), imCORE-Genentech 137515 Johns Medicine behalf MY).

Language: Английский

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Immune‐Mediated Liver Injury From Checkpoint Inhibitor: An Evolving Frontier With Emerging Challenges

Liver International, Journal Year: 2025, Volume and Issue: 45(2)

Published: Jan. 27, 2025

ABSTRACT Over the past decade, immune checkpoint inhibitors (ICIs) have transformed treatment of cancer, though they come with risk immune‐related adverse (irAEs) events such as hepatotoxicity or Immune‐mediated Liver Injury from Checkpoint Inhibitors (ILICI). ILICI is a serious irAE that, when severe, requires cessation ICI and initiation immunosuppression. Cytotoxic T Lymphocytes (CTLs) play central role in ILICI; however, are just part picture immunotherapy broadly impacts all aspects microenvironment can directly indirectly activate innate adaptive cells. Clinically, our understanding this entity grows, we encounter new challenges. The presentation heterogeneous respect to latency, pattern injury (hepatitis vs. cholangitis) severity. This review focuses on knowledge regarding factors, including refractory steroids. An emerging topic, possibility rechallenge while accepting some risk, patients who experience but require immunotherapy, also discussed. provides an update current knowns unknowns highlights several gaps where studies needed.

Language: Английский

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Clonally expanded, thyrotoxic effector CD8 ⁺ T cells driven by IL-21 contribute to checkpoint inhibitor thyroiditis

Science Translational Medicine, Journal Year: 2023, Volume and Issue: 15(696)

Published: May 17, 2023

Autoimmune toxicity occurs in up to 60% of patients treated with immune checkpoint inhibitor (ICI) therapy for cancer and represents an increasing clinical challenge expanding the use these treatments. To date, human immunopathogenic studies immune-related adverse events (IRAEs) have relied on sampling circulating peripheral blood cells rather than affected tissues. Here, we directly obtained thyroid specimens from individuals ICI-thyroiditis, one most common IRAEs, compared infiltrates those spontaneous autoimmune Hashimoto’s thyroiditis (HT) or no disease. Single-cell RNA sequencing revealed a dominant, clonally expanded population thyroid-infiltrating cytotoxic CXCR6 + CD8 T (effector cells) present ICI-thyroiditis but not HT healthy controls. Furthermore, identified crucial role interleukin-21 (IL-21), cytokine secreted by intrathyroidal follicular (T FH ) helper PH cells, as driver thyrotoxic effector cells. In presence IL-21, acquired activated phenotype up-regulation molecules interferon-γ (IFN-γ) granzyme B, increased expression chemokine receptor CXCR6, capacity. We validated findings vivo using mouse model IRAEs further demonstrated that genetic deletion IL-21 signaling protected ICI-treated mice infiltration. Together, reveal mechanisms candidate therapeutic targets who develop IRAEs.

Language: Английский

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Innate and adaptive immune cell interaction drives inflammasome activation and hepatocyte apoptosis in murine liver injury from immune checkpoint inhibitors

Cell Death and Disease, Journal Year: 2024, Volume and Issue: 15(2)

Published: Feb. 14, 2024

Immune checkpoints (CTLA4 & PD-1) are inhibitory pathways that block aberrant immune activity and maintain self-tolerance. Tumors co-opt these to avoid destruction. checkpoint inhibitors (ICIs) activate cells restore their tumoricidal potential, making them highly efficacious cancer therapies. However, immunotolerant organs such as the liver depend on tolerogenic mechanisms, disruption with ICI use can trigger unintended side effect of hepatotoxicity termed immune-mediated injury from ICIs (ILICI). Learning how uncouple ILICI anti-tumor is paramount clinical importance. We developed a murine model recapitulate human using CTLA4+/- mice treated either combined anti-CTLA4 + anti-PDL1 or IgG1 IgG2. tested two forms antisense oligonucleotides knockdown caspase-3 in total (parenchymal non-parenchymal cells) hepatocyte-specific manner. also employed imaging mass cytometry (IMC), powerful multiplex modality for immunophenotyping cell interaction analysis our model. ICI-treated had significant evidence injury. detected cleaved (cC3), indicating apoptosis was occurring, well Nod-like receptor protein 3 (NLRP3) inflammasome activation, but no necroptosis. Total worsened injury, induced further Gasdermin-D-mediated pyroptosis. Hepatocyte-specific reduced NLRP3 activation. IMC-generated single-cell data 77,692 used identify 22 unique phenotypic clusters. Spatial revealed cC3+ hepatocytes significantly closer interactions macrophages, Kupffer cells, NLRP3hi myeloid than other types. observed zones three-way between hepatocytes, CD8 T-cells, macrophages. Our work first hepatocyte activation drivers ILICI. Furthermore, we report interplay adaptive innate critical

Language: Английский

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The immune system in Hashimoto's thyroiditis: Updating the current state of knowledge on potential therapies and animal model construction

Autoimmunity Reviews, Journal Year: 2025, Volume and Issue: 24(6), P. 103783 - 103783

Published: March 2, 2025

Language: Английский

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Thyroid Dysfunction after Atezolizumab and Bevacizumab Is Associated with Favorable Outcomes in Hepatocellular Carcinoma

Liver Cancer, Journal Year: 2023, Volume and Issue: 13(1), P. 89 - 98

Published: May 25, 2023

<b><i>Introduction:</i></b> Atezolizumab and bevacizumab (Ate/Bev) combination has become the new first-line systemic therapy for unresectable hepatocellular carcinoma (HCC). Although several studies reported thyroid dysfunction after treatment with immune checkpoint inhibitors, clinical immunological significance of in patients treated Ate/Bev not been comprehensively addressed. We aimed to evaluate implications HCC Ate/Bev. <b><i>Methods:</i></b> enrolled 208 from three Korean cancer centers. Thyroid adverse events (AEs) were reviewed, cytokines T cells blood samples analyzed at baseline. For external validation, we outcomes according AEs IMbrave150 study. <b><i>Results:</i></b> Forty-one (19.7%) out experienced (hypothyroidism [17.3%] thyrotoxicosis [5.8%]) treatment. Median time onset hypothyroidism was 3.5 1.3 months, respectively. Patients demonstrated significantly better progression-free survival, overall objective response rate than those without AEs. These findings still consistent even adjusting confounding factors. Furthermore, favorable survival also validated a cohort patients. While showed lower level baseline IL-6, did show significant differences circulating cytokine levels CD8⁺ T-cell fractions. <b><i>Conclusions:</i></b> A fraction dysfunction, development associated outcomes.

Language: Английский

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