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Bracamonte-Baran W, Kim ST. The Current and Future of Biomarkers of Immune Related Adverse Events. Immunol Allergy Clin North Am 2025; 45:223-249. [PMID: 40287170 DOI: 10.1016/j.iac.2025.01.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/29/2025]
Abstract
With their groundbreaking clinical responses, immune checkpoint inhibitors (ICIs) have ushered in a new chapter in cancer therapeutics. However, they are often associated with life-threatening or organ-threatening autoimmune/autoinflammatory phenomena, collectively termed immune-related adverse events (irAEs). In this review, we will first describe the mechanisms of action of ICIs as well as irAEs. Next, we will review biomarkers for predicting the development of irAEs or stratifying risks.
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Affiliation(s)
- William Bracamonte-Baran
- Department of Rheumatology, Allergy & Immunology, Yale University, 300 Cedar Street, TAC S541, New Haven, CT 06520, USA
| | - Sang T Kim
- Department of Rheumatology, Allergy & Immunology, Yale University, 300 Cedar Street, TAC S541, New Haven, CT 06520, USA.
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Manger I, Schmitt C, Berking C, French LE, Vera-Gonzalez J, Heinzerling L. Association of HLA-A*02:01 type with efficacy and toxicity of immune checkpoint inhibitor therapy in melanoma patients: a retrospective cohort study. BMC Cancer 2025; 25:565. [PMID: 40155873 PMCID: PMC11954185 DOI: 10.1186/s12885-025-13857-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 03/04/2025] [Indexed: 04/01/2025] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICI) are highly effective but may induce severe or even fatal and unpredictable immune-related adverse events (irAEs). It is unclear whether human leukocyte antigen (HLA) genes contribute to the susceptibility of developing irAEs during ICI therapy. METHODS This multicentre retrospective study investigated the association of irAE and outcome with HLA-A*02:01 status in a cohort of 97 patients with metastatic melanoma undergoing ICI therapy. Organ-specific irAEs and therapy outcome as assessed by response rate, progression-free survival (PFS) and overall survival (OS) were analysed depending on HLA type HLA-A*02:01. For the outcome only patients with cutaneous melanoma were analysed. Chi square test, exact fisher test, Kruskal Wallis test and log rank test were employed for statistical analysis (p ≤ 0.05). RESULTS The cohort included 38 HLA-A*02:01 positive (39.2%) and 59 HLA-A*02:01 negative (60.8%) patients. Data showed no evidence of an association of HLA-A*02:01 with organ-specific irAEs except for a numerical difference in immune-related colitis. Furthermore, response rates of the subgroup of patients with metastatic cutaneous melanoma did not differ between the two cohorts. The median PFS was 5 months and 8 months in HLA-A*02:01 positive and negative patients with cutaneous melanoma, respectively. CONCLUSION HLA-A*02:01 was not associated with specific checkpoint inhibitor-induced organ toxicity in this cohort of HLA-A-typed melanoma patients. Interestingly, in the relatively small subgroup of patients with cutaneous melanoma an earlier progression in HLA-A*02:01 positive patients was observed, however not in the long term. These findings are exploratory due to the limited sample size and require validation in larger, prospective cohorts.
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Affiliation(s)
- Isabel Manger
- Department of Dermatology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Uniklinikum Erlangen, CCC Erlangen-EMN, CCC WERA, Erlangen, Germany
- Bavarian Centre for Cancer Research (BZKF), Uniklinikum Erlangen and LMU Munich, Munich, Germany
| | - Christina Schmitt
- Department of Dermatology and Allergy, LMU University Hospital, LMU Munich, Munich, Germany
- Bavarian Centre for Cancer Research (BZKF), Uniklinikum Erlangen and LMU Munich, Munich, Germany
| | - Carola Berking
- Department of Dermatology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Uniklinikum Erlangen, CCC Erlangen-EMN, CCC WERA, Erlangen, Germany
- Bavarian Centre for Cancer Research (BZKF), Uniklinikum Erlangen and LMU Munich, Munich, Germany
| | - Lars E French
- Department of Dermatology and Allergy, LMU University Hospital, LMU Munich, Munich, Germany
- Bavarian Centre for Cancer Research (BZKF), Uniklinikum Erlangen and LMU Munich, Munich, Germany
- Dr. Philip Frost, Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Julio Vera-Gonzalez
- Department of Dermatology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Uniklinikum Erlangen, CCC Erlangen-EMN, CCC WERA, Erlangen, Germany
- Bavarian Centre for Cancer Research (BZKF), Uniklinikum Erlangen and LMU Munich, Munich, Germany
| | - Lucie Heinzerling
- Department of Dermatology and Allergy, LMU University Hospital, LMU Munich, Munich, Germany.
- Bavarian Centre for Cancer Research (BZKF), Uniklinikum Erlangen and LMU Munich, Munich, Germany.
- Department of Dermatology, LMU University Hospital Munich, Frauenlobstr. 9-11, Munich, D-80337, Germany.
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Jayathilaka B, Mian F, Cockwill J, Franchini F, Au-Yeung G, IJzerman M. Analysis of risk factors for immune-related adverse events induced by immune checkpoint inhibitor treatment in cancer: A comprehensive systematic review. Crit Rev Oncol Hematol 2025; 207:104601. [PMID: 39706233 DOI: 10.1016/j.critrevonc.2024.104601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 12/13/2024] [Accepted: 12/16/2024] [Indexed: 12/23/2024] Open
Abstract
BACKGROUND Immune-related adverse events (irAE) pose challenges to the use of immune checkpoint inhibitors (ICI). While risk factors for irAE are emerging, most studies are small, retrospective analyses that seldom report on diverse cancers or rare irAE. This paper reports a systematic review that summarises literature on irAE risk factors across cancers and proposes a categorisation approach. METHOD A systematic search was conducted in Medline OVID, Embase and Web of Science databases following PRISMA guidelines (CRD42022310127). Original research published in peer-reviewed journals between January 2017-Decmeber 2021 were selected. Eligible studies included patients with any cancer and evaluated any potential risk factor for any grade/type of irAE. Study design, sample size, and method for analysing association between irAE and risk factors were compared. RESULTS A total of 293 eligible studies containing 305,879 patients receiving ICI reported irAE in 58,291 patients (19.1 %). There were 221 retrospective, 55 prospective studies, and 17 systematic reviews/meta-analyses. Eighteen studies evaluated the predictive validity of models. Proposed risk factors were grouped based on common themes and underlying aetiology: 1) patient, 2) laboratory, 3) medical history, 4) cancer-related, 5) clinical score, 6) medications, and 7) imaging features. Opposing associations were reported between advancing age and irAE risk. CONCLUSION This systematic review provides a comprehensive overview of evidence on irAE risk factors across a large patient population. Studies were heterogeneous resulting from variations in design, sample size and analysis method, and lack generalisability due to statistically underpowered evidence. We propose an approach to categorise potential irAE risk factors to support ongoing collaborative research.
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Affiliation(s)
- Bishma Jayathilaka
- Pharmacy Department, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Victoria, Australia; Cancer Health Services Research Unit, Centre for Cancer Research, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Victoria, Australia.
| | - Farah Mian
- Pharmacy Department, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Jo Cockwill
- Consumer Advisory Committee, Victorian Comprehensive Cancer Centre Alliance Cancer, Melbourne, Victoria, Australia
| | - Fanny Franchini
- Cancer Health Services Research Unit, Centre for Cancer Research, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Victoria, Australia
| | - George Au-Yeung
- Sir Peter MacCallum Department of Oncology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Victoria, Australia; Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Maarten IJzerman
- Sir Peter MacCallum Department of Oncology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Victoria, Australia; Cancer Health Services Research Unit, Centre for Cancer Research, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Victoria, Australia; Erasmus School of Health Policy & Management, Erasmus University, Rotterdam, the Netherlands
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Giesler S, Riemer R, Lowinus T, Zeiser R. Immune-mediated colitis after immune checkpoint inhibitor therapy. Trends Mol Med 2025; 31:265-280. [PMID: 39477757 DOI: 10.1016/j.molmed.2024.09.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 09/23/2024] [Accepted: 09/30/2024] [Indexed: 03/15/2025]
Abstract
Immune checkpoint inhibitors (ICIs) have led to improved outcome in patients with various types of cancer. Due to inhibition of physiological anti-inflammatory mechanisms, patients treated with ICIs may develop autoimmune inflammation of the colon, associated with morbidity, decreased quality of life (QoL), and mortality. In this review, we summarize clinical and pathophysiological aspects of immune-mediated colitis (ImC), highlighting novel treatment options. In the colon, ICIs trigger resident and circulating T cell activation and infiltration of myeloid cells. In addition, the gut microbiota critically contribute to intestinal immune dysregulation and loss of barrier function, thereby propagating local and systemic inflammation. Currently available therapies for ImC include corticosteroids, antitumor necrosis factor-α (TNF-α)- and anti-integrin α4β7 antibodies. Given that systemic immunosuppression might impair antitumor immune responses, novel therapeutic approaches are urgently needed.
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Affiliation(s)
- Sophie Giesler
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Roxane Riemer
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Theresa Lowinus
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Robert Zeiser
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
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Triantafyllou E, Gudd CLC, Possamai LA. Immune-mediated liver injury from checkpoint inhibitors: mechanisms, clinical characteristics and management. Nat Rev Gastroenterol Hepatol 2025; 22:112-126. [PMID: 39663461 DOI: 10.1038/s41575-024-01019-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/05/2024] [Indexed: 12/13/2024]
Abstract
Immunotherapy has changed the treatment landscape for patients with cancer in the past decade. Immune checkpoint inhibitor (ICI)-based therapies have proven effective in a range of malignancies, including liver and gastrointestinal cancers, but they can cause diverse off-target organ toxicities. With the increasingly wider application of these drugs, immune-mediated liver injury from ICIs has become a commonly encountered challenge in clinical hepatology and gastroenterology. In this Review, we discuss the evidence from human and animal studies on the immunological mechanisms of immune-mediated liver injury from ICIs and summarize its clinical features and practical considerations for its management.
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Affiliation(s)
- Evangelos Triantafyllou
- Section of Hepatology and Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom.
| | - Cathrin L C Gudd
- Section of Hepatology and Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Lucia A Possamai
- Section of Hepatology and Gastroenterology, Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom.
- Liver and Antiviral Unit, St Mary's Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom.
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Park SJ, Yang S, Lee S, Joo SH, Park T, Kim DH, Kim H, Park S, Kim JT, Kwack WG, Kang SW, Song YK, Cha JM, Rhee SY, Chung EK. Machine-Learning Parsimonious Prediction Model for Diagnostic Screening of Severe Hematological Adverse Events in Cancer Patients Treated with PD-1/PD-L1 Inhibitors: Retrospective Observational Study by Using the Common Data Model. Diagnostics (Basel) 2025; 15:226. [PMID: 39857110 PMCID: PMC11763827 DOI: 10.3390/diagnostics15020226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 01/08/2025] [Accepted: 01/17/2025] [Indexed: 01/27/2025] Open
Abstract
Background/Objectives: Earlier detection of severe immune-related hematological adverse events (irHAEs) in cancer patients treated with a PD-1 or PD-L1 inhibitor is critical to improving treatment outcomes. The study aimed to develop a simple machine learning (ML) model for predicting irHAEs associated with PD-1/PD-L1 inhibitors. Methods: We utilized the Observational Medical Outcomes Partnership-Common Data Model based on electronic medical records from a tertiary (KHMC) and a secondary (KHNMC) hospital in South Korea. Severe irHAEs were defined as Grades 3-5 by the Common Terminology Criteria for Adverse Events (version 5.0). The predictive model was developed using the KHMC dataset, and then cross-validated against an independent cohort (KHNMC). The full ML models were then simplified by selecting critical features based on the feature importance values (FIVs). Results: Overall, 397 and 255 patients were included in the primary (KHMC) and cross-validation (KHNMC) cohort, respectively. Among the tested ML algorithms, random forest achieved the highest accuracy (area under the receiver operating characteristic curve [AUROC] 0.88 for both cohorts). Parsimonious models reduced to 50% FIVs of the full models showed comparable performance to the full models (AUROC 0.83-0.86, p > 0.05). The KHMC and KHNMC parsimonious models shared common predictive features including furosemide, oxygen gas, piperacillin/tazobactam, and acetylcysteine. Conclusions: Considering the simplicity and adequate predictive performance, our simplified ML models might be easily implemented in clinical practice with broad applicability. Our model might enhance early diagnostic screening of irHAEs induced by PD-1/PD-L1 inhibitors, contributing to minimizing the risk of severe irHAEs and improving the effectiveness of cancer immunotherapy.
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Affiliation(s)
- Seok Jun Park
- Department of Regulatory Science, College of Pharmacy, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (S.J.P.); (S.Y.); (S.H.J.); (T.P.); (D.H.K.); (H.K.); (S.P.)
- Institute of Regulatory Innovation Through Science (IRIS), Kyung Hee University, Seoul 02447, Republic of Korea
| | - Seungwon Yang
- Department of Regulatory Science, College of Pharmacy, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (S.J.P.); (S.Y.); (S.H.J.); (T.P.); (D.H.K.); (H.K.); (S.P.)
- Institute of Regulatory Innovation Through Science (IRIS), Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea;
| | - Suhyun Lee
- Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea;
| | - Sung Hwan Joo
- Department of Regulatory Science, College of Pharmacy, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (S.J.P.); (S.Y.); (S.H.J.); (T.P.); (D.H.K.); (H.K.); (S.P.)
- Institute of Regulatory Innovation Through Science (IRIS), Kyung Hee University, Seoul 02447, Republic of Korea
| | - Taemin Park
- Department of Regulatory Science, College of Pharmacy, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (S.J.P.); (S.Y.); (S.H.J.); (T.P.); (D.H.K.); (H.K.); (S.P.)
- Institute of Regulatory Innovation Through Science (IRIS), Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea;
| | - Dong Hyun Kim
- Department of Regulatory Science, College of Pharmacy, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (S.J.P.); (S.Y.); (S.H.J.); (T.P.); (D.H.K.); (H.K.); (S.P.)
- Institute of Regulatory Innovation Through Science (IRIS), Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea;
| | - Hyeonji Kim
- Department of Regulatory Science, College of Pharmacy, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (S.J.P.); (S.Y.); (S.H.J.); (T.P.); (D.H.K.); (H.K.); (S.P.)
- Institute of Regulatory Innovation Through Science (IRIS), Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea;
| | - Soyun Park
- Department of Regulatory Science, College of Pharmacy, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (S.J.P.); (S.Y.); (S.H.J.); (T.P.); (D.H.K.); (H.K.); (S.P.)
- Institute of Regulatory Innovation Through Science (IRIS), Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea;
| | - Jung-Tae Kim
- Department of Pharmacy, Kyung Hee University Hospital at Gangdong, Seoul 05278, Republic of Korea;
| | - Won Gun Kwack
- Division of Pulmonary, Allergy and Critical Care Medicine, Kyung Hee University Hospital, Seoul 02447, Republic of Korea;
| | - Sung Wook Kang
- Department of Pulmonary and Critical Care Medicine, Kyung Hee University Hospital at Gangdong, Seoul 05278, Republic of Korea;
| | - Yun-Kyoung Song
- College of Pharmacy, The Catholic University of Korea-Sungsim Campus, Bucheon 14662, Gyeonggi-do, Republic of Korea;
| | - Jae Myung Cha
- Division of Gastroenterology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul 05278, Republic of Korea
| | - Sang Youl Rhee
- Center for Digital Health, Medical Science Research Institute, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, Seoul 02447, Republic of Korea
| | - Eun Kyoung Chung
- Department of Regulatory Science, College of Pharmacy, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (S.J.P.); (S.Y.); (S.H.J.); (T.P.); (D.H.K.); (H.K.); (S.P.)
- Institute of Regulatory Innovation Through Science (IRIS), Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea;
- Department of Pharmacy, Kyung Hee University Hospital at Gangdong, Seoul 05278, Republic of Korea;
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Nandre RM, Terse PS. An overview of immunotoxicity in drug discovery and development. Toxicol Lett 2025; 403:66-75. [PMID: 39603571 PMCID: PMC11734732 DOI: 10.1016/j.toxlet.2024.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 10/20/2024] [Accepted: 11/22/2024] [Indexed: 11/29/2024]
Abstract
The immune system is one of the common targets of drugs' toxicity (Immunotoxicity) and/or efficacy (Immunotherapy). Immunotoxicity leads to adverse effects on human health, which raises serious concerns for the regulatory agencies. Currently, immunotoxicity assessment is conducted using different in vitro and in vivo assays. In silico and in vitro human cell-based immunotoxicity assays should also be explored for screening purposes as these are time and cost effective as well as for ethical reasons. For in vivo studies, tier 1-3 assessments (Tier 1: hematology, serum globulin levels, lymphoid organ's weight and histopathology; Tier 2: immunophenotyping, TDAR and cell mediated immunity; and Tier 3: host resistance) should be used. These non-clinical in vivo assessments are useful to select immunological endpoints for clinical trials as well as for precautionary labeling. As per regulatory guidelines, adverse immunogenicity information of drug should be included in product's labeling to make health care practitioner aware of safety concerns before prescribing medicines and patient management (USFDA, 2022a, 2022b). This review mainly focuses on the importance of immunotoxicity assessment during drug discovery and development.
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Affiliation(s)
- Rahul M Nandre
- Therapeutic Development Branch, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD, United States.
| | - Pramod S Terse
- Therapeutic Development Branch, Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD, United States.
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Jayathilaka B, Mian F, Franchini F, Au-Yeung G, IJzerman M. Cancer and treatment specific incidence rates of immune-related adverse events induced by immune checkpoint inhibitors: a systematic review. Br J Cancer 2025; 132:51-57. [PMID: 39489880 PMCID: PMC11723908 DOI: 10.1038/s41416-024-02887-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 10/16/2024] [Accepted: 10/18/2024] [Indexed: 11/05/2024] Open
Abstract
BACKGROUND Immune-related adverse events (irAE) induced by immune checkpoint inhibitors (ICI) are a treatment-limiting barrier. There are few large-scale studies that estimate irAE prevalence. This paper presents a systematic review that reports the prevalence of irAE by cancer type and ICI. METHODS A systematic review was undertaken in MEDLINE OVID, EMBASE and Web of Science databases from 2017-2021. A total of 293 studies were identified for analysis and, of these, event rate was calculated for 272 studies, which involved 58,291 patients with irAE among 305,879 total patients on ICI. Event rate was calculated by irAE and ICI type. RESULTS Mean event rate for general irAE occurrence across any grade was 40.0% (37.3-42.7%) and high grade was 19.7% (15.8-23.7%). Mean event rates for six specific types of irAE are reported. Mean event rate for ICI monotherapy was 30.5% (28.1-32.9%), 45.7% (29.6-61.7%) for ICI combination therapy, and 30.0% (25.3-34.6%) for both ICI monotherapy and combination therapy. CONCLUSION This systematic review characterises irAE prevalence across current research that examines irAE risk factors across cancers and ICI. The findings confirms that irAE occurrence is very common in the real-world setting, both high grade and irAE across any grade.
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Affiliation(s)
- Bishma Jayathilaka
- Pharmacy Department, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
- Sir Peter MacCallum Department of Oncology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia.
- Cancer Health Services Research Unit, Centre for Cancer Research, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia.
| | - Farah Mian
- Pharmacy Department, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Fanny Franchini
- Cancer Health Services Research Unit, Centre for Cancer Research, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia
| | - George Au-Yeung
- Sir Peter MacCallum Department of Oncology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Maarten IJzerman
- Sir Peter MacCallum Department of Oncology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia
- Cancer Health Services Research Unit, Centre for Cancer Research, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia
- Erasmus School of Health Policy & Management, Erasmus University, Rotterdam, The Netherlands
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Furrer-Matcau C, Sieber C, Lehnick D, Brand CU, Hug B. Cutaneous adverse events due to checkpoint inhibitors - a retrospective analysis at a tertiary referral hospital in Switzerland 2019-2022. Front Oncol 2024; 14:1485594. [PMID: 39703836 PMCID: PMC11655322 DOI: 10.3389/fonc.2024.1485594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Accepted: 11/19/2024] [Indexed: 12/21/2024] Open
Abstract
Introduction Checkpoint inhibitors are increasingly important in anti-cancer treatment. Therefore, knowledge of immune-related cutaneous adverse events (ir-cAE) is crucial for therapy management and continuation. Objective The study aimed to analyze the incidence of cutaneous adverse events caused by checkpoint inhibitor therapy, including their clinical presentation, management, and impact on further treatment. Methods This is a descriptive, monocentric retrospective study that uses data from the electronic health record system at a tertiary referral hospital in Central Switzerland from September 2019 to September 2022. The electronic health records of patients who received a therapy with checkpoint inhibitors were examined for age, sex, type of immunotherapy, time to occurrence of ir-cAEs, characteristics of the ir-cAEs, the treatment approach, and the continuation or cessation of the therapy due to ir-cAEs. Results Out of 431 patients, for 131 patients (30.4%) at least one ir-cAE event was documented. In particular, 109 (25.3%) experienced pruritus and 61 (14.2%) showed a maculopapular exanthema. The severity of the ir-cAE was mild in 88 patients (67.2% out of those with ir-cAEs). Ir-cAE were observed in 10 out of 20 patients (50%) treated with ipilimumab/nivolumab and in 15 out of 24 (62.5%) treated with durvalumab. In 15 patients (3.5%), checkpoint inhibitor therapy had to be discontinued due to cutaneous side effects. Conclusions This study showed that approximately one third of the patients experienced ir-cAEs. The most frequently observed ir-cAEs were pruritus, maculopapular exanthema and xerosis cutis. In general, the dermatological manifestations are mild and responsive to topical treatment or self-limiting with no requirement for treatment interruption.
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Affiliation(s)
- Clara Furrer-Matcau
- Dermatology and Allergology, Cantonal Hospital Lucerne, Lucerne, Switzerland
| | - Chloé Sieber
- Biostatistics and Methodology, Clinical Trials Unit Central Switzerland, Lucerne, Switzerland
- Faculty of Health Sciences and Medicine, University of Lucerne, Lucerne, Switzerland
| | - Dirk Lehnick
- Biostatistics and Methodology, Clinical Trials Unit Central Switzerland, Lucerne, Switzerland
- Faculty of Health Sciences and Medicine, University of Lucerne, Lucerne, Switzerland
| | - Christoph Urs Brand
- Dermatology and Allergology, Cantonal Hospital Lucerne, Lucerne, Switzerland
| | - Balthasar Hug
- Department of Medicine, Cantonal Hospital Lucerne, Lucerne, Switzerland
- Community Medicine, Faculty of Health Sciences and Medicine, University of Lucerne, Lucerne, Switzerland
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Farina A, Villagrán-García M, Joubert B. Soluble biomarkers for immune checkpoint inhibitor-related encephalitis: A mini-review. Rev Neurol (Paris) 2024; 180:982-988. [PMID: 39307617 DOI: 10.1016/j.neurol.2024.08.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 08/02/2024] [Accepted: 08/28/2024] [Indexed: 11/02/2024]
Abstract
Immune checkpoint inhibitors lead to effective antitumour responses but also to immune-related adverse events (irAEs), which affect the nervous system in 1-5% of patients. Encephalitis is the most frequent central nervous system irAE and is clinically relevant due to its high severity and mortality. Early diagnosis is crucial but is hampered by the broad list of alternative diagnoses, the lack of established diagnostic criteria, and the need of extensive diagnostic procedures (e.g., spinal tap, brain MRI) alongside expert neurological evaluation. Additionally, the response to corticosteroids is inconsistent, and the management of corticosteroid-refractory patients remains poorly defined. This mini-review discusses the role of various soluble biomarkers in the diagnosis, prognostication, and management of ICI-encephalitis. Neural antibodies, which are well-established biomarkers of autoimmune and paraneoplastic encephalitis, are found in only a subset of ICI-encephalitis, in which they can aid to establish the diagnosis. The most prevalent are paraneoplastic neurological syndromes (PNS)-associated antibodies, which are found almost exclusively in focal ICI-encephalitis syndromes and are associated with poor outcomes, possibly due to predominantly cytotoxic T cell involvement leading to irreversible neuronal loss. Beside antibodies, serum brain injury biomarkers such as NfL and S100B are elevated in ICI-encephalitis and, even if non-specific, may be useful as a routine test to quickly identify patients in whom neurological evaluation and second-level diagnostic procedures should be prioritized. Additionally, higher serum and CSF NfL levels have been associated with lack of treatment response in ICI-encephalitis, suggesting they may have a prognostic role. Among cytokines, elevated interleukin 6 (IL6) levels have been observed in serum and/or CSF samples of some patients with ICI-encephalitis, but the role of IL6 as a biomarker for response to IL6-directed therapies requires further investigation. Likewise, the value of other biomarkers, including T cells markers and HLA haplotypes, still needs to be evaluated in large cohorts. Overall, neural antibodies are important diagnostic and prognostic biomarkers in ICI-encephalitis, and other soluble biomarkers, especially NfL, deserve further investigation since they have a promising application in clinical practice.
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Affiliation(s)
- A Farina
- French Reference Centre on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France; MeLiS-UCBL-CNRS UMR 5284, Inserm U1314, Université Claude-Bernard Lyon 1, Lyon, France.
| | - M Villagrán-García
- French Reference Centre on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France; MeLiS-UCBL-CNRS UMR 5284, Inserm U1314, Université Claude-Bernard Lyon 1, Lyon, France
| | - B Joubert
- French Reference Centre on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Hôpital Neurologique, Bron, France; MeLiS-UCBL-CNRS UMR 5284, Inserm U1314, Université Claude-Bernard Lyon 1, Lyon, France; ImmuCare, Institute of Cancerology, Hospices Civils de Lyon, 69002 Lyon, France
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11
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Pasoto SG, Franco AS, Silva CA, Bonfa E. Sicca syndrome/Sjögren's disease associated with cancer immunotherapy: a narrative review on clinical presentation, biomarkers, and management. Expert Rev Clin Immunol 2024; 20:1149-1167. [PMID: 38903050 DOI: 10.1080/1744666x.2024.2370327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Accepted: 06/17/2024] [Indexed: 06/22/2024]
Abstract
INTRODUCTION Almost one-quarter of immune checkpoint inhibitor (ICI) recipients experience sicca syndrome, while Sjögren's disease (SjD) is estimated at 0.3-2.5%, possibly underreported. AREAS COVERED This narrative review (Medline/Embase until January/31/2024) addresses the pathophysiology, incidence, demographic/clinical features, biomarkers, labial salivary gland biopsy (LSGB), fulfillment of the idiopathic SjD (iSjD) classificatory criteria, differential diagnosis, and management of sicca syndrome/SjD associated with ICIs. EXPERT OPINION SjD associated with ICIs is underdiagnosed, since studies that performed the mandatory SjD investigation identified that 40-60% of patients with sicca syndrome associated with ICIs meet the iSjD classificatory criteria. LSGB played a fundamental role in recognizing these cases, as most of them had negative anti-Ro/SS-A antibody. Despite the finding of focal lymphocytic sialoadenitis in LSGB samples mimicking iSjD, immunohistochemical analysis provided novel evidence of a distinct pattern for sicca syndrome/SjD associated with ICIs compared to iSjD. The former has scarcity of B lymphocytes, which are a hallmark of iSjD. Additionally, patients with sicca syndrome/SjD associated with ICIs have demographical/clinical/serological and treatment response dissimilarities compared to iSjD. Dryness symptoms are more acute in the former than in iSjD, with predominance of xerostomia over xerophthalmia, and partial/complete response to glucocorticoids. Dryness symptoms in ICI-treated patients warrant prompt SjD investigation.
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Affiliation(s)
- Sandra Gofinet Pasoto
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brasil
| | - André Silva Franco
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brasil
| | - Clovis Artur Silva
- Pediatric Rheumatology Unit, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brasil
| | - Eloisa Bonfa
- Rheumatology Division, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brasil
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Abed A, Reid A, Law N, Millward M, Gray ES. HLA-A01 and HLA-B27 Supertypes, but Not HLA Homozygocity, Correlate with Clinical Outcome among Patients with Non-Small Cell Lung Cancer Treated with Pembrolizumab in Combination with Chemotherapy. Cancers (Basel) 2024; 16:3102. [PMID: 39272960 PMCID: PMC11394546 DOI: 10.3390/cancers16173102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 09/04/2024] [Accepted: 09/04/2024] [Indexed: 09/15/2024] Open
Abstract
INTRODUCTION Maximal heterozygosity on the human leukocyte antigen (HLA) loci has been found to be associated with improved survival and development of immune-related adverse events (irAEs) among NSCLC patients treated with immunotherapy. Here, we investigated the effect of germline HLA-I/-II on clinical outcomes among NSCLC patients treated with first-line pembrolizumab in combination with chemotherapy. METHOD We prospectively recruited patients with NSCLC who were commencing first-line pembrolizumab in combination with chemotherapy. DNA from white blood cells was used for high-resolution HLA-I/II typing. RESULTS Of the 65 patients recruited, 53 complied with the inclusion criteria. We did not find an association between HLA-I/-II homozygosity and clinical outcome among the studied population. However, the presence of HLA-A01 was associated with unfavourable PFS (HR = 2.32, 95%CI 1.13-4.77, p = 0.022) and worsening OS (HR = 2.86, 95%CI 1.06-7.70, p = 0.038). The presence of HLA-B27 was associated with improved PFS (HR = 0.35, 95%CI 0.18-0.71, p = 0.004) and trends toward improving OS. None of the HLA-I supertypes were associated with the development or worsening of irAEs. CONCLUSIONS The absence of association between genomic HLA-I/-II homozygosity and clinical outcome among patients with advanced NSCLC treated with pembrolizumab in combination with chemotherapy might reflect a diminished role for HLA molecules among patients with low or no PD-L1. HLA-A01 and HLA-B27 might have a role in predicting clinical outcomes among this cohort of patients. Further studies are needed to explore biomarkers for this group of patients.
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Affiliation(s)
- Afaf Abed
- Centre for Precision Health, Edith Cowan University, Joondalup, WA 6027, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia
- School of Medicine, University of Western Australia, Crawley, WA 6009, Australia
| | - Anna Reid
- Centre for Precision Health, Edith Cowan University, Joondalup, WA 6027, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia
| | - Ngie Law
- Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia
| | - Michael Millward
- School of Medicine, University of Western Australia, Crawley, WA 6009, Australia
| | - Elin S Gray
- Centre for Precision Health, Edith Cowan University, Joondalup, WA 6027, Australia
- School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia
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13
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Guo AJ, Deng QY, Dong P, Zhou L, Shi L. Biomarkers associated with immune-related adverse events induced by immune checkpoint inhibitors. World J Clin Oncol 2024; 15:1002-1020. [PMID: 39193157 PMCID: PMC11346067 DOI: 10.5306/wjco.v15.i8.1002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 05/13/2024] [Accepted: 06/21/2024] [Indexed: 08/16/2024] Open
Abstract
Immune checkpoint inhibitors (ICIs) constitute a pivotal class of immunotherapeutic drugs in cancer treatment. However, their widespread clinical application has led to a notable surge in immune-related adverse events (irAEs), significantly affecting the efficacy and survival rates of patients undergoing ICI therapy. While conventional hematological and imaging tests are adept at detecting organ-specific toxicities, distinguishing adverse reactions from those induced by viruses, bacteria, or immune diseases remains a formidable challenge. Consequently, there exists an urgent imperative for reliable biomarkers capable of accurately predicting or diagnosing irAEs. Thus, a thorough review of existing studies on irAEs biomarkers is indispensable. Our review commences by providing a succinct overview of major irAEs, followed by a comprehensive summary of irAEs biomarkers across various dimensions. Furthermore, we delve into innovative methodologies such as machine learning, single-cell RNA sequencing, multiomics analysis, and gut microbiota profiling to identify novel, robust biomarkers that can facilitate precise irAEs diagnosis or prediction. Lastly, this review furnishes a concise exposition of irAEs mechanisms to augment understanding of irAEs prediction, diagnosis, and treatment strategies.
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Affiliation(s)
- An-Jie Guo
- School of Life Sciences, Chongqing University, Chongqing 400044, China
| | - Qing-Yuan Deng
- School of Life Sciences, Chongqing University, Chongqing 400044, China
| | - Pan Dong
- School of Life Sciences, Chongqing University, Chongqing 400044, China
| | - Lian Zhou
- Head and Neck Cancer Center, Chongqing University Cancer Hospital, Chongqing 400000, China
| | - Lei Shi
- School of Life Sciences, Chongqing University, Chongqing 400044, China
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Sutanto H, Safira A, Fetarayani D. From tumor to tolerance: A comprehensive review of immune checkpoint inhibitors and immune-related adverse events. Asia Pac Allergy 2024; 14:124-138. [PMID: 39220570 PMCID: PMC11365684 DOI: 10.5415/apallergy.0000000000000146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 05/02/2024] [Indexed: 09/04/2024] Open
Abstract
The advent of immune checkpoint inhibitors (ICIs) has revolutionized the treatment landscape for various malignancies by harnessing the body's immune system to target cancer cells. However, their widespread use has unveiled a spectrum of immune-related adverse events, highlighting a critical balance between antitumor immunity and autoimmunity. This review article delves into the molecular immunology of ICIs, mapping the journey from their therapeutic action to the unintended induction of immune-related adverse events. We provide a comprehensive overview of all available ICIs, including cytotoxic T-lymphocyte-associated protein 4, programmed cell death protein 1, programmed death-ligand 1 inhibitors, and emerging targets, discussing their mechanisms of action, clinical applications, and the molecular underpinnings of associated immune-related adverse events. Special attention is given to the activation of autoreactive T cells, B cells, cytokine release, and the inflammatory cascade, which together contribute to the development of immune-related adverse events. Through a molecular lens, we explore the clinical manifestations of immune-related adverse events across organ systems, offering insights into diagnosis, management, and strategies to mitigate these adverse effects. The review underscores the importance of understanding the delicate interplay between enhancing antitumor responses and minimizing immune-related adverse events, aiming to guide future research and the development of next-generation ICIs with improved drug safety profiles.
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Affiliation(s)
- Henry Sutanto
- Internal Medicine Study Program, Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Internal Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Ardea Safira
- Internal Medicine Study Program, Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Internal Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Deasy Fetarayani
- Internal Medicine Study Program, Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Internal Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
- Division of Allergy and Clinical Immunology, Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
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15
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Chen J, Liu JS, Liu JY, She L, Zou T, Yang F, Li XP, Wang Z, Liu Z. Plasma metabolomics of immune-related adverse events for patients with lung cancer treated with PD-1/PD-L1 inhibitors. J Immunother Cancer 2024; 12:e009399. [PMID: 38991728 PMCID: PMC11243122 DOI: 10.1136/jitc-2024-009399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/18/2024] [Indexed: 07/13/2024] Open
Abstract
BACKGROUND Metabolomics has the characteristics of terminal effects and reflects the physiological state of biological diseases more directly. Several current biomarkers of multiple omics were revealed to be associated with immune-related adverse events (irAEs) occurrence. However, there is a lack of reliable metabolic biomarkers to predict irAEs. This study aims to explore the potential metabolic biomarkers to predict risk of irAEs and to investigate the association of plasma metabolites level with survival in patients with lung cancer receiving PD-1/PD-L1 inhibitor treatment. METHODS The study collected 170 plasmas of 85 patients with lung cancer who received immune checkpoint inhibitors (ICIs) treatment. 58 plasma samples of 29 patients with irAEs were collected before ICIs treatment and at the onset of irAEs. 112 plasma samples of 56 patients who did not develop irAEs were collected before ICIs treatment and plasma matched by treatment cycles to onset of irAEs patients. Untargeted metabolomics analysis was used to identify the differential metabolites before initiating ICIs treatment and during the process that development of irAEs. Kaplan-Meier curves analysis was used to detect the associations of plasma metabolites level with survival of patients with lung cancer. RESULTS A total of 24 differential metabolites were identified to predict the occurrence of irAEs. Baseline acylcarnitines and steroids levels are significantly higher in patients with irAEs, and the model of eight acylcarnitine and six steroid metabolites baseline level predicts irAEs occurrence with area under the curve of 0.91. Patients with lower concentration of baseline decenoylcarnitine(AcCa(10:1) 2, decenoylcarnitine(AcCa(10:1) 3 and hexanoylcarnitine(AcCa(6:0) in plasma would have better overall survival (OS). Moreover, 52 differential metabolites were identified related to irAEs during ICIs treatment, dehydroepiandrosterone sulfate, corticoserone, cortisol, thyroxine and sphinganine 1-phaosphate were significantly decreased in irAEs group while oxoglutaric acid and taurocholic acid were significantly increased in irAEs group. CONCLUSIONS High levels of acylcarnitines and steroid hormone metabolites might be risk factor to development of irAEs, and levels of decenoylcarnitine (AcCa(10:1) 2, decenoylcarnitine (AcCa(10:1) 3 and hexanoylcarnitine (AcCa(6:0) could be used to predict OS for patients with lung cancer received ICIs treatment.
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Affiliation(s)
- Juan Chen
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Jia-Si Liu
- Department of Pharmacy, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, People's Republic of China
| | - Jun-Yan Liu
- Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Lei She
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Ting Zou
- National Institution of Drug Clinical Trial, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Fan Yang
- Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, People's Republic of China
| | - Xiang-Ping Li
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
- The Hunan Institute of Pharmacy Practice and Clinical Research, Changsha, Hunan, People's Republic of China
| | - Zhan Wang
- Lung Cancer and Gastrointestinal Unit, Department of Medical Oncology, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, People's Republic of China
| | - Zhaoqian Liu
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
- Institute of Clinical Pharmacology, Engineering Research Center for applied Technology of Pharmacogenomics of Ministry of Education, Central South University, Changsha, Hunan, People's Republic of China
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16
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Di C, Yu T, Ni L. Non-bacterial cystitis caused by pembrolizumab therapy for adenocarcinoma of the lung: a case report. Front Immunol 2024; 15:1423123. [PMID: 39034999 PMCID: PMC11257856 DOI: 10.3389/fimmu.2024.1423123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Accepted: 06/18/2024] [Indexed: 07/23/2024] Open
Abstract
Immune checkpoint inhibitors (ICIs) including anti-programmed death cell protein 1 (anti-PD1) and anti-programmed cell death-ligand 1 (PD-L1), by disinhibiting the antitumor responses of lymphocytes, have extended survival benefits for patients in lung cancer. ICIs can also lead to a wide spectrum of immune-related adverse events (irAEs), due to dysregulation of immune reactions. Here, we report a 27-year-old female patient with adenocarcinoma of the lung treated with pembrolizumab-combined chemotherapy treatment, who complained of urinary irritation symptoms. No bacteria were found in multiple urine cultures. B-mode ultrasonography indicated a high echo in the right lateral wall of the bladder, about 5.6 × 4.5 mm in size. Transurethral bladder tumor resection (TURBT) was operated. At biopsy, we found CD3+ CD8+ lymphocyte, plasma cell, and eosinophil infiltration and lymphoid follicle formation in the bladder mucosal layer. This is a report of non-bacterial inflammation of the urinary tract caused by immunotherapy.
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Affiliation(s)
- Caixia Di
- Department of Pulmonary and Critical Care Medicine, Shanghai Key Discipline for Respiratory Diseases, Institute of Respiratory Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Key Laboratory of Emergency Prevention, Diagnosis and Treatment of Respiratory Infectious Diseases, Shanghai, China
| | - Teng Yu
- Department of Pathology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Lei Ni
- Department of Pulmonary and Critical Care Medicine, Shanghai Key Discipline for Respiratory Diseases, Institute of Respiratory Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
- Key Laboratory of Emergency Prevention, Diagnosis and Treatment of Respiratory Infectious Diseases, Shanghai, China
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17
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Rajagopal D, MacLeod E, Corogeanu D, Vessillier S. Immune-related adverse events of antibody-based biological medicines in cancer therapy. J Cell Mol Med 2024; 28:e18470. [PMID: 38963257 PMCID: PMC11223167 DOI: 10.1111/jcmm.18470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 05/03/2024] [Accepted: 05/22/2024] [Indexed: 07/05/2024] Open
Abstract
Recombinant antibodies (Abs) are an integral modality for the treatment of multiple tumour malignancies. Since the Food and Drug Administration (FDA) approval of rituximab as the first monoclonal antibody (mAb) for cancer treatment, several mAbs and antibody (Ab)-based therapies have been approved for the treatment of solid tumour malignancies and other cancers. These Abs function by either blocking oncogenic pathways or angiogenesis, modulating immune response, or by delivering a conjugated drug. The use of Ab-based therapy in cancer patients who could benefit from the treatment, however, is still limited by associated toxicity profiles which may stem from biological features and processes related to target binding, alongside biochemical and/or biophysical characteristics of the therapeutic Ab. A significant immune-related adverse event (irAE) associated with Ab-based therapies is cytokine release syndrome (CRS), characterized by the development of fever, rash and even marked, life-threatening hypotension, and acute inflammation with secondary to systemic uncontrolled increase in a range of pro-inflammatory cytokines. Here, we review irAEs associated with specific classes of approved, Ab-based novel cancer immunotherapeutics, namely immune checkpoint (IC)-targeting Abs, bispecific Abs (BsAbs) and Ab-drug-conjugates (ADCs), highlighting the significance of harmonization in preclinical assay development for safety assessment of Ab-based biotherapeutics as an approach to support and refine clinical translation.
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Affiliation(s)
- Deepa Rajagopal
- Immunotherapy, Biotherapeutics and Advanced Therapies Division, Science, Research, and Innovation Group, Medicines and Healthcare products Regulatory Agency (MHRA)HertfordshireUK
| | - Elliot MacLeod
- Immunotherapy, Biotherapeutics and Advanced Therapies Division, Science, Research, and Innovation Group, Medicines and Healthcare products Regulatory Agency (MHRA)HertfordshireUK
- Present address:
Gilead Sciences, Winchester HouseOxfordUK
| | - Diana Corogeanu
- Immunotherapy, Biotherapeutics and Advanced Therapies Division, Science, Research, and Innovation Group, Medicines and Healthcare products Regulatory Agency (MHRA)HertfordshireUK
- Present address:
East Sussex Healthcare NHS Trust, Conquest HospitalEast SussexUK
| | - Sandrine Vessillier
- Immunotherapy, Biotherapeutics and Advanced Therapies Division, Science, Research, and Innovation Group, Medicines and Healthcare products Regulatory Agency (MHRA)HertfordshireUK
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18
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Wan G, Khattab S, Leung BW, Zhang S, Nguyen N, Tran M, Lin C, Chang C, Alexander N, Jairath R, Phillipps J, Tang K, Rajeh A, Zubiri L, Chen ST, Demehri S, Yu KH, Gusev A, Kwatra SG, LeBoeuf NR, Reynolds KL, Semenov YR. Cancer type and histology influence cutaneous immunotherapy toxicities: a multi-institutional cohort study. Br J Dermatol 2024; 191:117-124. [PMID: 38366637 PMCID: PMC11188738 DOI: 10.1093/bjd/ljae053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 01/08/2024] [Accepted: 02/02/2024] [Indexed: 02/18/2024]
Abstract
BACKGROUND Cutaneous immune-related adverse events (cirAEs) are the most common toxicities to occur in the setting of immune checkpoint inhibitor (ICI) therapy. Identifying patients who are at increased risk of developing cirAEs may improve quality of life and outcomes. OBJECTIVES To investigate the influence of cancer type and histology on the development of cirAEs in the setting of ICI therapy and survival outcomes. METHODS This retrospective cohort study included patients recruited between 1 December 2011 and 30 October 2020. They received ICI from 2011 to 2020 with follow-up of outcomes through October 2021. We identified 3668 recipients of ICI therapy who were seen at Massachusetts General Brigham and Dana-Farber. Of these, 669 developed cirAEs. Records that were incomplete or categories of insufficient sample size were excluded from the study cohort. Multivariate Cox proportional hazards models were used to investigate the impact of cancer organ system and histology on cirAE development, after adjusting for demographics, Charlson Comorbidity Index, ICI type, cancer stage at ICI initiation, and year of ICI initiation. Time-varying Cox proportional hazards modelling was used to examine the impact of cirAE development on mortality. RESULTS Compared with other nonepithelial cancers (neuroendocrine, leukaemia, lymphoma, myeloma, sarcoma and central nervous system malignancies), cutaneous squamous cell carcinoma [cSCC; hazard ratio (HR) 3.57, P < 0.001], melanoma (HR 2.09, P < 0.001), head and neck adenocarcinoma (HR 2.13, P = 0.009), genitourinary transitional cell carcinoma (HR 2.15, P < 0.001) and genitourinary adenocarcinoma (HR 1.53, P = 0.037) were at significantly higher risk of cirAEs in multivariate analyses. The increased risk of cirAEs translated into an adjusted survival benefit for melanoma (HR 0.37, P < 0.001) and cSCC (HR 0.51, P = 0.011). CONCLUSIONS The highest rate of cirAEs and subsequent survival benefits were observed in cutaneous malignancies treated with ICI therapies. This study improves our understanding of patients who are at highest risk of developing cirAEs and would, therefore, benefit from appropriate counselling and closer monitoring by their oncologists and dermatologists throughout their ICI therapy. Limitations include its retrospective nature and cohort from one geography.
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Affiliation(s)
- Guihong Wan
- Department of Dermatology, Massachusetts General Hospital, Boston, MA
- Harvard Medical School, Boston, MA
| | - Sara Khattab
- Department of Dermatology, Massachusetts General Hospital, Boston, MA
| | - Bonnie W Leung
- Department of Dermatology, Massachusetts General Hospital, Boston, MA
- Department of Dermatology, Brigham and Women’s Hospital, Boston, MA
- Center for Cutaneous Oncology, Department of Dermatology, Dana-Farber Cancer Institute, Boston, MA
| | - Shijia Zhang
- Department of Dermatology, Massachusetts General Hospital, Boston, MA
| | - Nga Nguyen
- Department of Dermatology, Massachusetts General Hospital, Boston, MA
| | - Matthew Tran
- Department of Dermatology, Massachusetts General Hospital, Boston, MA
| | - Chuck Lin
- Department of Dermatology, Massachusetts General Hospital, Boston, MA
| | - Crystal Chang
- Department of Dermatology, Massachusetts General Hospital, Boston, MA
| | - Nora Alexander
- Department of Dermatology, Massachusetts General Hospital, Boston, MA
| | - Ruple Jairath
- Department of Dermatology, Massachusetts General Hospital, Boston, MA
| | - Jordan Phillipps
- Department of Dermatology, Massachusetts General Hospital, Boston, MA
| | - Kimberly Tang
- Department of Dermatology, Massachusetts General Hospital, Boston, MA
| | - Ahmad Rajeh
- Department of Dermatology, Massachusetts General Hospital, Boston, MA
| | - Leyre Zubiri
- Department of Dermatology, Massachusetts General Hospital, Boston, MA
| | - Steven T Chen
- Department of Dermatology, Massachusetts General Hospital, Boston, MA
| | - Shadmehr Demehri
- Department of Dermatology, Massachusetts General Hospital, Boston, MA
| | | | - Alexander Gusev
- Center for Cutaneous Oncology, Department of Dermatology, Dana-Farber Cancer Institute, Boston, MA
| | - Shawn G Kwatra
- Department of Dermatology, Johns Hopkins University, Baltimore, MD, USA
| | - Nicole R LeBoeuf
- Harvard Medical School, Boston, MA
- Department of Dermatology, Brigham and Women’s Hospital, Boston, MA
- Center for Cutaneous Oncology, Department of Dermatology, Dana-Farber Cancer Institute, Boston, MA
| | - Kerry L Reynolds
- Department of Dermatology, Massachusetts General Hospital, Boston, MA
- Harvard Medical School, Boston, MA
| | - Yevgeniy R Semenov
- Department of Dermatology, Massachusetts General Hospital, Boston, MA
- Harvard Medical School, Boston, MA
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Sasaki E, Natori Y, Tokuda E, Kimura-Tsuchiya R, Suga J, Kanazawa K, Koguchi T, Kikuchi N, Okabe N, Murono S, Tachibana K, Soeda S, Shimabukuro M, Saji S. Association between specific human leukocyte antigen alleles and development of thyroid immune-related adverse event. Immunotherapy 2024; 16:723-732. [PMID: 38889451 PMCID: PMC11421297 DOI: 10.1080/1750743x.2024.2353539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Accepted: 05/03/2024] [Indexed: 06/20/2024] Open
Abstract
Aim: Inherent variations in human leukocyte antigen (HLA) alleles have been revealed epidemiologically to influence the development of autoimmune diseases. HLA alleles may thus also be associated with the development of immune-related adverse events (irAEs), such as thyroid irAE.Materials & methods: In this case-control study, 71 cancer patients who received immune checkpoint inhibitors were enrolled and HLA-genotyped and the frequency of HLA alleles was compared.Results: A*26:01, DPA1*01:03 and DPB1*02:01 were significantly more frequent in patients with thyroid irAE than in patients without any irAEs (35.0 vs 3.2% [p = 0.004], 80.0 vs 45.2% [p = 0.020] and 55.0 vs 25.8% [p = 0.044], respectively).Conclusion: A*26:01, DPA1*01:03 and DPB1*02:01 appear to be associated with thyroid irAE.
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Affiliation(s)
- Eisaku Sasaki
- Department of Medical Oncology, Fukushima Medical University, Fukushima, 960-1295, Japan
| | - Yutaka Natori
- Department of Medical Oncology, Fukushima Medical University, Fukushima, 960-1295, Japan
| | - Emi Tokuda
- Department of Medical Oncology, Fukushima Medical University, Fukushima, 960-1295, Japan
| | - Reiko Kimura-Tsuchiya
- Department of Medical Oncology, Fukushima Medical University, Fukushima, 960-1295, Japan
| | - Junko Suga
- Division of Cancer Genome Medicine, Cancer Center, Kyoto University Hospital, Kyoto, 606-8507, Japan
| | - Kenya Kanazawa
- Department of Pulmonary Medicine, Fukushima Medical University, Fukushima, 960-1295, Japan
| | - Tomoyuki Koguchi
- Department of Urology, Fukushima Medical University, Fukushima, 960-1295, Japan
| | - Nobuyuki Kikuchi
- Department of Dermatology, Fukushima Medical University, Fukushima, 960-1295, Japan
| | - Naoyuki Okabe
- Department of Chest Surgery, Fukushima Medical University, Fukushima, 960-1295, Japan
| | - Shigeyuki Murono
- Department of Otorhinolaryngology, Fukushima Medical University, Fukushima, 960-1295, Japan
| | - Kazunoshin Tachibana
- Department of Breast Surgery, Fukushima Medical University, Fukushima, 960-1295, Japan
| | - Shu Soeda
- Department of Obstetrics & Gynecology, Fukushima Medical University, Fukushima, 960-1295, Japan
| | - Michio Shimabukuro
- Department of Diabetes, Endocrinology & Metabolism, Fukushima Medical University, Fukushima, 960-1295, Japan
| | - Shigehira Saji
- Department of Medical Oncology, Fukushima Medical University, Fukushima, 960-1295, Japan
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20
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Stavropoulou De Lorenzo S, Andravizou A, Alexopoulos H, Michailidou I, Bokas A, Kesidou E, Boziki MK, Parissis D, Bakirtzis C, Grigoriadis N. Neurological Immune-Related Adverse Events Induced by Immune Checkpoint Inhibitors. Biomedicines 2024; 12:1319. [PMID: 38927526 PMCID: PMC11202292 DOI: 10.3390/biomedicines12061319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 06/07/2024] [Accepted: 06/11/2024] [Indexed: 06/28/2024] Open
Abstract
The use of immune checkpoint inhibitors (ICIs) for the treatment of various advanced and aggressive types of malignancy has significantly increased both survival and long-term remission rates. ICIs block crucial inhibitory pathways of the immune system, in order to trigger an aggravated immune response against the tumor. However, this enhanced immune activation leads to the development of numerous immune-related adverse events (irAEs), which may affect any system. Although severe neurological irAEs are relatively rare, they carry a high disability burden, and they can be potentially life-threatening. Therefore, clinicians must be alert and act promptly when individuals receiving ICIs present with new-onset neurological symptoms. In this narrative review, we have collected all the currently available data regarding the epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment of post-ICI neurological irAEs. This review aims to raise physicians' awareness, enrich their knowledge regarding disease pathogenesis, and guide them through the diagnosis and management of post-ICI neurological irAEs.
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Affiliation(s)
- Sotiria Stavropoulou De Lorenzo
- Second Department of Neurology, School of Medicine, Aristotle University of Thessaloniki, 54621 Thessaloniki, Greece; (S.S.D.L.); (A.A.); (I.M.); (E.K.); (M.-K.B.); (D.P.); (N.G.)
| | - Athina Andravizou
- Second Department of Neurology, School of Medicine, Aristotle University of Thessaloniki, 54621 Thessaloniki, Greece; (S.S.D.L.); (A.A.); (I.M.); (E.K.); (M.-K.B.); (D.P.); (N.G.)
| | - Harry Alexopoulos
- Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, University Campus, 15784 Athens, Greece;
| | - Iliana Michailidou
- Second Department of Neurology, School of Medicine, Aristotle University of Thessaloniki, 54621 Thessaloniki, Greece; (S.S.D.L.); (A.A.); (I.M.); (E.K.); (M.-K.B.); (D.P.); (N.G.)
| | - Alexandros Bokas
- Department of Medical Oncology, Theageneio Cancer Hospital, 54639 Thessaloniki, Greece;
| | - Evangelia Kesidou
- Second Department of Neurology, School of Medicine, Aristotle University of Thessaloniki, 54621 Thessaloniki, Greece; (S.S.D.L.); (A.A.); (I.M.); (E.K.); (M.-K.B.); (D.P.); (N.G.)
| | - Marina-Kleopatra Boziki
- Second Department of Neurology, School of Medicine, Aristotle University of Thessaloniki, 54621 Thessaloniki, Greece; (S.S.D.L.); (A.A.); (I.M.); (E.K.); (M.-K.B.); (D.P.); (N.G.)
| | - Dimitrios Parissis
- Second Department of Neurology, School of Medicine, Aristotle University of Thessaloniki, 54621 Thessaloniki, Greece; (S.S.D.L.); (A.A.); (I.M.); (E.K.); (M.-K.B.); (D.P.); (N.G.)
| | - Christos Bakirtzis
- Second Department of Neurology, School of Medicine, Aristotle University of Thessaloniki, 54621 Thessaloniki, Greece; (S.S.D.L.); (A.A.); (I.M.); (E.K.); (M.-K.B.); (D.P.); (N.G.)
| | - Nikolaos Grigoriadis
- Second Department of Neurology, School of Medicine, Aristotle University of Thessaloniki, 54621 Thessaloniki, Greece; (S.S.D.L.); (A.A.); (I.M.); (E.K.); (M.-K.B.); (D.P.); (N.G.)
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21
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Del Gaudio A, Di Vincenzo F, Petito V, Giustiniani MC, Gasbarrini A, Scaldaferri F, Lopetuso LR. Focus on Immune Checkpoint Inhibitors-related Intestinal Inflammation: From Pathogenesis to Therapeutical Approach. Inflamm Bowel Dis 2024; 30:1018-1031. [PMID: 37801695 PMCID: PMC11144981 DOI: 10.1093/ibd/izad229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Indexed: 10/08/2023]
Abstract
Recently, antitumor immunotherapies have witnessed a breakthrough with the emergence of immune checkpoint inhibitors (ICIs) including programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors. Unfortunately, the use of ICIs has also led to the advent of a novel class of adverse events that differ from those of classic chemotherapeutics and are more reminiscent of autoimmune diseases, the immune-related adverse events (IRAEs). Herein, we performed an insight of the main IRAEs associated with ICIs, focusing on gastroenterological IRAEs and specifically on checkpoint inhibitor colitis, which represents the most widely reported IRAE to date. We comprehensively dissected the current evidence regarding pathogenesis, diagnosis, and management of ICIs-induced colitis, touching upon also on innovative therapies.
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Affiliation(s)
- Angelo Del Gaudio
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
| | - Federica Di Vincenzo
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
| | - Valentina Petito
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
| | | | - Antonio Gasbarrini
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
| | - Franco Scaldaferri
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
| | - Loris Riccardo Lopetuso
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- Department of Medicine and Ageing Sciences, G. d’Annunzio University of Chieti-Pescara, Chieti, 66100, Italy
- Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, Chieti, 66100, Italy
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22
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Storgard R, Markova A. Cutaneous Hypersensitivity Reactions to Immune Checkpoint Inhibitors. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2024; 12:1132-1136. [PMID: 38548170 DOI: 10.1016/j.jaip.2024.03.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 03/25/2024] [Accepted: 03/25/2024] [Indexed: 04/14/2024]
Abstract
The introduction of immune checkpoint inhibitors (ICIs) has transformed the management of various malignancies. Alongside their therapeutic success, the widespread application of ICIs has unveiled a spectrum of immune-related adverse events (irAEs), most often affecting the skin. Cutaneous irAEs (cirAEs) encompass a range from common morbilliform and lichenoid rashes to more severe conditions such as bullous dermatoses and psoriasiform eruptions, each presenting distinct clinical challenges. Moreover, less common but clinically severe cutaneous reactions like toxic epidermal necrolysis have also been observed. cirAEs are frequently observed, with an incidence ranging from 37% to 70% for anti-cytotoxic T lymphocyte-associated antigen-4 antibodies and 17% to 40% for anti- programmed death-1/anti-programmed death ligand-1 antibodies. Recognizing the critical need for effective therapeutic strategies, this review carefully examines current approaches and guidelines for managing cirAEs.
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Affiliation(s)
- Ryan Storgard
- Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
| | - Alina Markova
- Dermatology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
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23
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Bracamonte-Baran W, Kim ST. The Current and Future of Biomarkers of Immune Related Adverse Events. Rheum Dis Clin North Am 2024; 50:201-227. [PMID: 38670721 PMCID: PMC11232920 DOI: 10.1016/j.rdc.2024.01.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/28/2024]
Abstract
With their groundbreaking clinical responses, immune checkpoint inhibitors (ICIs) have ushered in a new chapter in cancer therapeutics. However, they are often associated with life-threatening or organ-threatening autoimmune/autoinflammatory phenomena, collectively termed immune-related adverse events (irAEs). In this review, we will first describe the mechanisms of action of ICIs as well as irAEs. Next, we will review biomarkers for predicting the development of irAEs or stratifying risks.
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Affiliation(s)
- William Bracamonte-Baran
- Department of Rheumatology, Allergy & Immunology, Yale University, 300 Cedar Street, TAC S541, New Haven, CT 06520, USA
| | - Sang T Kim
- Department of Rheumatology, Allergy & Immunology, Yale University, 300 Cedar Street, TAC S541, New Haven, CT 06520, USA.
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24
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Casagrande S, Sopetto GB, Bertalot G, Bortolotti R, Racanelli V, Caffo O, Giometto B, Berti A, Veccia A. Immune-Related Adverse Events Due to Cancer Immunotherapy: Immune Mechanisms and Clinical Manifestations. Cancers (Basel) 2024; 16:1440. [PMID: 38611115 PMCID: PMC11011060 DOI: 10.3390/cancers16071440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 04/02/2024] [Accepted: 04/03/2024] [Indexed: 04/14/2024] Open
Abstract
The landscape of cancer treatment has undergone a significant transformation with the introduction of Immune Checkpoint Inhibitors (ICIs). Patients undergoing these treatments often report prolonged clinical and radiological responses, albeit with a potential risk of developing immune-related adverse events (irAEs). Here, we reviewed and discussed the mechanisms of action of ICIs and their pivotal role in regulating the immune system to enhance the anti-tumor immune response. We scrutinized the intricate pathogenic mechanisms responsible for irAEs, arising from the evasion of self-tolerance checkpoints due to drug-induced immune modulation. We also summarized the main clinical manifestations due to irAEs categorized by organ types, detailing their incidence and associated risk factors. The occurrence of irAEs is more frequent when ICIs are combined; with neurological, cardiovascular, hematological, and rheumatic irAEs more commonly linked to PD1/PD-L1 inhibitors and cutaneous and gastrointestinal irAEs more prevalent with CTLA4 inhibitors. Due to the often-nonspecific signs and symptoms, the diagnosis of irAEs (especially for those rare ones) can be challenging. The differential with primary autoimmune disorders becomes sometimes intricate, given the clinical and pathophysiological similarities. In conclusion, considering the escalating use of ICIs, this area of research necessitates additional clinical studies and practical insights, especially the development of biomarkers for predicting immune toxicities. In addition, there is a need for heightened education for both clinicians and patients to enhance understanding and awareness.
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Affiliation(s)
- Silvia Casagrande
- Unit of Neurology, Rovereto Hospital, Azienda Provinciale per i Servizi Sanitari-APSS, 38122 Trento, Italy; (S.C.); (B.G.)
| | - Giulia Boscato Sopetto
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38122 Trento, Italy; (G.B.S.); (G.B.); (V.R.)
| | - Giovanni Bertalot
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38122 Trento, Italy; (G.B.S.); (G.B.); (V.R.)
- Center for Medical Sciences (CISMed), University of Trento, 38122 Trento, Italy
- Multizonal Unit of Pathology, APSS, 38122 Trento, Italy
| | - Roberto Bortolotti
- Unit of Rheumatology, Santa Chiara Regional Hospital, APSS, 38122 Trento, Italy;
| | - Vito Racanelli
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38122 Trento, Italy; (G.B.S.); (G.B.); (V.R.)
- Center for Medical Sciences (CISMed), University of Trento, 38122 Trento, Italy
- Unit of Internal Medicine, Santa Chiara Regional Hospital, APSS, 38122 Trento, Italy
| | - Orazio Caffo
- Unit of Oncology, Santa Chiara Regional Hospital, APSS, 38122 Trento, Italy; (O.C.); (A.V.)
| | - Bruno Giometto
- Unit of Neurology, Rovereto Hospital, Azienda Provinciale per i Servizi Sanitari-APSS, 38122 Trento, Italy; (S.C.); (B.G.)
- Center for Medical Sciences (CISMed), University of Trento, 38122 Trento, Italy
- Department of Psychology and Cognitive Sciences (DIPSCO), University of Trento, 38122 Trento, Italy
| | - Alvise Berti
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38122 Trento, Italy; (G.B.S.); (G.B.); (V.R.)
- Center for Medical Sciences (CISMed), University of Trento, 38122 Trento, Italy
- Unit of Rheumatology, Santa Chiara Regional Hospital, APSS, 38122 Trento, Italy;
| | - Antonello Veccia
- Unit of Oncology, Santa Chiara Regional Hospital, APSS, 38122 Trento, Italy; (O.C.); (A.V.)
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25
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Liang Y, Maeda O, Ando Y. Biomarkers for immune-related adverse events in cancer patients treated with immune checkpoint inhibitors. Jpn J Clin Oncol 2024; 54:365-375. [PMID: 38183211 PMCID: PMC11771318 DOI: 10.1093/jjco/hyad184] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 12/12/2023] [Indexed: 01/07/2024] Open
Abstract
Although immune checkpoint inhibitors have greatly improved cancer therapy, they also cause immune-related adverse events, including a wide range of inflammatory side effects resulting from excessive immune activation. Types of immune-related adverse events are diverse and can occur in almost any organ, with different frequencies and severities. Furthermore, immune-related adverse events may occur within the first few weeks after treatment or even several months after treatment discontinuation. Predictive biomarkers include blood cell counts and cell surface markers, serum proteins, autoantibodies, cytokines/chemokines, germline genetic variations and gene expression profiles, human leukocyte antigen genotype, microRNAs and the gut microbiome. Given the inconsistencies in research results and limited practical utility, there is to date no established biomarker that can be used in routine clinical practice, and additional investigations are essential to demonstrate efficacy and subsequently facilitate integration into routine clinical use.
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Affiliation(s)
- Yao Liang
- Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Aichi, Japan
| | - Osamu Maeda
- Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Aichi, Japan
| | - Yuichi Ando
- Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, Nagoya, Aichi, Japan
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26
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Riveiro-Barciela M, Carballal S, Díaz-González Á, Mañosa M, Gallego-Plazas J, Cubiella J, Jiménez-Fonseca P, Varela M, Menchén L, Sangro B, Fernández-Montes A, Mesonero F, Rodríguez-Gandía MÁ, Rivera F, Londoño MC. Management of liver and gastrointestinal toxicity induced by immune checkpoint inhibitors: Position statement of the AEEH-AEG-SEPD-SEOM-GETECCU. GASTROENTEROLOGIA Y HEPATOLOGIA 2024; 47:401-432. [PMID: 38228461 DOI: 10.1016/j.gastrohep.2023.10.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 09/28/2023] [Accepted: 10/19/2023] [Indexed: 01/18/2024]
Abstract
The development of the immune checkpoint inhibitors (ICI) is one of the most remarkable achievements in cancer therapy in recent years. However, their exponential use has led to an increase in immune-related adverse events (irAEs). Gastrointestinal and liver events encompass hepatitis, colitis and upper digestive tract symptoms accounting for the most common irAEs, with incidence rates varying from 2% to 40%, the latter in patients undergoing combined ICIs therapy. Based on the current scientific evidence derived from both randomized clinical trials and real-world studies, this statement document provides recommendations on the diagnosis, treatment and prognosis of the gastrointestinal and hepatic ICI-induced adverse events.
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Affiliation(s)
- Mar Riveiro-Barciela
- Liver Unit, Internal Medicine Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Universitat Autònoma de Barcelona (UAB), Department of Medicine, Spain.
| | - Sabela Carballal
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Gastroenterology Department, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain; Universitat de Barcelona, Spain
| | - Álvaro Díaz-González
- Gastroenterology Department, Grupo de Investigación Clínica y Traslacional en Enfermedades Digestivas, Instituto de Investigación Valdecilla (IDIVAL), Hospital Universitario Marqués de Valdecilla, Santander, Spain
| | - Míriam Mañosa
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Gastroenterology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | | | - Joaquín Cubiella
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Gastroenterology Department, Hospital Universitario de Ourense, Grupo de Investigación en Oncología Digestiva-Ourense, Spain
| | - Paula Jiménez-Fonseca
- Medical Oncology Department, Hospital Universitario Central de Asturias, ISPA, Oviedo, Spain
| | - María Varela
- Gastroenterology Department, Hospital Universitario Central de Asturias, IUOPA, ISPA, FINBA, University of Oviedo, Oviedo, Spain
| | - Luis Menchén
- Servicio de Aparato Digestivo - CEIMI, Instituto de Investigación Sanitaria Gregorio, Marañón, Spain; Departamento de Medicina, Universidad Complutense, Madrid, Spain
| | - Bruno Sangro
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Liver Unit, Cancer Center Clinica Universidad de Navarra, Pamplona-Madrid, Spain
| | - Ana Fernández-Montes
- Medical Oncology Department, Complexo Hospitalario Universitario de Ourense, Ourense, Spain
| | - Francisco Mesonero
- Gastroenterology and Hepatology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain; Universidad de Alcalá de Henares, Spain
| | - Miguel Ángel Rodríguez-Gandía
- Gastroenterology and Hepatology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRyCIS), Madrid, Spain
| | - Fernando Rivera
- Medical Oncology Department, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain
| | - María-Carlota Londoño
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Universitat de Barcelona, Spain; Liver Unit, Hospital Clínic Barcelona, Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Spain
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27
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Suijkerbuijk KPM, van Eijs MJM, van Wijk F, Eggermont AMM. Clinical and translational attributes of immune-related adverse events. NATURE CANCER 2024; 5:557-571. [PMID: 38360861 DOI: 10.1038/s43018-024-00730-3] [Citation(s) in RCA: 37] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 01/12/2024] [Indexed: 02/17/2024]
Abstract
With immune checkpoint inhibitors (ICIs) becoming the mainstay of treatment for many cancers, managing their immune-related adverse events (irAEs) has become an important part of oncological care. This Review covers the clinical presentation of irAEs and crucial aspects of reversibility, fatality and long-term sequelae, with special attention to irAEs in specific patient populations, such as those with autoimmune diseases. In addition, the genetic basis of irAEs, along with cellular and humoral responses to ICI therapy, are discussed. Detrimental effects of empirically used high-dose steroids and second-line immunosuppression, including impaired ICI effectiveness, call for more tailored irAE-treatment strategies. We discuss open therapeutic challenges and propose potential avenues to accelerate personalized management strategies and optimize outcomes.
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Affiliation(s)
- Karijn P M Suijkerbuijk
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.
| | - Mick J M van Eijs
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Femke van Wijk
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Alexander M M Eggermont
- University Medical Center Utrecht and Princess Máxima Center, Utrecht, the Netherlands
- Comprehensive Cancer Center Munich of the Technical University of Munich and the Ludwig Maximilian University, Munich, Germany
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Lin X, Xie M, Yao J, Ma X, Qin L, Zhang X, Song J, Bao X, Zhang X, Zhang Y, Liu Y, Han W, Liang Y, Jing Y, Xue X. Immune-related adverse events in non-small cell lung cancer: Occurrence, mechanisms and therapeutic strategies. Clin Transl Med 2024; 14:e1613. [PMID: 38451000 PMCID: PMC10918746 DOI: 10.1002/ctm2.1613] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 02/13/2024] [Accepted: 02/18/2024] [Indexed: 03/08/2024] Open
Abstract
The emergence of immune checkpoint inhibitors (ICIs) has heralded a transformative era in the therapeutic landscape of non-small cell lung cancer (NSCLC). While ICIs have demonstrated clinical efficacy in a portion of patients with NSCLC, these treatments concurrently precipitate a spectrum of immune-related adverse events (irAEs), encompassing mild to severe manifestations, collectively posing a risk of significant organ damage. Consequently, there exists an imperative to augment our comprehension of the pathophysiological underpinnings of irAEs and to formulate more efficacious preventive and ameliorative strategies. In this comprehensive review, we delineate the clinical presentation of organ-specific irAEs in patients with NSCLC and provide an in-depth analysis of recent advancements in understanding the mechanisms driving ICI-induced toxicity. Furthermore, we discuss potential strategies and targets for ameliorating these irAEs. Ultimately, this review aims to furnish valuable insights to guide further research endeavours in the context of irAEs in NSCLC patients.
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Affiliation(s)
- Xuwen Lin
- Department of Respiratory and Critical CareEmergency and Critical Care Medical CenterBeijing Shijitan HospitalCapital Medical UniversityBeijingChina
| | - Mei Xie
- Department of Respiratory and Critical CareChinese PLA General HospitalBeijingChina
| | - Jie Yao
- Department of Respiratory and Critical CareEmergency and Critical Care Medical CenterBeijing Shijitan HospitalCapital Medical UniversityBeijingChina
| | - Xidong Ma
- Department of Respiratory and Critical CareEmergency and Critical Care Medical CenterBeijing Shijitan HospitalCapital Medical UniversityBeijingChina
| | - Lin Qin
- Department of Endoscopic Diagnosis and TreatmentTuberculosis and Thoracic Tumor InstituteBeijing Chest HospitalCapital Medical UniversityBeijingChina
| | - Xu‐Mei Zhang
- Department of PathologyAffiliated Hospital of Weifang Medical UniversityWeifangShandongChina
| | - Jialin Song
- Department of Respiratory and Critical CareShandong Second Medical UniversityShandongChina
| | - Xinyu Bao
- Department of Respiratory and Critical CareShandong Second Medical UniversityShandongChina
| | - Xin Zhang
- Department of Respiratory and Critical CareShandong Second Medical UniversityShandongChina
| | - Yinguang Zhang
- Department of Thoracic SurgeryBeijing Tiantan HospitalCapital Medical UniversityBeijingChina
| | - Yiming Liu
- Department of Thoracic SurgeryChinese PLA General HospitalBeijingChina
| | - Wenya Han
- Department of Respiratory and Critical CareTaihe HospitalHubei University of MedicineShiyanChina
| | - Yiran Liang
- Department of Respiratory and Critical CareEmergency and Critical Care Medical CenterBeijing Shijitan HospitalCapital Medical UniversityBeijingChina
| | - Ying Jing
- Center for Intelligent MedicineGreater Bay Area Institute of Precision Medicine (Guangzhou)School of Life SciencesFudan UniversityGuangzhouGuangdongChina
| | - Xinying Xue
- Department of Respiratory and Critical CareEmergency and Critical Care Medical CenterBeijing Shijitan HospitalCapital Medical UniversityBeijingChina
- Department of Respiratory and Critical CareShandong Second Medical UniversityShandongChina
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Velikova T, Krastev B, Gulinac M, Zashev M, Graklanov V, Peruhova M. New strategies in the diagnosis and treatment of immune-checkpoint inhibitor-mediated colitis. World J Clin Cases 2024; 12:1050-1062. [PMID: 38464930 PMCID: PMC10921308 DOI: 10.12998/wjcc.v12.i6.1050] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/20/2023] [Accepted: 01/19/2024] [Indexed: 02/20/2024] Open
Abstract
Immune-checkpoint inhibitor-mediated colitis (IMC) is an increasingly recognized adverse event in cancer immunotherapy, particularly associated with immune checkpoint inhibitors (ICIs) such as anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed cell death protein-1 antibodies. As this revolutionary immunotherapy gains prominence in cancer treatment, understanding, diagnosing, and effectively managing IMC becomes paramount. IMC represents a unique challenge due to its immune-mediated nature and potential for severe complications. However, a precise picture of IMC pathophysiology is currently unavailable. Therefore, we aimed to summarize the existing data while acknowledging the need for further research. This comprehensive review explores the mechanisms underlying ICIs, gastrointestinal adverse effects, and, in particular, IMC's incidence, prevalence, and features. Our review also emphasizes the importance of recognizing IMC's distinct clinical and histopathological features to differentiate it from other forms of colitis. Furthermore, this paper highlights the urgent need for evolving diagnostic methods, therapeutic strategies, and a multidisciplinary approach to effectively manage IMC.
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Affiliation(s)
- Tsvetelina Velikova
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
| | - Boris Krastev
- Medical Center Nadezhda, Medical Center Nadezhda, Sofia 1407, Bulgaria
| | - Milena Gulinac
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
- General and Clinical Pathology, Medical University of Plovdiv, Plovdiv 4002, Bulgaria
| | - Miroslav Zashev
- Department of General Surgery, University Hospital “Heart and Brain”, Burgas 8000, Bulgaria
| | - Vasko Graklanov
- First Department of Internal Diseases, Medical University of Plovdiv, Plovdiv 4000, Bulgaria
- Department of Hematology, University Hospital “St. George”, Plovdiv 4000, Bulgaria
| | - Milena Peruhova
- Division of Gastroenterology, University Hospital “Heart and Brain”, Burgas 1000, Bulgaria
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Rogiers A, Dimitriou F, Lobon I, Harvey C, Vergara IA, Pires da Silva I, Lo SN, Scolyer RA, Carlino MS, Menzies AM, Long GV. Seasonal patterns of toxicity in melanoma patients treated with combination anti-PD-1 and anti-CTLA-4 immunotherapy. Eur J Cancer 2024; 198:113506. [PMID: 38184928 DOI: 10.1016/j.ejca.2023.113506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 12/06/2023] [Accepted: 12/19/2023] [Indexed: 01/09/2024]
Abstract
BACKGROUND Immune checkpoint inhibitors are frequently associated with the development of immunotherapy-related adverse events (irAEs). The exact etiology, including the role of environmental factors, remains incompletely understood. METHODS We analyzed the records of 394 melanoma patients from three centers (northern and southern hemisphere). Patients had received at least one cycle of anti-PD-1/anti-CTLA-4 with a minimum follow-up of 3 months. We study the distribution and time to irAEs onset throughout the calendar year. RESULTS 764 irAEs were recorded; the most frequent were skin rash (35%), hepatitis (32%) and colitis (30%). The irAEs incidence was the highest in autumn and winter, and the ratio for the 'number of irAEs' per 'therapies commenced' was the highest in winter and lowest in summer (2.4 and 1.7, respectively). Season-specific patterns in the time of irAEs onset were observed for pneumonitis (shorter time to onset in autumn, p = 0.025), hepatitis (shorter time to onset in spring, p = 0.016) and sarcoid-like immune reaction (shorter time to onset in autumn, p = 0.041). Season-specific patterns for early-onset irAEs were observed for hepatitis (spring, p = 0.023) and nephritis (summer, p = 0.017). Early-onset pneumonitis was more frequent in autumn-winter (p = 0.008) and early-onset nephritis in spring-summer (p = 0.004). CONCLUSIONS Environmental factors that are associated with particular seasons may contribute to the development of certain irAEs and suggest the potential effect of environmental triggers. The identification of these factors may enhance preventive and therapeutic strategies to reduce the morbidity of irAEs.
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Affiliation(s)
- Aljosja Rogiers
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Florentia Dimitriou
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Department of Dermatology, University Hospital of Zurich, Zurich, Switzerland; Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Irene Lobon
- Cancer Dynamics Laboratory, The Francis Crick Institute, London, United Kingdom
| | - Catriona Harvey
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Charles Perkin Centre, The University of Sydney, Sydney, NSW, Australia
| | - Ismael A Vergara
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Charles Perkin Centre, The University of Sydney, Sydney, NSW, Australia
| | - Ines Pires da Silva
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Westmead and Blacktown Hospitals, Sydney, New South Wales, Australia
| | - Serigne N Lo
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Richard A Scolyer
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia
| | - Matteo S Carlino
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Westmead and Blacktown Hospitals, Sydney, New South Wales, Australia
| | - Alexander M Menzies
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, NSW, Australia
| | - Georgina V Long
- Melanoma Institute Australia, The University of Sydney, Sydney, New South Wales, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; Department of Medical Oncology, Royal North Shore and Mater Hospitals, Sydney, NSW, Australia.
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Riveiro-Barciela M, Carballal S, Díaz-González Á, Mañosa M, Gallgo-Plazas J, Cubiella J, Jiménez-Fonseca P, Varela M, Menchén L, Sangro B, Fernández-Montes A, Mesonero F, Rodríguez-Gandía MÁ, Rivera F, Londoño MC. Management of liver and gastrointestinal toxicity induced by immune checkpoint inhibitors: Position statement of the AEEH-AEG-SEPD-SEOM-GETECCU. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2024; 116:83-113. [PMID: 38226597 DOI: 10.17235/reed.2024.10250/2024] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2024]
Abstract
The development of the immune checkpoint inhibitors (ICI) is one of the most remarkable achievements in cancer therapy in recent years. However, their exponential use has led to an increase in immune-related adverse events (irAEs). Gastrointestinal and liver events encompass hepatitis, colitis and upper digestive tract symptoms accounting for the most common irAEs, with incidence rates varying from 2 % to 40 %, the latter in patients undergoing combined ICIs therapy. Based on the current scientific evidence derived from both randomized clinical trials and real-world studies, this statement document provides recommendations on the diagnosis, treatment and prognosis of the gastrointestinal and hepatic ICI-induced adverse events.
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Affiliation(s)
| | | | | | - Miriam Mañosa
- Gastroenterology, Hospital Universitari Germans Trias i Pujol
| | | | | | | | - María Varela
- Gastroenterology, Hospital Universitario Central de Asturias
| | - Luis Menchén
- Digestive Diseases, Instituto de Investigación Sanitaria Gregorio Marañón
| | | | | | | | | | - Fernando Rivera
- Hospital Universitario Marqués de Valdecilla, Medical Oncology
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Gandarillas S, Newland ES, Toppmeyer D, Stephenson R, Denzin L, Dasgeb B. HLA inherence as a potential parameter in checkpoint inhibitor-associated autoimmune adverse event assessment. Front Med (Lausanne) 2024; 10:1288844. [PMID: 38259857 PMCID: PMC10800809 DOI: 10.3389/fmed.2023.1288844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 12/11/2023] [Indexed: 01/24/2024] Open
Abstract
Background The success of immunotherapy has made it a lifesaving treatment, but not without side effects. Currently, the risk factors for developing immune-related adverse events (irAEs) in patients who receive immunotherapy are poorly understood, and there is no risk-stratifying mechanism for potentially fatal irAEs. It is postulated that oncology patients with preexisting autoimmune diseases are likely to have flares on immunotherapy. However, some patients develop de novo autoimmune conditions on immunotherapy without a prior history. Literature reports have postulated that human leukocyte antigen (HLA) inherence may play a role in irAEs. However, this potential remains underexplored. Methods The oncology patients who developed autoimmune adverse events on immunotherapy for whom the continuation of treatment was prudent or lifesaving were selected. Of note, all nine patients received checkpoint inhibitors (CIs). Of the nine selected patients, only one had a prior history of an autoimmune condition. None of the nine selected patients had an active autoimmune condition at the time of CI initiation. Their HLA was typed, and the results were cross-referenced with the literature reports in PubMed and Google search with the corresponding autoimmune condition of each patient. Results Herein, we report nine patients with irAEs for whom retrospective HLA typing revealed the inherence of multiple related HLA alleles that may correspond to the autoimmune condition that they had developed on immunotherapy. It is to be mentioned that the inherence of enriched disease-related HLA alleles was shared among patients with the same irAEs. These patients developed a range of irAEs including bullous pemphigoid, pemphigus foliaceus/vulgaris, thyroiditis, vitiligo, and hepatitis on immunotherapy. Although some combinations of disease-related HLA were well reported in otherwise idiopathic autoimmune diseases, a frequently repeated HLA allele combination in our patient population was found to be rarely seen in the general population. Conclusion The authors suggest that an enriched inherence of disease-related HLA alleles may play a role in the genetic propensity for the development of irAEs in oncology patients, who receive immunotherapy, including CIs. Inherence of more than one or a cluster of particular autoimmune disease-related HLA alleles in patients who receive immunotherapy may unmask the corresponding autoimmune disease as the genotype inherence presents with the phenotype of the corresponding condition. It is suggested that enriched linked HLA genotypes, which are otherwise rare in the general population, may present as the corresponding phenotype of the autoimmune condition. Such clinical presentation, enhanced by immunotherapy, such as CIs, can play a role in risk stratifying patients for precision medicine and improve the outcome.
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Affiliation(s)
- Sophia Gandarillas
- Department of Dermatology, Wayne State University, Detroit, MI, United States
| | | | - Deborah Toppmeyer
- Department of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States
| | - Ryan Stephenson
- Department of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States
| | - Lisa Denzin
- Department of Pediatrics, Child Health Institute of New Jersey, Rutgers Medical School, New Brunswick, NJ, United States
| | - Bahar Dasgeb
- Department of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States
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Jiang CY, Zhao L, Green MD, Ravishankar S, Towlerton AMH, Scott AJ, Raghavan M, Cusick MF, Warren EH, Ramnath N. Class II HLA-DRB4 is a predictive biomarker for survival following immunotherapy in metastatic non-small cell lung cancer. Sci Rep 2024; 14:345. [PMID: 38172168 PMCID: PMC10764770 DOI: 10.1038/s41598-023-48546-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 11/28/2023] [Indexed: 01/05/2024] Open
Abstract
Immune checkpoint inhibitors (ICI) are important treatment options for metastatic non-small cell lung cancer (mNSCLC). However, not all patients benefit from ICIs and can experience immune-related adverse events (irAEs). Limited understanding exists for germline determinants of ICI efficacy and toxicity, but Human Leukocyte Antigen (HLA) genes have emerged as a potential predictive biomarker. We performed HLA typing on 85 patients with mNSCLC, on ICI therapy and analyzed the impact of HLA Class II genotype on progression free survival (PFS), overall survival (OS), and irAEs. Most patients received pembrolizumab (83.5%). HLA-DRB4 genotype was seen in 34/85 (40%) and its presence correlated with improved OS in both univariate (p = 0.022; 26.3 months vs 10.2 months) and multivariate analysis (p = 0.011, HR 0.49, 95% CI [0.29, 0.85]). PFS did not reach significance (univariate, p = 0.12, 8.2 months vs 5.1 months). Eleven patients developed endocrine irAEs. HLA-DRB4 was the predominant genotype among these patients (9/11, 81.8%). Cumulative incidence of endocrine irAEs was higher in patients with HLA-DRB4 (p = 0.0139). Our study is the first to suggest that patients with metastatic NSCLC patients on ICI therapy with HLA-DRB4 genotype experience improved survival outcomes. Patients with HLA-DRB4 had the longest median OS (26.3 months). Additionally, we found a correlation between HLA-DRB4 and the occurrence of endocrine irAEs.
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Affiliation(s)
- Cindy Y Jiang
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
- Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Lili Zhao
- Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA
| | - Michael D Green
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA
| | | | - Andrea M H Towlerton
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Anthony J Scott
- Division of Clinical Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Malini Raghavan
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA
| | - Matthew F Cusick
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Edus H Warren
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Nithya Ramnath
- Lieutenant Colonel Charles S. Kettles VA Medical Center (VA Ann Arbor Health System), 2215 Fuller Ave, Ann Arbor, MI, 48105, USA.
- Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
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Farina A, Villagrán-García M, Vogrig A, Zekeridou A, Muñiz-Castrillo S, Velasco R, Guidon AC, Joubert B, Honnorat J. Neurological adverse events of immune checkpoint inhibitors and the development of paraneoplastic neurological syndromes. Lancet Neurol 2024; 23:81-94. [PMID: 38101905 DOI: 10.1016/s1474-4422(23)00369-1] [Citation(s) in RCA: 34] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 09/14/2023] [Accepted: 09/20/2023] [Indexed: 12/17/2023]
Abstract
Immune checkpoint inhibitors, a class of oncological treatments that enhance antitumour immunity, can trigger neurological adverse events closely resembling paraneoplastic neurological syndromes. Unlike other neurological adverse events caused by these drugs, post-immune checkpoint inhibitor paraneoplastic neurological syndromes predominantly affect the CNS and are associated with neural antibodies and cancer types commonly found also in spontaneous paraneoplastic neurological syndromes. Furthermore, post-immune checkpoint inhibitor paraneoplastic neurological syndromes have poorer neurological outcomes than other neurological adverse events of immune checkpoint inhibitors. Early diagnosis and initiation of immunosuppressive therapy are likely to be crucial in preventing the accumulation of neurological disability. Importantly, the neural antibodies found in patients with post-immune checkpoint inhibitor paraneoplastic neurological syndromes are sometimes detected before treatment, indicating that these antibodies might help to predict the development of neurological adverse events. Experimental and clinical evidence suggests that post-immune checkpoint inhibitor paraneoplastic neurological syndromes probably share immunological features with spontaneous paraneoplastic syndromes. Hence, the study of post-immune checkpoint inhibitor paraneoplastic neurological syndromes can help in deciphering the immunopathogenesis of paraneoplastic neurological syndromes and in identifying novel therapeutic targets.
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Affiliation(s)
- Antonio Farina
- Reference Centre for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Neurological Hospital, Bron, France; MeLiS, UCBL-CNRS UMR 5284, INSERM U1314, Université Claude Bernard Lyon 1, Lyon, France; Department of Neuroscience, Psychology, Pharmacology and Child Health, University of Florence, Florence, Italy
| | - Macarena Villagrán-García
- Reference Centre for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Neurological Hospital, Bron, France; MeLiS, UCBL-CNRS UMR 5284, INSERM U1314, Université Claude Bernard Lyon 1, Lyon, France
| | - Alberto Vogrig
- Clinical Neurology, Santa Maria della Misericordia University Hospital, Azienda Sanitaria Universitaria Friuli Centrale (ASU FC), Udine, Italy; Department of Medicine (DAME), University of Udine Medical School, Udine, Italy
| | - Anastasia Zekeridou
- Department of Neurology, Mayo Clinic, Rochester, MN, USA; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Sergio Muñiz-Castrillo
- Reference Centre for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Neurological Hospital, Bron, France; MeLiS, UCBL-CNRS UMR 5284, INSERM U1314, Université Claude Bernard Lyon 1, Lyon, France; Stanford Center for Sleep Sciences and Medicine, Palo Alto, CA, USA
| | - Roser Velasco
- Neuro-Oncology Unit, Hospital Universitari de Bellvitge-Institut Català d Oncologia L'Hospitalet, Institut d'Investigació Biomèdica de Bellvitge, l'Hospitalet de Llobregat, Barcelona, Spain; Institute of Neurosciences and Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Amanda C Guidon
- Harvard Medical School, Boston, MA, USA; Division of Neuromuscular Medicine, Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
| | - Bastien Joubert
- Reference Centre for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Neurological Hospital, Bron, France; MeLiS, UCBL-CNRS UMR 5284, INSERM U1314, Université Claude Bernard Lyon 1, Lyon, France; Department of Neurology, Hôpital Lyon Sud, Hospices Civils de Lyon, Lyon, France
| | - Jérôme Honnorat
- Reference Centre for Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Neurological Hospital, Bron, France; MeLiS, UCBL-CNRS UMR 5284, INSERM U1314, Université Claude Bernard Lyon 1, Lyon, France.
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de Joode K, Heersche N, Basak EA, Bins S, van der Veldt AAM, van Schaik RHN, Mathijssen RHJ. Review - The impact of pharmacogenetics on the outcome of immune checkpoint inhibitors. Cancer Treat Rev 2024; 122:102662. [PMID: 38043396 DOI: 10.1016/j.ctrv.2023.102662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 11/22/2023] [Accepted: 11/23/2023] [Indexed: 12/05/2023]
Abstract
The development of immune checkpoint inhibitors (ICIs) has a tremendous effect on the treatment options for multiple types of cancer. Nonetheless, there is a large interpatient variability in response, survival, and the development of immune-related adverse events (irAEs). Pharmacogenetics is the general term for germline genetic variations, which may cause the observed interindividual differences in response or toxicity to treatment. These genetic variations can either be single-nucleotide polymorphisms (SNPs) or structural variants, such as gene deletions, amplifications or rearrangements. For ICIs, pharmacogenetic variation in the human leukocyte antigen molecules has also been studied with regard to treatment outcome. This review presents a summary of the literature regarding the pharmacogenetics of ICI treatment, discusses the most important known genetic variations and offers recommendations on the application of pharmacogenetics for ICI treatment.
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Affiliation(s)
- Karlijn de Joode
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Niels Heersche
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Department of Clinical Chemistry, Erasmus MC, Erasmus University Hospital, Rotterdam, the Netherlands
| | - Edwin A Basak
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Sander Bins
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - Astrid A M van der Veldt
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands; Department of Radiology & Nuclear Medicine, Erasmus MC, Erasmus University Hospital, Rotterdam, the Netherlands
| | - Ron H N van Schaik
- Department of Clinical Chemistry, Erasmus MC, Erasmus University Hospital, Rotterdam, the Netherlands
| | - Ron H J Mathijssen
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
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Rong Y, Bentley JP, Bhattacharya K, Yang Y, Chang Y, Earl S, Ramachandran S. Incidence and risk factors of immune-related adverse events induced by immune checkpoint inhibitors among older adults with non-small cell lung cancer. Cancer Med 2024; 13:e6879. [PMID: 38164655 PMCID: PMC10807682 DOI: 10.1002/cam4.6879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 10/31/2023] [Accepted: 12/16/2023] [Indexed: 01/03/2024] Open
Abstract
BACKGROUND Immune checkpoint inhibitor (ICI) treatment has been linked to a variety of immune-related adverse events (irAEs), which can affect any organ system. The incidence and risk factors of irAEs have not been adequately evaluated among older adults with NSCLC. METHODS A cohort study was conducted using 1999-2019 SEER-Medicare data among beneficiaries aged ≥65 years with a diagnosis of NSCLC who received nivolumab, pembrolizumab, or atezolizumab. Incident irAEs were identified post-ICI initiation. Demographic, cancer-related characteristics, and clinical history risk factors of irAEs were evaluated with competing events considered. RESULTS A total of 8175 older NSCLC patients were included (with 46.8% experiencing irAEs). Pneumonitis (16.5%), hypothyroidism (10.5%), arrhythmia (11.18%), and acute kidney injury (AKI) (5.8%) were the most common irAEs. The median time to first irAE was 82 days (IQR: 29-182 days). The earliest onset of irAE occurrence was for hematologic irAEs, while the latest were gastrointestinal, dermatologic, and musculoskeletal irAEs. Fine-Gray regression modeling revealed significantly greater hazards of irAE occurrence in patients who received pembrolizumab at index, did not have CNS metastases, had a history of autoimmune disorder, and had chemotherapy in combination with ICI. Race, socioeconomic status, previous radiation therapy, and comorbidity burden were found to be associated with the occurrence of certain type of irAEs. CONCLUSION A significant proportion of older patients with NSCLC develop an irAE after receiving ICI treatment. Factors related to cancer and treatment as well as demographics contribute to the increased risk of irAEs. Close monitoring and prediction of irAE among older patients receiving ICI is warranted.
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Affiliation(s)
- Yiran Rong
- Department of Pharmacy AdministrationUniversity of MississippiUniversityMississippiUSA
| | - John P. Bentley
- Department of Pharmacy AdministrationUniversity of MississippiUniversityMississippiUSA
- Center for Pharmaceutical Marketing and ManagementCenter for Pharmaceutical Marketing and ManagementUniversity of MississippiUniversityMississippiUSA
| | - Kaustuv Bhattacharya
- Department of Pharmacy AdministrationUniversity of MississippiUniversityMississippiUSA
- Center for Pharmaceutical Marketing and ManagementCenter for Pharmaceutical Marketing and ManagementUniversity of MississippiUniversityMississippiUSA
| | - Yi Yang
- Department of Pharmacy AdministrationUniversity of MississippiUniversityMississippiUSA
| | - Yunhee Chang
- Department of Nutrition and Hospitality ManagementUniversity of MississippiUniversityMississippiUSA
| | - Sally Earl
- Department of Pharmacy PracticeUniversity of MississippiUniversityMississippiUSA
| | - Sujith Ramachandran
- Department of Pharmacy AdministrationUniversity of MississippiUniversityMississippiUSA
- Center for Pharmaceutical Marketing and ManagementCenter for Pharmaceutical Marketing and ManagementUniversity of MississippiUniversityMississippiUSA
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Zhou Y, Ding S. Key Determinants of Immune-Mediated Adverse Reactions to Oncology Drugs. Cancers (Basel) 2023; 15:5622. [PMID: 38067327 PMCID: PMC10705334 DOI: 10.3390/cancers15235622] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 11/23/2023] [Accepted: 11/23/2023] [Indexed: 06/16/2024] Open
Abstract
To overcome the epidemiological severity of cancer, developing effective treatments is urgently required. In response, immune checkpoint inhibitors (ICIs) have been revealed as a promising resolution for treatment-resistant cancers across the world. Yet, they have both advantages and disadvantages, bringing therapeutic benefits while simultaneously inducing toxicity, and in particular, immune-mediated adverse drug reactions (imADRs), to the human body. These imADRs can be pathogenic and sometimes lethal, hampering health prediction and monitoring following the provision of ICI treatment. Therefore, it is necessary to collectively identify the determinant factors that contribute to these imADRs induced by ICIs. This article evaluated treatment-, tumor-, and patient-related determinants, and indicated a research gap for future investigations on the pathogenic mechanism of imADRs and translational conversion of determinants into clinical biomarkers to aid pharmacovigilance and cancer therapies.
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Affiliation(s)
- Yihan Zhou
- Medical Sciences Division, Department of Oncology, University of Oxford, Old Road Campus Building, Roosevelt Drive, Oxford OX3 7DQ, UK
| | - Shan Ding
- Department of Life Science, Imperial College London, South Kensington Campus, Exhibition Road, London SW7 2AZ, UK;
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Ding P, Liu P, Meng L, Zhao Q. Mechanisms and biomarkers of immune-related adverse events in gastric cancer. Eur J Med Res 2023; 28:492. [PMID: 37936161 PMCID: PMC10631148 DOI: 10.1186/s40001-023-01365-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 09/12/2023] [Indexed: 11/09/2023] Open
Abstract
Immune-checkpoint inhibitors (ICIs), different from traditional cancer treatment models, have shown unprecedented anti-tumor effects in the past decade, greatly improving the prognosis of many malignant tumors in clinical practice. At present, the most widely used ICIs in clinical immunotherapy for a variety of solid tumors are monoclonal antibodies against cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed cell death protein 1 (PD-1) and their ligand PD-L1. However, tumor patients may induce immune-related adverse events (irAEs) while performing immunotherapy, and irAE is an obstacle to the prospect of ICI treatment. IrAE is a non-specific disease caused by immune system imbalance, which can occur in many tissues and organs. For example, skin, gastrointestinal tract, endocrine system and lung. Although the exact mechanism is not completely clear, related studies have shown that irAE may develop through many ways. Such as excessive activation of autoreactive T cells, excessive release of inflammatory cytokines, elevated levels of autoantibodies, and common antigens between tumors and normal tissues. Considering that the occurrence of severe IrAE not only causes irreversible damage to the patient's body, but also terminates immunotherapy due to immune intolerance. Therefore, accurate identification and screening of sensitive markers of irAE are the main beneficiaries of ICI treatment. Additionally, irAEs usually require specific management, the most common of which are steroids and immunomodulatory therapies. This review aims to summarize the current biomarkers for predicting irAE in gastric cancer and their possible mechanisms.
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Affiliation(s)
- Ping'an Ding
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, Hebei, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, 050011, China
| | - Pengpeng Liu
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, Hebei, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, 050011, China
| | - Lingjiao Meng
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, 050011, China.
- Research Center of the Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, China.
| | - Qun Zhao
- The Third Department of Surgery, the Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, Hebei, China.
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, 050011, China.
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Marks ME, Botta RK, Abe R, Beachkofsky TM, Boothman I, Carleton BC, Chung WH, Cibotti RR, Dodiuk-Gad RP, Grimstein C, Hasegawa A, Hoofnagle JH, Hung SI, Kaffenberger B, Kroshinsky D, Lehloenya RJ, Martin-Pozo M, Micheletti RG, Mockenhaupt M, Nagao K, Pakala S, Palubinsky A, Pasieka HB, Peter J, Pirmohamed M, Reyes M, Saeed HN, Shupp J, Sukasem C, Syu JY, Ueta M, Zhou L, Chang WC, Becker P, Bellon T, Bonnet K, Cavalleri G, Chodosh J, Dewan AK, Dominguez A, Dong X, Ezhkova E, Fuchs E, Goldman J, Himed S, Mallal S, Markova A, McCawley K, Norton AE, Ostrov D, Phan M, Sanford A, Schlundt D, Schneider D, Shear N, Shinkai K, Tkaczyk E, Trubiano JA, Volpi S, Bouchard CS, Divito SJ, Phillips EJ. Updates in SJS/TEN: collaboration, innovation, and community. Front Med (Lausanne) 2023; 10:1213889. [PMID: 37901413 PMCID: PMC10600400 DOI: 10.3389/fmed.2023.1213889] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 07/31/2023] [Indexed: 10/31/2023] Open
Abstract
Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) is a predominantly drug-induced disease, with a mortality rate of 15-20%, that engages the expertise of multiple disciplines: dermatology, allergy, immunology, clinical pharmacology, burn surgery, ophthalmology, urogynecology, and psychiatry. SJS/TEN has an incidence of 1-5/million persons per year in the United States, with even higher rates globally. One of the challenges of SJS/TEN has been developing the research infrastructure and coordination to answer questions capable of transforming clinical care and leading to improved patient outcomes. SJS/TEN 2021, the third research meeting of its kind, was held as a virtual meeting on August 28-29, 2021. The meeting brought together 428 international scientists, in addition to a community of 140 SJS/TEN survivors and family members. The goal of the meeting was to brainstorm strategies to support the continued growth of an international SJS/TEN research network, bridging science and the community. The community workshop section of the meeting focused on eight primary themes: mental health, eye care, SJS/TEN in children, non-drug induced SJS/TEN, long-term health complications, new advances in mechanisms and basic science, managing long-term scarring, considerations for skin of color, and COVID-19 vaccines. The meeting featured several important updates and identified areas of unmet research and clinical need that will be highlighted in this white paper.
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Affiliation(s)
- Madeline E. Marks
- Center for Drug Interactions and Immunology, Division of Infectious Disease, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Ramya Krishna Botta
- Center for Drug Interactions and Immunology, Division of Infectious Disease, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Riichiro Abe
- Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Thomas M. Beachkofsky
- Departments of Dermatology and Medicine, Uniformed Services University, Bethesda, MD, United States
| | - Isabelle Boothman
- The SFI Centre for Research Training in Genomics Data Science, Dublin, Ireland
| | - Bruce C. Carleton
- Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, University of British Columbia and the British Columbia Children’s Hospital Research Institute, Vancouver, BC, Canada
| | - Wen-Hung Chung
- Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Ricardo R. Cibotti
- National Institute of Arthritis and Musculoskeletal and Skin (NIAMS), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Roni P. Dodiuk-Gad
- Department of Dermatology, Emek Medical Center, Afula, Israel
- Division of Dermatology, Department of Medicine, University of Toronto, Toronto, ON, Canada
- Department of Dermatology, Bruce Rappaport Faculty of Medicine, Technion Institute of Technology, Haifa, Israel
| | - Christian Grimstein
- Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, United States
| | - Akito Hasegawa
- Division of Dermatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Jay H. Hoofnagle
- Liver Disease Research Branch, Division of Digestive Diseases and Nutrition of NIDDK, National Institutes of Health (NIH), Bethesda, MD, United States
| | - Shuen-Iu Hung
- Cancer Vaccine and Immune Cell Therapy Core Laboratory, Department of Medical Research, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Benjamin Kaffenberger
- Department of Dermatology, Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Daniela Kroshinsky
- Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Rannakoe J. Lehloenya
- Division of Dermatology, Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Michelle Martin-Pozo
- Center for Drug Interactions and Immunology, Division of Infectious Disease, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Robert G. Micheletti
- Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Maja Mockenhaupt
- Dokumentationszentrum schwerer Hautreaktionen (dZh), Department of Dermatology, Medical Center and Medical Faculty, University of Freiburg, Freiburg, Germany
| | - Keisuke Nagao
- National Institute of Arthritis and Musculoskeletal and Skin (NIAMS), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Suman Pakala
- Center for Drug Interactions and Immunology, Division of Infectious Disease, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Amy Palubinsky
- Center for Drug Interactions and Immunology, Division of Infectious Disease, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Helena B. Pasieka
- Departments of Dermatology and Medicine, Uniformed Services University, Bethesda, MD, United States
- The Burn Center, MedStar Washington Hospital Center, Washington, D.C., DC, United States
- Department of Dermatology, MedStar Health/Georgetown University, Washington, D.C., DC, United States
| | - Jonathan Peter
- Division of Allergy and Clinical Immunology, Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Munir Pirmohamed
- Department of Pharmacology and Therapeutics, University of Liverpool, Liverpool, United Kingdom
| | - Melissa Reyes
- Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, United States
| | - Hajirah N. Saeed
- Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, United States
| | - Jeffery Shupp
- Department of Surgery, Plastic and Reconstructive Surgery, Biochemistry, and Molecular and Cellular Biology, MedStar Washington Hospital Center, Georgetown University School of Medicine, Washington, D.C., DC, United States
| | - Chonlaphat Sukasem
- Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Jhih Yu Syu
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Mayumi Ueta
- Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Li Zhou
- Division of General Internal Medicine and Primary Care, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Wan-Chun Chang
- Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, University of British Columbia and the British Columbia Children’s Hospital Research Institute, Vancouver, BC, Canada
| | - Patrice Becker
- Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Disease, Bethesda, MD, United States
| | - Teresa Bellon
- Drug Hypersensitivity Laboratory, La Paz Health Research Institute (IdiPAZ), Madrid, Spain
| | - Kemberlee Bonnet
- Department of Psychology, Vanderbilt University, Nashville, TN, United States
| | - Gianpiero Cavalleri
- The SFI Centre for Research Training in Genomics Data Science, Dublin, Ireland
| | - James Chodosh
- University of New Mexico School of Medicine, Albuquerque, NM, United States
| | - Anna K. Dewan
- Department of Dermatology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Arturo Dominguez
- Department of Dermatology and Internal Medicine, UT Southwestern Medical Center, Dallas, TX, United States
| | - Xinzhong Dong
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Elena Ezhkova
- Department of Cell, Developmental, and Regenerative Biology and Dermatology, Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, NY, United States
| | - Esther Fuchs
- Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, United States
| | - Jennifer Goldman
- Division of Pediatric Infectious Diseases and Clinical Pharmacology, Children’s Mercy, Kansas City, MO, United States
| | - Sonia Himed
- College of Medicine, University of Cincinnati, Cincinnati, OH, United States
| | - Simon Mallal
- Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Alina Markova
- Department of Dermatology, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, United States
| | - Kerry McCawley
- Stevens-Johnson Syndrome Foundation, Westminster, CO, United States
| | - Allison E. Norton
- Division of Pediatric Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, United States
| | - David Ostrov
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL, United States
| | - Michael Phan
- Division of Pharmacovigilance-I, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, United States
| | - Arthur Sanford
- Division of Trauma, Surgical Critical Care, and Burns, Loyola University Medical Center, Chicago, IL, United States
| | - David Schlundt
- Department of Psychology, Vanderbilt University, Nashville, TN, United States
| | - Daniel Schneider
- Department of Psychiatry and Surgery, MedStar Washington Hospital Center, Georgetown University School of Medicine, Washington, D.C., DC, United States
| | - Neil Shear
- Department of Dermatology, Emek Medical Center, Afula, Israel
| | - Kanade Shinkai
- Department of Dermatology, University of California, San Francisco, San Francisco, CA, United States
| | - Eric Tkaczyk
- Department of Veterans Affairs, Vanderbilt Dermatology Translational Research Clinic (VDTRC.org), Nashville, TN, United States
| | - Jason A. Trubiano
- Department of Infectious Diseases and Medicine, Austin Health, University of Melbourne, Melbourne, VIC, Australia
| | - Simona Volpi
- National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Charles S. Bouchard
- Department of Opthalmology, Loyola University Medical Center, Chicago, IL, United States
| | - Sherrie J. Divito
- Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Elizabeth J. Phillips
- Center for Drug Interactions and Immunology, Division of Infectious Disease, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
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Liu L, Li S, Wang G, Qu Y, Wang Z, Duan J, Wang C, Xue P, Zhang X, Ma Z, Bai H, Wang J. Dynamic toxicity landscape of immunotherapy for solid tumors across treatment lines. JOURNAL OF THE NATIONAL CANCER CENTER 2023; 3:186-196. [PMID: 39035191 PMCID: PMC11256535 DOI: 10.1016/j.jncc.2023.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 07/12/2023] [Accepted: 07/12/2023] [Indexed: 07/23/2024] Open
Abstract
Objective Immune checkpoint inhibitors (ICIs) targeting programmed cell death-1/ligand-1 (PD-1/PD-L1), cytotoxic T lymphocyte antigen-4 (CTLA-4), and lymphocyte-activation gene-3 (LAG-3) have been widely studied and applied throughout the course of cancer treatment. This study aimed to provide a comprehensive profile of ICI-associated toxicity and elucidate the toxicity patterns of ICIs across different treatment lines. Methods In total, 155 cohorts comprising 24 539 eligible patients were included in the safety analysis. Trial name, registration number, cancer type, trial phase, clinical setting, trial design, regimen, dosing schedule, age, sex and ethnicity distributions, number of patients, number of treatment-related adverse events (trAEs), and number of treatment-related death were extracted. We defined a timeline from the neoadjuvant setting to the third-line setting. We also introduced a synthesizing principle for adverse event rates (SPAER) of immunotherapy to ensure the comparability and reliability across different treatment lines. The study protocol was registered and approved by the PROSPERO protocol review committee (CRD42021242368). Results After excluding the neoadjuvant setting group, we observed a distinct reduction in the incidence of treatment-related adverse events (trAEs) with an advancement of the line of ICI treatment. The incidence of trAEs was negatively correlated with the line of treatment, irrespective of whether monotherapy or dual-ICI combination therapy was administered. Sensitivity analyses also confirmed the coincident negative correlations. Conclusion In summary, using a timeline-based concept centered around treatment lines, we revealed the dynamic landscape of ICI-associated toxicity and found that patients treated with ICIs during later lines of therapy may have a lower risk of trAEs.
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Affiliation(s)
- Lihui Liu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Sini Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | | | - Yan Qu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhijie Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianchun Duan
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chao Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Pei Xue
- Department of Surgical Sciences, Sleep Science Laboratory (BMC), Uppsala University, Uppsala, Sweden
| | - Xue Zhang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zixiao Ma
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hua Bai
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jie Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Berner F, Flatz L. Autoimmunity in immune checkpoint inhibitor-induced immune-related adverse events: A focus on autoimmune skin toxicity and pneumonitis. Immunol Rev 2023; 318:37-50. [PMID: 37548043 DOI: 10.1111/imr.13258] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 06/29/2023] [Indexed: 08/08/2023]
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. However, their use is frequently associated with immune-related adverse events (irAEs) potentially affecting any organ. The mechanisms mediating such irAEs remain poorly understood and biomarkers to predict the development of irAEs are lacking. Growing evidence shows the importance of self-antigens in mediating irAEs during ICI therapy, in particular the well-described melanocyte differentiation antigens in melanoma patients. This review will focus on two novel classes of self-antigens involved in mediating autoimmune skin toxicity and pneumonitis in non-small cell lung cancer patients treated with immunotherapy. T cells specific for these self-antigens are thought to not only mediate irAEs but are thought to simultaneously mediate anti-tumor responses and are therefore associated with both autoimmune toxicity and response to ICI therapy. We further discuss emerging cellular and proteomic immune signatures of irAEs that may serve as biomarkers to help predict which patients are at higher risk of developing these irAEs. The determination of new tumor antigens involved in ICI therapy and the identification of related biomarkers brings us a step forward in the mechanistic understanding of ICIs and will help to monitor patients at higher risk of developing irAEs. Lastly, we discuss the current challenges in collecting research samples for the study of ICI-related mechanisms and in distinguishing between immune signatures of response and those of irAEs.
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Affiliation(s)
- Fiamma Berner
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Lukas Flatz
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland
- Department of Dermatology, University Hospital Tübingen, University of Tübingen, Tübingen, Germany
- Department of Dermatology, Kantonsspital St. Gallen, St. Gallen, Switzerland
- Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
- Department of Oncology and Hematology, Kantonsspital St. Gallen, St. Gallen, Switzerland
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Hara N, Suwanai H, Yakou F, Ishii K, Iwasaki H, Abe H, Shikuma J, Sakai H, Miwa T, Suzuki R. Clinical characteristics and human leukocyte antigens in patients with immune checkpoint inhibitor-induced type 1 diabetes and pituitary dysfunction: a single center prospective study. Endocrine 2023; 81:477-483. [PMID: 37178310 DOI: 10.1007/s12020-023-03394-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 05/01/2023] [Indexed: 05/15/2023]
Abstract
PURPOSE Immune checkpoint inhibitor (ICI) induced type 1 diabetes (T1D) and pituitary dysfunction are life-threatening adverse events, yet there is little clinical data available. We aimed to investigate the clinical characteristics of patients with these adverse events and report their human leukocyte antigen (HLA) profile to determine its relevance. METHODS This is a single-center prospective study. We enrolled patients with cancers who were administered ICI and diagnosed as ICI induced T1D (ICI-T1D) and pituitary dysfunction (ICI-PD). Clinical data and extracted DNA from blood samples were collected. HLA typing was performed using next-generation sequencing. We compared our results with those previously reported in healthy controls and investigated the correlation between HLA and the occurrence of ICI-T1D and ICI-PD. RESULTS We identified 914 patients treated with ICI in our facility from 1st September, 2017 to 30th June, 2022. Six of these patients developed T1D and 15 developed pituitary dysfunction. The duration from the initiation of ICI treatment to the onset of T1D or pituitary dysfunction averaged 492 ± 196 days and 191 ± 169 days. Among the six patients with T1D, two were positive for anti-GAD antibody. The frequencies of HLA-DR11, -Cw10, -B61, -DRB1*11:01, and -C*03:04 were significantly higher in patients with ICI-T1D than in controls. The frequencies of HLA-DR15 and -DRB*15:02 were significantly higher in patients with ICI-PD than in controls. CONCLUSION This study revealed the clinical characteristics of ICI-T1D and ICI-PD and the association between specific HLAs and these adverse events.
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Affiliation(s)
- Natsuko Hara
- Department of Diabetes, Metabolism, and Endocrinology, Tokyo Medical University, Tokyo, 160-0023, Japan
| | - Hirotsugu Suwanai
- Department of Diabetes, Metabolism, and Endocrinology, Tokyo Medical University, Tokyo, 160-0023, Japan.
| | - Fumiyoshi Yakou
- Department of Diabetes, Endocrinology and Metabolism, Tokyo Medical University Hachioji Medical Center, Tokyo, 193-0998, Japan
| | - Keitaro Ishii
- Department of Diabetes, Metabolism, and Endocrinology, Tokyo Medical University, Tokyo, 160-0023, Japan
| | - Hajime Iwasaki
- Department of Diabetes, Metabolism, and Endocrinology, Tokyo Medical University, Tokyo, 160-0023, Japan
| | - Hironori Abe
- Department of Diabetes, Metabolism, and Endocrinology, Tokyo Medical University, Tokyo, 160-0023, Japan
| | - Jumpei Shikuma
- Department of Diabetes, Metabolism, and Endocrinology, Tokyo Medical University, Tokyo, 160-0023, Japan
| | - Hiroyuki Sakai
- Department of Diabetes, Metabolism, and Endocrinology, Tokyo Medical University, Tokyo, 160-0023, Japan
| | - Takashi Miwa
- Department of Diabetes, Metabolism, and Endocrinology, Tokyo Medical University, Tokyo, 160-0023, Japan
| | - Ryo Suzuki
- Department of Diabetes, Metabolism, and Endocrinology, Tokyo Medical University, Tokyo, 160-0023, Japan
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Singh N, Hocking AM, Buckner JH. Immune-related adverse events after immune check point inhibitors: Understanding the intersection with autoimmunity. Immunol Rev 2023; 318:81-88. [PMID: 37493210 PMCID: PMC12100745 DOI: 10.1111/imr.13247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 06/28/2023] [Indexed: 07/27/2023]
Abstract
Immune checkpoint inhibitor therapies act through blockade of inhibitory molecules involved in the regulation of T cells, thus releasing tumor specific T cells to destroy their tumor targets. However, immune checkpoint inhibitors (ICI) can also lead to a breach in self-tolerance resulting in immune-related adverse events (irAEs) that include tissue-specific autoimmunity. This review addresses the question of whether the mechanisms that drive ICI-induced irAEs are shared or distinct with those driving spontaneous autoimmunity, focusing on ICI-induced diabetes, ICI-induced arthritis, and ICI-induced thyroiditis due to the wealth of knowledge about the development of autoimmunity in type 1 diabetes, rheumatoid arthritis, and Hashimoto's thyroiditis. It reviews current knowledge about role of genetics and autoantibodies in the development of ICI-induced irAEs and presents new studies utilizing single-cell omics approaches to identify T-cell signatures associated with ICI-induced irAEs. Collectively, these studies indicate that there are similarities and differences between ICI-induced irAEs and autoimmune disease and that studying them in parallel will provide important insight into the mechanisms critical for maintaining immune tolerance.
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Affiliation(s)
| | - Anne M. Hocking
- Center for Translational Immunology, Benaroya Research Institute at Virginia Mason
| | - Jane H. Buckner
- Center for Translational Immunology, Benaroya Research Institute at Virginia Mason
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Teng YS, Yu S. Molecular Mechanisms of Cutaneous Immune-Related Adverse Events (irAEs) Induced by Immune Checkpoint Inhibitors. Curr Oncol 2023; 30:6805-6819. [PMID: 37504358 PMCID: PMC10378098 DOI: 10.3390/curroncol30070498] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 07/14/2023] [Accepted: 07/15/2023] [Indexed: 07/29/2023] Open
Abstract
Over the past few decades, immune checkpoint inhibitors (ICIs) have emerged as promising therapeutic options for the treatment of various cancers. These novel treatments effectively target key mediators of immune checkpoint pathways. Currently, ICIs primarily consist of monoclonal antibodies that specifically block cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), programmed cell death-ligand 1 (PD-L1), and lymphocyte activation gene 3 protein (LAG-3). Despite the notable efficacy of ICIs in cancer treatment, they can also trigger immune-related adverse events (irAEs), which present as autoimmune-like or inflammatory conditions. IrAEs have the potential to affect multiple organ systems, with cutaneous toxicities being the most commonly observed. Although cutaneous irAEs are typically of low-grade severity and can usually be managed effectively, there are cases where severe irAEs can become life-threatening. Therefore, early recognition and a comprehensive understanding of the mechanisms underlying cutaneous irAEs are crucial for improving clinical outcomes in cancer patients. However, the precise pathogenesis of cutaneous irAEs remains unclear. This review focuses on the skin manifestations induced by ICIs, the prognosis related to cutaneous irAEs, and the exploration of potential mechanisms involved in cutaneous irAEs.
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Affiliation(s)
- Yi-Shan Teng
- Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
| | - Sebastian Yu
- Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
- Department of Dermatology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
- Neuroscience Research Center, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
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Cao T, Zhou X, Wu X, Zou Y. Cutaneous immune-related adverse events to immune checkpoint inhibitors: from underlying immunological mechanisms to multi-omics prediction. Front Immunol 2023; 14:1207544. [PMID: 37497220 PMCID: PMC10368482 DOI: 10.3389/fimmu.2023.1207544] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 06/05/2023] [Indexed: 07/28/2023] Open
Abstract
The development of immune checkpoint inhibitors (ICIs) has dramatically altered the landscape of therapy for multiple malignancies, including urothelial carcinoma, non-small cell lung cancer, melanoma and gastric cancer. As part of their anti-tumor properties, ICIs can enhance susceptibility to inflammatory side effects known as immune-related adverse events (irAEs), in which the skin is one of the most commonly and rapidly affected organs. Although numerous questions still remain unanswered, multi-omics technologies have shed light into immunological mechanisms, as well as the correlation between ICI-induced activation of immune systems and the incidence of cirAE (cutaneous irAEs). Therefore, we reviewed integrated biological layers of omics studies combined with clinical data for the prediction biomarkers of cirAEs based on skin pathogenesis. Here, we provide an overview of a spectrum of dermatological irAEs, discuss the pathogenesis of this "off-tumor toxicity" during ICI treatment, and summarize recently investigated biomarkers that may have predictive value for cirAEs via multi-omics approach. Finally, we demonstrate the prognostic significance of cirAEs for immune checkpoint blockades.
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Cheng Y, Ling F, Li J, Chen Y, Xu M, Li S, Zhu L. An updated review of gastrointestinal toxicity induced by PD-1 inhibitors: from mechanisms to management. Front Immunol 2023; 14:1190850. [PMID: 37404814 PMCID: PMC10315615 DOI: 10.3389/fimmu.2023.1190850] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 06/05/2023] [Indexed: 07/06/2023] Open
Abstract
PD-1 inhibitors, as one of commonly used immune checkpoint inhibitors, enable T-cell activation and prevent immune escape by blocking the PD-1/PD-L1 signaling pathway. They have transformed the treatment landscape for cancer in recent years, due to the advantages of significantly prolonging patients' survival and improving their life quality. However, the ensuing unpredictable immune-related adverse effects (irAEs) plague clinicians, such as colitis and even potentially fatal events like intestinal perforation and obstruction. Therefore, understanding the clinical manifestations and grading criteria, underlying mechanisms, available diverse therapies, accessible biomarkers, and basis for risk stratification is of great importance for the management. Current evidence suggests that irAEs may be a marker of clinical benefit to immunotherapy in patients, so whether to discontinue PD-1 inhibitors after the onset of irAEs and rechallenge after remission of irAEs requires further evaluation of potential risk-reward ratios as well as more data from large-scale prospective studies to fully validate. At the end, the rare gastrointestinal toxicity events caused by PD-1 inhibitors are also sorted out. This review provides a summary of available data on the gastrointestinal toxicity profile caused by PD-1 inhibitors, with the aim of raising clinicians' awareness in daily practice, so that patients can safely benefit from therapy.
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Ibis B, Aliazis K, Cao C, Yenyuwadee S, Boussiotis VA. Immune-related adverse effects of checkpoint immunotherapy and implications for the treatment of patients with cancer and autoimmune diseases. Front Immunol 2023; 14:1197364. [PMID: 37342323 PMCID: PMC10277501 DOI: 10.3389/fimmu.2023.1197364] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 05/15/2023] [Indexed: 06/22/2023] Open
Abstract
During the past decade, there has been a revolution in cancer therapeutics by the emergence of antibody-based immunotherapies that modulate immune responses against tumors. These therapies have offered treatment options to patients who are no longer responding to classic anti-cancer therapies. By blocking inhibitory signals mediated by surface receptors that are naturally upregulated during activation of antigen-presenting cells (APC) and T cells, predominantly PD-1 and its ligand PD-L1, as well as CTLA-4, such blocking agents have revolutionized cancer treatment. However, breaking these inhibitory signals cannot be selectively targeted to the tumor microenvironment (TME). Since the physiologic role of these inhibitory receptors, known as immune checkpoints (IC) is to maintain peripheral tolerance by preventing the activation of autoreactive immune cells, IC inhibitors (ICI) induce multiple types of immune-related adverse effects (irAEs). These irAEs, together with the natural properties of ICs as gatekeepers of self-tolerance, have precluded the use of ICI in patients with pre-existing autoimmune diseases (ADs). However, currently accumulating data indicates that ICI might be safely administered to such patients. In this review, we discuss mechanisms of well established and newly recognized irAEs and evolving knowledge from the application of ICI therapies in patients with cancer and pre-existing ADs.
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Affiliation(s)
- Betul Ibis
- Division of Hematology-Oncology Beth Israel Deaconess Medical Center, Boston, MA, United States
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States
| | - Konstantinos Aliazis
- Division of Hematology-Oncology Beth Israel Deaconess Medical Center, Boston, MA, United States
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States
| | - Carol Cao
- Division of Hematology-Oncology Beth Israel Deaconess Medical Center, Boston, MA, United States
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States
- Harvard College, Cambridge, MA, United States
| | - Sasitorn Yenyuwadee
- Division of Hematology-Oncology Beth Israel Deaconess Medical Center, Boston, MA, United States
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States
| | - Vassiliki A. Boussiotis
- Division of Hematology-Oncology Beth Israel Deaconess Medical Center, Boston, MA, United States
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States
- Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
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Van Mol P, Donders E, Lambrechts D, Wauters E. Immune checkpoint biology in health & disease: Immune checkpoint biology and autoimmunity in cancer patients. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2023; 382:181-206. [PMID: 38225103 DOI: 10.1016/bs.ircmb.2023.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2024]
Abstract
Immune checkpoints (ICs) play a central role in maintaining immune homoeostasis. The discovery that tumours use this physiological mechanism to avoid elimination by the immune system, opened up avenues for therapeutic targeting of ICs as a novel way of treating cancer. However, this therapy a new array of autoimmune side effects, termed immune-related adverse events (irAEs). In this narrative review, we first recapitulate the physiological function of ICs that are approved targets for cancer immunotherapy (CTLA-4, PD-(L)1 and LAG-3), as the groundwork to critically discuss current knowledge on irAEs. Specifically, we summarize clinical aspects and examine a molecular classification and predisposing factors of irAEs. Finally, we discuss irAE treatment, particularly emphasizing how molecular knowledge is changing the current treatment paradigm.
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Affiliation(s)
- Pierre Van Mol
- VIB - CCB Laboratory of Translational Genetics, KU Leuven, Leuven, Belgium; Pneumology - Respiratory Oncology, University Hospitals Leuven, Leuven, Belgium
| | - Elena Donders
- VIB - CCB Laboratory of Translational Genetics, KU Leuven, Leuven, Belgium; Pneumology - Respiratory Oncology, University Hospitals Leuven, Leuven, Belgium
| | - Diether Lambrechts
- VIB - CCB Laboratory of Translational Genetics, KU Leuven, Leuven, Belgium
| | - Els Wauters
- Pneumology - Respiratory Oncology, University Hospitals Leuven, Leuven, Belgium.
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Lechner MG, Zhou Z, Hoang AT, Huang N, Ortega J, Scott LN, Chen HC, Patel AY, Yakhshi-Tafti R, Kim K, Hugo W, Famini P, Drakaki A, Ribas A, Angell TE, Su MA. Clonally expanded, thyrotoxic effector CD8 + T cells driven by IL-21 contribute to checkpoint inhibitor thyroiditis. Sci Transl Med 2023; 15:eadg0675. [PMID: 37196065 PMCID: PMC10227862 DOI: 10.1126/scitranslmed.adg0675] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 04/19/2023] [Indexed: 05/19/2023]
Abstract
Autoimmune toxicity occurs in up to 60% of patients treated with immune checkpoint inhibitor (ICI) therapy for cancer and represents an increasing clinical challenge for expanding the use of these treatments. To date, human immunopathogenic studies of immune-related adverse events (IRAEs) have relied on sampling of circulating peripheral blood cells rather than affected tissues. Here, we directly obtained thyroid specimens from individuals with ICI-thyroiditis, one of the most common IRAEs, and compared immune infiltrates with those from individuals with spontaneous autoimmune Hashimoto's thyroiditis (HT) or no thyroid disease. Single-cell RNA sequencing revealed a dominant, clonally expanded population of thyroid-infiltrating cytotoxic CXCR6+ CD8+ T cells (effector CD8+ T cells) present in ICI-thyroiditis but not HT or healthy controls. Furthermore, we identified a crucial role for interleukin-21 (IL-21), a cytokine secreted by intrathyroidal T follicular (TFH) and T peripheral helper (TPH) cells, as a driver of these thyrotoxic effector CD8+ T cells. In the presence of IL-21, human CD8+ T cells acquired the activated effector phenotype with up-regulation of the cytotoxic molecules interferon-γ (IFN-γ) and granzyme B, increased expression of the chemokine receptor CXCR6, and thyrotoxic capacity. We validated these findings in vivo using a mouse model of IRAEs and further demonstrated that genetic deletion of IL-21 signaling protected ICI-treated mice from thyroid immune infiltration. Together, these studies reveal mechanisms and candidate therapeutic targets for individuals who develop IRAEs.
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Affiliation(s)
- Melissa G. Lechner
- Division of Endocrinology, Diabetes, and Metabolism, UCLA David Geffen School of Medicine; Los Angeles, CA 90095
| | - Zikang Zhou
- Department of Microbiology, Immunology, and Molecular Genetics, UCLA David Geffen School of Medicine; Los Angeles, CA 90095
| | - Aline T. Hoang
- Department of Microbiology, Immunology, and Molecular Genetics, UCLA David Geffen School of Medicine; Los Angeles, CA 90095
- Drexel Medical School; Philadelphia, PA 19129
| | - Nicole Huang
- Department of Microbiology, Immunology, and Molecular Genetics, UCLA David Geffen School of Medicine; Los Angeles, CA 90095
| | - Jessica Ortega
- Department of Microbiology, Immunology, and Molecular Genetics, UCLA David Geffen School of Medicine; Los Angeles, CA 90095
| | - Lauren N. Scott
- Department of Microbiology, Immunology, and Molecular Genetics, UCLA David Geffen School of Medicine; Los Angeles, CA 90095
| | - Ho-Chung Chen
- Department of Microbiology, Immunology, and Molecular Genetics, UCLA David Geffen School of Medicine; Los Angeles, CA 90095
| | - Anushi Y. Patel
- Department of Microbiology, Immunology, and Molecular Genetics, UCLA David Geffen School of Medicine; Los Angeles, CA 90095
| | - Rana Yakhshi-Tafti
- Department of Microbiology, Immunology, and Molecular Genetics, UCLA David Geffen School of Medicine; Los Angeles, CA 90095
- Rosalind Franklin Medical School; Chicago, IL 60064
| | - Kristy Kim
- UCLA David Geffen School of Medicine; Los Angeles, CA 90095
| | - Willy Hugo
- Division of Dermatology, Department of Medicine, UCLA David Geffen School of Medicine; Los Angeles, CA 90095
| | - Pouyan Famini
- Division of Endocrinology, Diabetes, and Metabolism, UCLA David Geffen School of Medicine; Los Angeles, CA 90095
| | - Alexandra Drakaki
- Division of Hematology and Oncology, UCLA David Geffen School of Medicine; Los Angeles, CA 90095
| | - Antoni Ribas
- Division of Hematology and Oncology, UCLA David Geffen School of Medicine; Los Angeles, CA 90095
| | - Trevor E. Angell
- Division of Endocrinology and Diabetes, USC Keck School of Medicine; Los Angeles, CA 90033
| | - Maureen A. Su
- Department of Microbiology, Immunology, and Molecular Genetics, UCLA David Geffen School of Medicine; Los Angeles, CA 90095
- Division of Pediatric Endocrinology, UCLA David Geffen School of Medicine; Los Angeles, CA 90095
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50
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Marques-Piubelli ML, Seervai RNH, Mudaliar KM, Ma W, Milton DR, Wang J, Muhlbauer A, Parra ER, Solis LM, Nagarajan P, Speiser J, Hudgens C, Cho WC, Aung PP, Patel A, Pacha O, Nelson KC, Tetzlaff MT, Amaria RN, Torres-Cabala CA, Prieto VG, Wistuba II, Curry JL. Gene expression profiling and multiplex immunofluorescence analysis of bullous pemphigoid immune-related adverse event reveal upregulation of toll-like receptor 4/complement-induced innate immune response and increased density of T H 1 T-cells. J Cutan Pathol 2023. [PMID: 37150813 DOI: 10.1111/cup.14442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 03/22/2023] [Accepted: 04/19/2023] [Indexed: 05/09/2023]
Abstract
BACKGROUND Immune checkpoint inhibitor (ICI)-based cancer therapies cause a variety of cutaneous immune-related adverse events (irAEs) including immunobullous skin eruptions like bullous pemphigoid (BP). However, little is known about the underlying immunopathogenic drivers of these reactions, and understanding the unique gene expression profile and immune composition of BP-irAE remains a critical knowledge gap in the field of oncodermatology/oncodermatopathology. METHODS BP-irAE (n = 8) and de novo BP control (n = 8) biopsy samples were subjected to gene expression profiling using the NanoString® Technologies nCounter PanCancer Immune Profiling Panel. Multiplex immunofluorescence (mIF) studies using markers for T-cells (CD3 and CD8), T helper 1 (TH 1) cells (Tbet), TH 2 cells (Gata3), TH 17 cells (RORγT), and regulatory T-cells (Tregs; FoxP3) were further evaluated using InForm® image analysis. RESULTS Compared with de novo BP controls, BP-irAE samples exhibited upregulation of 30 mRNA transcripts (p < 0.025), including toll-like receptor 4 (TLR4) and genes associated with complement activation, and downregulation of 89 mRNA transcripts (p < 0.025), including genes associated with TH 2, TH 17, and B-cell immune response. BP-irAE demonstrated a greater density of Tbet+ (TH 1) cells in the dermis (p = 0.004) and fewer Tregs in the blister floor (p = 0.028) when compared with that of de novo control BP samples. CONCLUSIONS BP-irAE exhibited activation of the TLR4/complement-driven classical innate immune response pathway, with dermal TH 1 immune cell polarization and decreased Tregs in the blister floor. TLR/complement signaling may underlie the immunopathogenesis of BP-irAE.
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Affiliation(s)
- Mario L Marques-Piubelli
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Riyad N H Seervai
- Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas, USA
- Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, Texas, USA
- Internal Medicine Residency Program, Providence Portland Medical Center, Portland, Oregon, USA
| | - Kumaran M Mudaliar
- Department of Pathology, Loyola University Medical Center, Maywood, Illinois, USA
| | - Wencai Ma
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Denái R Milton
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jing Wang
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Aaron Muhlbauer
- Department of Pathology, Loyola University Medical Center, Maywood, Illinois, USA
| | - Edwin R Parra
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Luisa M Solis
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Priyadharsini Nagarajan
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jodi Speiser
- Department of Pathology, Loyola University Medical Center, Maywood, Illinois, USA
| | - Courtney Hudgens
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Woo Cheal Cho
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Phyu P Aung
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Anisha Patel
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Omar Pacha
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Kelly C Nelson
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Michael T Tetzlaff
- Departments of Pathology and Dermatology, Oral Pathology and Dermatopathology Unit, The University of California San Francisco, San Francisco, California, USA
| | - Rodabe N Amaria
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Carlos A Torres-Cabala
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Victor G Prieto
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ignacio I Wistuba
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jonathan L Curry
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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