1
|
Kazanas S, Anastasopoulou A, Ziogas D, Gogas H, Angelousi A. An Extremely Rare Case of Immune Checkpoint Inhibitors-Related Hypoparathyroidism and a Critical Literature Review. JCEM CASE REPORTS 2025; 3:luaf097. [PMID: 40356787 PMCID: PMC12066411 DOI: 10.1210/jcemcr/luaf097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2025] [Indexed: 05/15/2025]
Abstract
Immune checkpoint inhibitors (ICIs) have been approved to treat a variety of malignancies, including melanoma, improving the prognosis of these patients. However, they also cause a wide spectrum of rare immune-related adverse events (irAEs), not well-described yet. Although many endocrinopathies have been recognized as irAEs, primary hypoparathyroidism has rarely been reported, and thus clinical suspicion remains low. Herein, we describe the case of a 68-year-old female patient with metastatic melanoma who was admitted to the emergency department with acute symptomatic hypocalcemia due to immune-related (ir)-hypoparathyroidism after 2 cycles of nivolumab/ipilimumab. The patient was treated symptomatically, and her calcium levels were normalized. Parathyroid hormone levels were partially restored during the 6 months of follow-up. A literature review was conducted, summarizing all other subjects who developed ir-hypoparathyroidism after exposure to ICI-based regimen. The review identified 10 additional cases of hypoparathyroidism during immunotherapy. Interestingly, all melanoma cases with ir-hypoparathyroidism had received nivolumab/ipilimumab; 3 of them were also screened and detected with positive calcium-sensing receptor (CaSR) antibodies. Primary hypoparathyroidism may acutely manifest with symptomatic hypocalcemia and care providers should be aware of this rare irAE.
Collapse
Affiliation(s)
- Spyridon Kazanas
- First Department of Internal Medicine, Laiko General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens 11527, Greece
| | - Amalia Anastasopoulou
- First Department of Internal Medicine, Laiko General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens 11527, Greece
| | - Dimitrios Ziogas
- First Department of Internal Medicine, Laiko General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens 11527, Greece
| | - Helen Gogas
- First Department of Internal Medicine, Laiko General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens 11527, Greece
| | - Anna Angelousi
- First Department of Internal Medicine, Unit of Endocrinology, Laiko General Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens 11527, Greece
| |
Collapse
|
2
|
Köylü B, Kıkılı Cİ, Dikensoy Ö, Selçukbiricik F. Late-onset recurrent immune checkpoint inhibitor-related pneumonitis after cessation of pembrolizumab: a case report. Immunotherapy 2025; 17:317-320. [PMID: 40171983 PMCID: PMC12045559 DOI: 10.1080/1750743x.2025.2488609] [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: 12/07/2024] [Accepted: 04/01/2025] [Indexed: 04/04/2025] Open
Abstract
Immune-related adverse events typically occur during the early phases of immune checkpoint inhibitor therapy. However, late-onset immune-related adverse events can still arise long after the immune checkpoint inhibitor therapy has ended. Immune checkpoint inhibitor-related pneumonitis warrants special attention for risk assessment and early detection due to its potential for serious outcomes, including hospitalization and death. Despite its rarity, late-onset immune checkpoint inhibitor-related pneumonitis should be considered in the differential diagnosis for dyspnea in patients with a history of immune checkpoint inhibitor therapy to prevent morbidity and mortality. In this case report, we present a case of an 84-year-old female patient suffering from locally advanced triple-negative breast cancer and late-onset immune checkpoint inhibitor-related pneumonitis requiring hospitalization 104 days after the last cycle of pembrolizumab. Following successful treatment of late-onset immune checkpoint inhibitor-related pneumonitis with corticosteroids, a recurrence of immune checkpoint inhibitor-related pneumonitis occurred a month later. Corticosteroid therapy was reinitiated, gradually tapered after radiological improvement, and eventually discontinued. The patient remains in remission from breast cancer. For patients with a history of immune checkpoint inhibitor therapy, medical vigilance, accurate diagnosis, and timely management of late-onset immune checkpoint inhibitor-related pneumonitis are crucial.
Collapse
Affiliation(s)
- Bahadır Köylü
- Department of Medical Oncology, Koç University School of Medicine, Istanbul, Turkey
| | - Cevat İlteriş Kıkılı
- Department of Medical Oncology, Koç University School of Medicine, Istanbul, Turkey
| | - Öner Dikensoy
- Department of Pulmonary Medicine, Koç University School of Medicine, Istanbul, Turkey
| | - Fatih Selçukbiricik
- Department of Medical Oncology, Koç University School of Medicine, Istanbul, Turkey
| |
Collapse
|
3
|
Durbin SM, Zubiri L, Perlman K, Wu CY, Lim T, Grealish K, Hathaway N, LoPiccolo J, Wang M, Falade A, Molina G, Jacoby TV, Shah N, Mooradian MJ, Reynolds KL. Late-Onset Immune-Related Adverse Events After Immune Checkpoint Inhibitor Therapy. JAMA Netw Open 2025; 8:e252668. [PMID: 40146104 PMCID: PMC11950896 DOI: 10.1001/jamanetworkopen.2025.2668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 01/19/2025] [Indexed: 03/28/2025] Open
Abstract
Importance The use of immune checkpoint inhibitors (ICIs) is increasing. Little is known about the frequency of late-onset immune-related adverse events (irAEs) and the patient-specific risk factors associated with their development. Objectives To assess the incidence of persistent or de novo late-onset irAEs requiring hospitalization and identify patient factors associated with risk of late-onset irAEs. Design, Setting, and Participants This retrospective observational cohort study conducted from January 2011 to October 2022 included patients who received ICIs and were hospitalized with irAEs at an academic medical center. Exclusion criteria included ICI therapy outside of the hospital system and no irAE diagnosis during admission. Data were analyzed from November 15, 2022, to January 8, 2025. Exposure Late-onset irAEs. Main Outcomes and Measures The main study outcomes were (1) incidence of irAE hospitalization at 0 to 6 months (early), more than 6 to 12 months (intermediate), and more than 12 months (late) after ICI initiation and (2) patient factors associated with risk of late-onset irAEs. Results Among the 795 patients hospitalized with irAEs, the median age was 67.3 years (IQR, 58.3-74.8 years); 476 (59.9%) were male. Most patients (n = 517 [65.0%]) received anti-programmed death ligand 1 (PD-L1) and anti-programmed cell death 1 monotherapy, with the most common indications being melanoma (n = 335 [42.1%]) and lung cancer (n = 167 [21.0%]). The median time from start of ICI therapy to hospital admission was 2.7 months (IQR, 1.2-6.1 months), with 14.7% of patients (n = 117 of 795) presenting 6 to 12 months after initial ICI exposure and 10.8% of patients (86 of 795) presenting more than 12 months after initial exposure. The irAEs most likely to present late included those involving the kidney (10 of 32 [31.3%]) and hematologic (5 of 23 [21.7%]) organ systems. In univariate analysis, ICI type was significantly associated with the timing of hospital admission for irAEs; of the 517 patients receiving anti-PD-L1-based therapy, 13.5% (n = 70) presented late compared with 5.4% (9 of 167) receiving dual therapy with anti-cytotoxic T-lymphocyte-associated protein 4 (P < .001). Patients receiving perioperative ICI therapy were significantly more likely to be admitted at the intermediate interval (16 of 68 [23.5%]) compared with those with metastatic disease (87 of 678 [12.8%]) (P = .03). Timing of irAE was also significantly associated with active ICI exposure; among the patients presenting late, 7.4% (48 of 651) had received ICI therapy within the last 60 days compared with 26.4% (38 of 144) who had not had recent ICI exposure (P < .001). Conclusions and Relevance The findings of this retrospective observational cohort study suggest that late irAEs are possible, with a subset of patients presenting years after the start of ICI therapy. Clinicians must remain vigilant for irAEs regardless of elapsed time from ICI therapy, especially as patients live longer and ICIs become more widely used. Future investigations are needed to better understand the risk factors for late-onset irAEs and the distinct immunologic pathways that underlie such events.
Collapse
Affiliation(s)
- Sienna M. Durbin
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston
- Harvard Medical School, Boston, Massachusetts
| | - Leyre Zubiri
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston
- Harvard Medical School, Boston, Massachusetts
| | - Katherine Perlman
- Department of Dermatology, Massachusetts General Hospital & Harvard Medical School, Boston
- Department of Medicine, University of Chicago, Chicago, Illinois
| | - Chia-Yun Wu
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston
- Harvard Medical School, Boston, Massachusetts
- Far Eastern Memorial Hospital, New Taipei City, Taiwan
| | - Tristan Lim
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston
- Harvard Medical School, Boston, Massachusetts
| | - Kelley Grealish
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston
- Harvard Medical School, Boston, Massachusetts
| | - Nora Hathaway
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston
- Harvard Medical School, Boston, Massachusetts
| | - Jaclyn LoPiccolo
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston
- Harvard Medical School, Boston, Massachusetts
- Dana Farber Cancer Institute, Boston, Massachusetts
| | - Mike Wang
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston
- Harvard Medical School, Boston, Massachusetts
| | - Ayo Falade
- Department of Oncology, Mayo Clinic, Rochester, Minnesota
- Department of Internal Medicine, Mass General Brigham Salem Hospital, Salem, Massachusetts
| | - Gabriel Molina
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston
- Harvard Medical School, Boston, Massachusetts
| | - Ted Victor Jacoby
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston
- Harvard Medical School, Boston, Massachusetts
| | - Nishi Shah
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston
- Harvard Medical School, Boston, Massachusetts
| | - Meghan J. Mooradian
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston
- Harvard Medical School, Boston, Massachusetts
| | - Kerry L. Reynolds
- Division of Hematology & Oncology, Department of Medicine, Massachusetts General Hospital, Boston
- Harvard Medical School, Boston, Massachusetts
| |
Collapse
|
4
|
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.
Collapse
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
| |
Collapse
|
5
|
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.
Collapse
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;
| |
Collapse
|
6
|
Lin SY, Huang H, Yu JJ, Su F, Jiang T, Zhang SY, Lv L, Long T, Pan HW, Qi JQ, Zhou Q, Tang WF, Ding GW, Wang LM, Tan LJ, Yin J. Activin A receptor type 1C single nucleotide polymorphisms associated with esophageal squamous cell carcinoma risk in Chinese population. World J Gastrointest Oncol 2025; 17:96702. [PMID: 39817119 PMCID: PMC11664604 DOI: 10.4251/wjgo.v17.i1.96702] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 09/01/2024] [Accepted: 10/14/2024] [Indexed: 12/12/2024] Open
Abstract
BACKGROUND Transforming growth factor-β (TGF-β) superfamily plays an important role in tumor progression and metastasis. Activin A receptor type 1C (ACVR1C) is a TGF-β type I receptor that is involved in tumorigenesis through binding to different ligands. AIM To evaluate the correlation between single nucleotide polymorphisms (SNPs) of ACVR1C and susceptibility to esophageal squamous cell carcinoma (ESCC) in Chinese Han population. METHODS In this hospital-based cohort study, 1043 ESCC patients and 1143 healthy controls were enrolled. Five SNPs (rs4664229, rs4556933, rs77886248, rs77263459, rs6734630) of ACVR1C were assessed by the ligation detection reaction method. Hardy-Weinberg equilibrium test, genetic model analysis, stratified analysis, linkage disequilibrium test, and haplotype analysis were conducted. RESULTS Participants carrying ACVR1C rs4556933 GA mutant had significantly decreased risk of ESCC, and those with rs77886248 TA mutant were related with higher risk, especially in older male smokers. In the haplotype analysis, ACVR1C Trs4664229Ars4556933Trs77886248Crs77263459Ars6734630 increased risk of ESCC, while Trs4664229Grs4556933Trs77886248Crs77263459Ars6734630 was associated with lower susceptibility to ESCC. CONCLUSION ACVR1C rs4556933 and rs77886248 SNPs were associated with the susceptibility to ESCC, which could provide a potential target for early diagnosis and treatment of ESCC in Chinese Han population.
Collapse
Affiliation(s)
- Si-Yun Lin
- Department of Thoracic Surgery, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Hou Huang
- Shanghai Key Laboratory of Clinical Geriatric Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Jin-Jie Yu
- Department of Thoracic Surgery, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, China
| | - Feng Su
- Department of Thoracic Surgery, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, China
| | - Tian Jiang
- Department of Thoracic Surgery, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, China
| | - Shao-Yuan Zhang
- Department of Thoracic Surgery, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, China
| | - Lu Lv
- Department of Cardiothoracic Surgery, The Affiliated People's Hospital of Jiangsu University, Zhenjiang 212002, Jiangsu Province, China
| | - Tao Long
- Department of Cardiothoracic Surgery, The Affiliated People's Hospital of Jiangsu University, Zhenjiang 212002, Jiangsu Province, China
| | - Hui-Wen Pan
- Department of Cardiothoracic Surgery, The Affiliated People's Hospital of Jiangsu University, Zhenjiang 212002, Jiangsu Province, China
| | - Jun-Qing Qi
- Department of Cardiothoracic Surgery, The Affiliated People's Hospital of Jiangsu University, Zhenjiang 212002, Jiangsu Province, China
| | - Qiang Zhou
- Department of Thoracic Surgery, Sichuan Cancer Hospital & Institute, Chengdu 610042, Sichuan Province, China
| | - Wei-Feng Tang
- Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210000, Jiangsu Province, China
| | - Guo-Wen Ding
- Department of Cardiothoracic Surgery, The Affiliated People's Hospital of Jiangsu University, Zhenjiang 212002, Jiangsu Province, China
| | - Li-Ming Wang
- Department of Respiratory and Critical Care Medicine, Shanghai Xuhui Central Hospital, Shanghai 200032, China
| | - Li-Jie Tan
- Department of Thoracic Surgery, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, China
| | - Jun Yin
- Department of Thoracic Surgery, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, China
| |
Collapse
|
7
|
Tasaki Y, Hamamoto S, Yamashita S, Furukawa J, Fujita K, Tomida R, Miyake M, Ito N, Iwamoto H, Mimura Y, Sugiyama Y, Unno R, Okada A, Yasui T, Furukawa-Hibi Y. Eosinophil is a predictor of severe immune-related adverse events induced by ipilimumab plus nivolumab therapy in patients with renal cell carcinoma: a retrospective multicenter cohort study. Front Immunol 2025; 15:1483956. [PMID: 39850887 PMCID: PMC11754295 DOI: 10.3389/fimmu.2024.1483956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 12/23/2024] [Indexed: 01/25/2025] Open
Abstract
Introduction Immune-related adverse events (irAEs) induced by immune checkpoint inhibitors are difficult to predict and can lead to severe events. Although it is important to develop strategies for the early detection of severe irAEs, there is a lack of evidence on irAEs associated with ipilimumab plus nivolumab therapy for metastatic renal cell carcinoma (RCC). Therefore, this study aimed to investigate the association between eosinophil and severe irAEs in patients receiving ipilimumab plus nivolumab therapy for RCC. Methods In this retrospective study, 161 patients receiving ipilimumab plus nivolumab therapy for RCC were divided into three groups based on whether they experienced Results Although the eosinophil in the baseline samples did not differ between the severe irAE and non-irAE groups (2.8% vs. 2.5%, P = 0.75), regarding the 2-week samples, the eosinophil was significantly higher in the severe irAE group (mean, 6.6% vs. 3.3%; P < 0.05). Multivariate analysis showed that an eosinophil of ≥3.0% was a risk factor for severe irAEs (odds ratio, 6.01). Median progression-free survival (mPFS), mPFS from the start of ipilimumab plus nivolumab therapy to second-line therapy (mPFS2), and median overall survival (mOS) were the shortest in the non-irAE group. Although the mPFS did not differ between the severe and non-severe irAE groups (9.2 vs 14.2 months, P = 0.45), notably, mPFS2 and mOS in the former group tended to be shorter than those in the latter group (mPFS2: 29.2 vs not reached, P = 0.10; mOS: 36.9 vs 52.3 months, P = 0.06). Discussion An increased eosinophil 2 weeks after ipilimumab plus nivolumab therapy may be a predictor of severe irAEs, which are associated with poor prognoses, compared with non-severe irAEs among patients with RCC. We provide a novel rationale for the importance of monitoring eosinophil counts for the early detection of severe irAEs.
Collapse
Affiliation(s)
- Yoshihiko Tasaki
- Department of Clinical Pharmaceutics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Shuzo Hamamoto
- Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | | | - Junya Furukawa
- Department of Urology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Kazutoshi Fujita
- Department of Urology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Ryotaro Tomida
- Department of Urology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Makito Miyake
- Department of Urology, Nara Medical University, Nara, Japan
| | - Noriyuki Ito
- Department of Urology, Japanese Red Cross Wakayama Medical Center, Wakayama, Japan
| | - Hideto Iwamoto
- Division of Urology, Department of Surgery, Tottori University Faculty of Medicine Graduate School of Medicine, Tottori, Japan
| | - Yoshihisa Mimura
- Department of Clinical Pharmaceutics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Yosuke Sugiyama
- Department of Clinical Pharmaceutics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Rei Unno
- Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Atsushi Okada
- Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Takahiro Yasui
- Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| | - Yoko Furukawa-Hibi
- Department of Clinical Pharmaceutics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan
| |
Collapse
|
8
|
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.
Collapse
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
| |
Collapse
|
9
|
Xu Q, Hu J, Wang Y, Wang Z. The role of tumor types in immune-related adverse events. Clin Transl Oncol 2024:10.1007/s12094-024-03798-6. [PMID: 39738878 DOI: 10.1007/s12094-024-03798-6] [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: 08/02/2024] [Accepted: 11/13/2024] [Indexed: 01/02/2025]
Abstract
Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block inhibitors of T cell activation and function. With the widespread use of ICIs in cancer therapy, immune-related adverse events (irAEs) have gradually emerged as urgent clinical issues. Tumors not only exhibit high heterogeneity, and their response to ICIs varies, with "hot" tumors showing better anti-tumor effects but also a higher susceptibility to irAEs. The manifestation of irAEs displays a tumor-heterogeneous pattern, correlating with the tumor type in terms of the affected organs, incidence, median onset time, and severity. Understanding the mechanisms underlying the pathogenic patterns of irAEs can provide novel insights into the prevention and management of irAEs, guide the development of biomarkers, and contribute to a deeper understanding of the toxicological characteristics of ICIs. In this review, we explore the impact of tumor type on the therapeutic efficacy of ICIs and further elucidate how these tumor types influence the occurrence of irAEs. Finally, we assess key candidate biomarkers and their relevance to proposed irAE mechanisms. This paper also outlines management strategies for patients with various types of tumors, based on their disease patterns.
Collapse
Affiliation(s)
- Qian Xu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Hubei, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Hubei, China
- Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Hubei, China
| | - Jing Hu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Hubei, China
| | - Yan Wang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Hubei, China.
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Hubei, China.
- Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Hubei, China.
| | - Zhaohui Wang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Hubei, China.
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Hubei, China.
- Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, Hubei, China.
| |
Collapse
|
10
|
Lavalle S, Masiello E, Valerio MR, Aliprandi A, Scandurra G, Gebbia V, Sambataro D. Immune checkpoint inhibitor therapy‑related pneumonitis: How, when and why to diagnose and manage (Review). Exp Ther Med 2024; 28:381. [PMID: 39113908 PMCID: PMC11304171 DOI: 10.3892/etm.2024.12670] [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: 05/13/2024] [Accepted: 07/11/2024] [Indexed: 08/10/2024] Open
Abstract
Immune checkpoint inhibitor (ICI) therapy has revolutionized cancer treatment by enhancing the immune response against tumor cells. However, their influence on immune pathways can lead to immune-related adverse events such as pneumonitis, necessitating rapid diagnosis and management to prevent severe complications. These adverse events arise from the activation of the immune system by immunotherapeutic drugs, leading to immune-mediated inflammation and tissue damage in various organs and tissues throughout the body. The present review article discusses the pathophysiology, clinical presentation, diagnostic modalities and management strategies for ICI-related pneumonitis, emphasizing early recognition and tailored interventions. Future research endeavors should focus on elucidating the underlying mechanisms of pneumonitis and identifying predictive biomarkers to guide personalized treatment strategies in this evolving field of oncology.
Collapse
Affiliation(s)
- Salvatore Lavalle
- Department of Medicine and Surgery, Kore University of Enna, I-94100 Enna, Italy
| | - Edoardo Masiello
- Radiology Unit, University Vita e Salute, Institute San Raffaele, I-20132 Milan, Italy
| | - Maria Rosaria Valerio
- Medical Oncology Unit, Policlinic P Giaccone, University of Palermo, I-90127 Palermo, Italy
| | - Alberto Aliprandi
- Radiology Unit, Zucchi Clinical Institutes, University of Milan-Bicocca, I-20900 Monza, Italy
| | - Giuseppa Scandurra
- Department of Medicine and Surgery, Kore University of Enna, I-94100 Enna, Italy
- Medical Oncology Unit, Cannizzaro Hospital, I-95126 Catania, Italy
| | - Vittorio Gebbia
- Department of Medicine and Surgery, Kore University of Enna, I-94100 Enna, Italy
- Medical Oncology Unit, Torina Clinic, I-90145 Palermo, Italy
| | - Daniela Sambataro
- Department of Medicine and Surgery, Kore University of Enna, I-94100 Enna, Italy
- Medical Oncology Unit, Umberto I Hospital, I-94100 Enna, Italy
| |
Collapse
|
11
|
Fontana RJ, Li YJ, Chen V, Kleiner D, Stolz A, Odin J, Vuppalanchi R, Gu J, Dara L, Barnhart H. Genetic variants associated with immune-mediated liver injury from checkpoint inhibitors. Hepatol Commun 2024; 8:e0518. [PMID: 39185906 PMCID: PMC11357698 DOI: 10.1097/hc9.0000000000000518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 07/14/2024] [Indexed: 08/27/2024] Open
Abstract
BACKGROUND The clinical features, liver histology, and genetic variants in 57 patients with moderate to severe immune-mediated liver injury from checkpoint inhibitors (ILICI) are presented. METHODS Between 2010 and 2022, 57 high-causality ILICI cases were enrolled in the Drug-Induced Liver Injury Network. HLA and selected candidate gene variants were tested for association with ILICI risk compared to the general population and other DILI controls. RESULTS The 57 high-causality cases were attributed to pembrolizumab (16), ipilimumab (15), ipilimumab and nivolumab (13), and other immune checkpoint inhibitors (13) and occurred at a median of 72 days after the first infusion. Median age was 57.8 years, 66% male, and 89% were non-Hispanic Whites. At DILI onset, 53% had hepatocellular, 35% mixed, and 15% cholestatic, with younger patients more likely to have hepatocellular injury. The incidence of ANA, smooth muscle antibody, and elevated IgG levels was low (17%, 23%, and 0%), but corticosteroids were given to 86%. Microgranulomas and hepatic steatosis were seen in 54% and 46% of the 26 liver biopsies, respectively. The HLA alleles associated with autoimmune hepatitis were not over-represented, but 2 host immune response genes (EDIL3 and SAMA5A) and 3 other genes (GABRP, SMAD3, and SLCO1B1) were associated with ILICI (OR: 2.08-2.4, p<0.01). CONCLUSIONS ILICI typically arises within 12 weeks of initiating immunotherapy and is self-limited in most cases. Genetic variants involved in host T-cell regulation and drug disposition were identified, implicating these pathways in the pathogenesis of ILICI. If validated, these findings could lead to improved diagnostic instruments and possible treatments for ILICI.
Collapse
Affiliation(s)
- Robert J. Fontana
- Division of Gastroenterology & Hepatology, Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Yi-Ju Li
- Department of Biostatistics and Bioinformatics, Duke School of Medicine, Durham, North Carolina, USA
| | - Vincent Chen
- Division of Gastroenterology & Hepatology, Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - David Kleiner
- Laboratory of Pathology, Intramural Division, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Andrew Stolz
- Department of Medicine, University of Southern California, Los Angeles, California, USA
| | - Joe Odin
- Recanati-Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Raj Vuppalanchi
- Division of Gastroenterology & Hepatology, Department of Medicine, Indiana University, Indianapolis, Indiana, USA
| | - Jiezhun Gu
- Duke Clinical Research Institute, Durham, North Carolina, USA
| | - Lily Dara
- Department of Medicine, University of Southern California, Los Angeles, California, USA
| | - Huiman Barnhart
- Duke Clinical Research Institute, Durham, North Carolina, USA
| |
Collapse
|
12
|
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.
Collapse
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
| |
Collapse
|
13
|
Abdel-Wahab N, Suarez-Almazor ME. Rheumatic adverse events of immune checkpoint inhibitors in cancer immunotherapy. Expert Rev Clin Immunol 2024; 20:873-893. [PMID: 38400840 PMCID: PMC11449381 DOI: 10.1080/1744666x.2024.2323966] [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: 11/03/2023] [Accepted: 02/19/2024] [Indexed: 02/26/2024]
Abstract
INTRODUCTION The advent of immune checkpoint inhibitors (ICIs) in cancer treatment has marked a transformative era, albeit tempered by immune-related adverse events (irAEs), including those impacting the musculoskeletal system. The lack of precise epidemiologic data on rheumatic irAEs is attributed to factors such as potential underrecognition, underreporting in clinical trials, and the tendency to overlook manifestations without immediate life-threatening implications, further complicating the determination of accurate incidence rates, while the complete understanding of the mechanisms driving rheumatic irAEs remains elusive. AREAS COVERED This literature review comprehensively examines rheumatic irAEs in cancer patients undergoing ICI therapy, encompassing epidemiology, risk factors, mechanisms, clinical manifestations, and current management guidance for prevalent conditions such as inflammatory arthritis, polymyalgia rheumatica, and myositis. Less frequent rheumatic and musculoskeletal irAEs are also explored, alongside insights into ongoing clinical trials testing therapeutic and preventive strategies for irAEs. A thorough literature search on Medline and the National Cancer Institute Clinical Trials Database was conducted up to October 2023 to compile relevant information. EXPERT OPINION In light of the evolving landscape of cancer immunotherapy, there is a compelling need for prospective longitudinal studies to enhance understanding and inform clinical management strategies for rheumatic irAEs.
Collapse
Affiliation(s)
- Noha Abdel-Wahab
- Section of Rheumatology and Clinical Immunology, Department of General Internal Medicine; and Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Rheumatology and Rehabilitation, Assiut University Faculty of Medicine, Assiut University Hospitals, Assiut, Egypt
| | - Maria E Suarez-Almazor
- Department of Health Services Research; and Section of Rheumatology and Clinical Immunology, Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| |
Collapse
|
14
|
Jaing TH, Wang YL, Chiu CC. Immune Checkpoint Inhibitors for Pediatric Cancers: Is It Still a Stalemate? Pharmaceuticals (Basel) 2024; 17:991. [PMID: 39204096 PMCID: PMC11357301 DOI: 10.3390/ph17080991] [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: 05/18/2024] [Revised: 07/11/2024] [Accepted: 07/24/2024] [Indexed: 09/03/2024] Open
Abstract
The knowledge surrounding the application of immune checkpoint inhibitors (ICIs) in the treatment of pediatric cancers is continuously expanding and evolving. These therapies work by enhancing the body's natural immune response against tumors, which may have been suppressed by certain pathways. The effectiveness of ICIs in treating adult cancers has been widely acknowledged. However, the results of early phase I/II clinical trials that exclusively targeted the use of ICIs for treating different pediatric cancers have been underwhelming. The response rates to ICIs have generally been modest, except for cases of pediatric classic Hodgkin lymphoma. There seems to be a notable disparity in the immunogenicity of childhood cancers compared to adult cancers, potentially accounting for this phenomenon. On average, childhood cancers tend to have significantly fewer neoantigens. In recent times, there has been a renewed sense of optimism regarding the potential benefits of ICI therapies for specific groups of children with cancer. In initial research, individuals diagnosed with pediatric hypermutated and SMARCB1-deficient cancers have shown remarkable positive outcomes when treated with ICI therapies. This is likely due to the underlying biological factors that promote the expression of neoantigens and inflammation within the tumor. Ongoing trials are diligently assessing the effectiveness of ICIs for pediatric cancer patients in these specific subsets. This review aimed to analyze the safety and effectiveness of ICIs in pediatric patients with different types of highly advanced malignancies.
Collapse
Affiliation(s)
- Tang-Her Jaing
- Division of Hematology and Oncology, Department of Pediatrics, Chang Gung Memorial Hospital, 5 Fu-Shin Street, Kwei-Shan, Taoyuan 33315, Taiwan, China;
| | - Yi-Lun Wang
- Division of Hematology and Oncology, Department of Pediatrics, Chang Gung Memorial Hospital, 5 Fu-Shin Street, Kwei-Shan, Taoyuan 33315, Taiwan, China;
| | - Chia-Chi Chiu
- Division of Nursing, Chang Gung Memorial Hospital, 5 Fu-Shin Street, Kwei-Shan, Taoyuan 33315, Taiwan, China;
| |
Collapse
|
15
|
Likhitsup A, Fontana RJ. Diagnosis and management of immune mediated liver injury from checkpoint inhibitors. Curr Opin Gastroenterol 2024; 40:164-171. [PMID: 38375823 DOI: 10.1097/mog.0000000000001015] [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] [Indexed: 02/21/2024]
Abstract
PURPOSE OF REVIEW The aim is to summarize the latest data on the incidence, clinical manifestations, and management of immune- mediated liver injury from checkpoint inhibitors (ILICI). RECENT FINDINGS ILICI develops in 10-15% of oncology patients receiving immunotherapy with most having asymptomatic serum aminotransferase and/or alkaline phosphatase elevations. Most grade 1-2 ILICI patients improve with drug discontinuation and/or short-term oral corticosteroids. In contrast, the 2-3% with grade 3/4 hepatotoxicity frequently require oral or intravenous corticosteroids and some are hospitalized to initiate further immunosuppression with mycophenolate mofetil or azathioprine. Liver biopsy is generally reserved for patients with atypical features or those with severe hepatotoxicity who fail to respond to treatment. Up to 3% of ILICI patients with a cholestatic profile have MRI evidence of intra or extrahepatic cholangitis that responds poorly to immunosuppression. Most ILICI patients improve during follow-up and liver-related death is very uncommon (<1%). Up to 30% of rechallenged ILICI patients develop recurrent hepatotoxicity with a shorter latency. SUMMARY ILICI is increasingly encountered by gastroenterologists evaluating oncology patients with abnormal liver biochemistries. A stepwise approach to exclude viral hepatitis, alcohol, hepatic metastases, and pancreaticobiliary disease is recommended. The majority of ILICI patients fully recover with ICI discontinuation and short-term corticosteroids or a second line immunosuppressant.
Collapse
Affiliation(s)
- Alisa Likhitsup
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | | |
Collapse
|
16
|
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.
Collapse
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
| |
Collapse
|
17
|
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.
Collapse
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.)
| |
Collapse
|
18
|
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.
Collapse
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
| |
Collapse
|
19
|
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.
Collapse
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
| |
Collapse
|
20
|
Xiao CL, Liu WH, Luo ZY, Li WR, Li YK, Ren H, Luo JQ. Blood Group Antigen A Carriers Exhibit an Extended Progression-Free Survival with no more Immune-Related Adverse Events. Clin Pharmacol Ther 2024; 115:545-555. [PMID: 38069481 DOI: 10.1002/cpt.3140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 12/01/2023] [Indexed: 12/27/2023]
Abstract
Extensive investigations have been conducted regarding the potential correlation between blood type and the immune system, as well as cancer risk in the Southern Chinese population. However, the prognostic value of the blood group and its genetic determinants in the context of immune checkpoint inhibitor (ICI) treatment remains unclear. Therefore, the associations between the ABO blood group and its single nucleotide polymorphisms (SNPs) were examined in relation to ICI treatment outcomes in 370 eligible patients with cancer. This approach allowed us to derive the blood group from the SNPs responsible for blood group determination. In the discovery cohort (N = 168), antigen A carriers (blood types A and AB) exhibited an extended progression-free survival (PFS; hazard ratio (HR) = 0.58, 95% confidence interval (CI) = 0.34-0.98). The association results from the SNP-derived blood were consistent with those from the measured blood group. In the validation cohort (N = 202), Cox regression analysis revealed that the antigen A carriers (rs507666 AA+GA genotype carriers) experienced significantly extended PFS compared with the non-antigen A carriers (HR = 0.61, 95% CI = 0.40-0.93). Therefore, a longer PFS was observed in antigen A carriers (P value = 0.003, HR = 0.60, 95% CI = 0.44-0.84). Furthermore, haplotype 2 carriers (rs507666 GA and rs659104 GG) demonstrated both extended PFS and improved overall survival. Notably, the presence of antigen A was not associated with the occurrence of overall immune-related adverse events (irAEs) or organ-specific toxicity. In summary, our findings revealed that antigen A carriers did not experience a higher incidence of irAEs while exhibiting better immunotherapy efficacy.
Collapse
Affiliation(s)
- Chen-Lin Xiao
- Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Wen-Hui Liu
- Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Zhi-Ying Luo
- Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Wen-Ru Li
- Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Yi-Ke Li
- Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Huan Ren
- Department of Pharmacy, Hunan Provincial People's Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Jian-Quan Luo
- Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| |
Collapse
|
21
|
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.
Collapse
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
| | | |
Collapse
|
22
|
Abstract
Cancer remains a leading cause of mortality on a global scale. Lung cancer, specifically non-small cell lung cancer (NSCLC), is a prominent contributor to this burden. The management of NSCLC has advanced substantially in recent years, with immunotherapeutic agents, such as immune checkpoint inhibitors (ICIs), leading to improved patient outcomes. Although generally well tolerated, the administration of ICIs can result in unique side effects known as immune-related adverse events (irAEs). The occurrence of irAEs involving the lungs, specifically checkpoint inhibitor pneumonitis (CIP), can have a profound effect on both future therapy options and overall survival. Despite CIP being one of the more common serious irAEs, limited treatment options are currently available, in part due to a lack of understanding of the underlying mechanisms involved in its development. In this Review, we aim to provide an overview of the epidemiology and clinical characteristics of CIP, followed by an examination of the emerging literature on the pathobiology of this condition.
Collapse
Affiliation(s)
| | - Karthik Suresh
- Division of Pulmonary & Critical Care Medicine, Department of Medicine, and
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| |
Collapse
|
23
|
Cunningham M, Gupta R, Butler M. Checkpoint inhibitor hepatotoxicity: pathogenesis and management. Hepatology 2024; 79:198-212. [PMID: 36633259 DOI: 10.1097/hep.0000000000000045] [Citation(s) in RCA: 19] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 11/08/2022] [Indexed: 01/13/2023]
Abstract
Immunotherapy, including immune checkpoint inhibitor (ICI) therapy, has been a paradigm shift in cancer therapeutics, producing durable cancer responses across a range of primary malignancies. ICI drugs increase immune activity against tumor cells, but may also reduce immune tolerance to self-antigens, resulting in immune-mediated tissue damage. ICI-associated hepatotoxicity usually manifests as hepatocellular enzyme elevation and may occur in 2%-25% of ICI-treated patients. Although ICI-associated hepatotoxicity is clinically and pathologically distinct from idiopathic autoimmune hepatitis, our understanding of its pathogenesis continues to evolve. Pending greater understanding of the pathophysiology, mainstay of management remains through treatment with high-dose corticosteroids. This approach works for many patients, but up to 30% of patients with high-grade hepatotoxicity may not respond to corticosteroids alone. Furthermore, atypical cholestatic presentations are increasingly recognized, and rare cases of fulminant hepatitis due to ICI hepatotoxicity have been reported. Optimal management for these challenging patients remains uncertain. Herein, we review the current understanding of pathogenesis of ICI-associated toxicities, with a focus on hepatotoxicity. Based on the existing literature, we propose evolving management approaches to incorporate strategies to limit excess corticosteroid exposure, and address rare but important presentations of cholestatic hepatitis and fulminant liver failure. Finally, as ICI hepatotoxicity frequently occurs in the context of treatment for advanced malignancy, we review the impact of hepatotoxicity and its treatment on cancer outcomes, and the overall safety of re-challenge with ICI, for patients who may have limited treatment options.
Collapse
Affiliation(s)
- Morven Cunningham
- Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada
| | - Rohit Gupta
- Toronto Centre for Liver Disease, University Health Network, Toronto, Ontario, Canada
| | - Marcus Butler
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| |
Collapse
|
24
|
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.
Collapse
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.
| |
Collapse
|
25
|
Boutros A, Carosio R, Campanella D, Spagnolo F, Banelli B, Morabito A, Pistillo M, Croce E, Cecchi F, Pronzato P, Queirolo P, Raposio E, Fontana V, Tanda E. The predictive and prognostic role of single nucleotide gene variants of PD-1 and PD-L1 in patients with advanced melanoma treated with PD-1 inhibitors. IMMUNO-ONCOLOGY TECHNOLOGY 2023; 20:100408. [PMID: 38192613 PMCID: PMC10772261 DOI: 10.1016/j.iotech.2023.100408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/10/2024]
Abstract
Background Despite having revolutionized the treatment paradigm for advanced melanoma, not all patients benefit from immune checkpoint inhibitor therapy. To date, there are no predictive biomarkers for response or the occurrence of immune-related adverse events (irAEs) to programmed cell death protein 1 (PD-1) inhibitors. Our aim was to investigate the predictive and prognostic role of single nucleotide variants (SNVs) of genes involved in the PD-1 axis. Methods We analysed, in metastatic melanoma patients treated with nivolumab or pembrolizumab, five PD-1 SNVs, namely PD1.3 G>A (rs11568821), PD1.5 C>T (rs2227981), PD1.6 G>A (rs10204525), PD1.7 T>C(rs7421861), PD1.10 C>G (rs5582977) and three programmed death-ligand 1 (PD-L1) SNVs: +8293 C>A (rs2890658), PD-L1 C>T (rs2297136) and PD-L1 G>C (rs4143815). Association of SNV genotypic frequencies with best overall response to PD-1 inhibitors and development of irAEs were estimated through a modified Poisson regression. A Cox regression modelling approach was applied to evaluate the SNV association with OS. Results A total of 125 patients with advanced melanoma were included in the analysis. A reduction in irAEs risk was observed in patients carrying the PD-L1 +8293 C/A genotype compared with those carrying the C/C genotype (risk ratio = 0.45; 95% CL 0.22-0.93; P = 0.031). A trend for a reduction in irAEs was also observed with the PD1.5 T allele (risk ratio = 0.70, 95% confidence limits 0.48-1.01 versus C allele). None of the SNVs was associated with response to therapy. Finally, a survival benefit was observed in patients harbouring the PD1.7 C/C genotype (hazard ratio = 0.37; 95% confidence limits 0.14-0.96; P = 0.028) in the homozygous model. Conclusions Our study showed that PD-1.5 and PD-L1 +8293 SNVs may play a role as a predictive biomarker of development of irAEs to PD-1 inhibitors. PD1.7 SNV may also be associated with a reduction of the risk of death, although further translational research is needed to confirm these results.
Collapse
Affiliation(s)
- A. Boutros
- Skin Cancer Unit, Medical Oncology 2, IRCCS Ospedale Policlinico San Martino, Genoa
- Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Genoa
| | - R. Carosio
- Tumor Epigenetics Unit, IRCCS Ospedale Policlinico San Martino, Genoa
| | - D. Campanella
- Clinical Epidemiology Unit, IRCCS Ospedale Policlinico San Martino, Genoa
| | - F. Spagnolo
- Skin Cancer Unit, Medical Oncology 2, IRCCS Ospedale Policlinico San Martino, Genoa
- Department of Surgical Sciences and Integrated Diagnostics (DISC), Plastic Surgery Division, University of Genova, Genoa
| | - B. Banelli
- Tumor Epigenetics Unit, IRCCS Ospedale Policlinico San Martino, Genoa
| | - A. Morabito
- Tumor Epigenetics Unit, IRCCS Ospedale Policlinico San Martino, Genoa
| | - M.P. Pistillo
- Tumor Epigenetics Unit, IRCCS Ospedale Policlinico San Martino, Genoa
| | - E. Croce
- Skin Cancer Unit, Medical Oncology 2, IRCCS Ospedale Policlinico San Martino, Genoa
- Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Genoa
| | - F. Cecchi
- Skin Cancer Unit, Medical Oncology 2, IRCCS Ospedale Policlinico San Martino, Genoa
| | - P. Pronzato
- Skin Cancer Unit, Medical Oncology 2, IRCCS Ospedale Policlinico San Martino, Genoa
| | - P. Queirolo
- Division of Melanoma Sarcoma and Rare Tumors, IRCCS European Institute of Oncology, Milan, Italy
| | - E. Raposio
- Department of Surgical Sciences and Integrated Diagnostics (DISC), Plastic Surgery Division, University of Genova, Genoa
| | - V. Fontana
- Clinical Epidemiology Unit, IRCCS Ospedale Policlinico San Martino, Genoa
| | - E.T. Tanda
- Skin Cancer Unit, Medical Oncology 2, IRCCS Ospedale Policlinico San Martino, Genoa
| |
Collapse
|
26
|
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.
Collapse
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;
| |
Collapse
|
27
|
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.
Collapse
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
| |
Collapse
|
28
|
Curkovic NB, Johnson DB. Updates in toxicities associated with immune checkpoint inhibitors. Expert Rev Clin Immunol 2023; 19:1117-1129. [PMID: 37276071 PMCID: PMC10527235 DOI: 10.1080/1744666x.2023.2221434] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 05/31/2023] [Indexed: 06/07/2023]
Abstract
INTRODUCTION Immune checkpoint inhibitors (ICIs) have become a pillar of treatment for numerous cancers with increasing use in combination with other ICIs and in earlier stages of disease treatment. Although effective, ICI use is accompanied by a milieu of potentially bothersome or even life-threatening toxicities known as immune-related adverse events (irAEs), necessitating careful monitoring and early intervention. AREAS COVERED In this review, we provide an overview of recent advances surrounding toxicity pathophysiology and treatment in the context of relevant organ systems. An emphasis on current treatments by toxicity, as well as updates on steroid-refractory toxicities, chronic toxicities, and biomarkers will be a focus of this update on the current understanding of irAEs. EXPERT OPINION ICI toxicities are a major limitation on the deployment of multi-agent ICI regimens and are thus a major priority to understand, treat, and prevent. Recent developments have led to greater understanding of the pathophysiology of these events, which may lead to improved prevention or mitigation strategies. Further, early studies have also suggested steroid-sparing approaches that may be useful. Ultimately, preventing and managing irAEs will be a key goal toward successful ICI treatment across a broader range of patients with cancer.
Collapse
Affiliation(s)
| | - Douglas B. Johnson
- Department of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, Tennessee
| |
Collapse
|
29
|
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.
Collapse
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.
| |
Collapse
|
30
|
Les I, Martínez M, Pérez-Francisco I, Cabero M, Teijeira L, Arrazubi V, Torrego N, Campillo-Calatayud A, Elejalde I, Kochan G, Escors D. Predictive Biomarkers for Checkpoint Inhibitor Immune-Related Adverse Events. Cancers (Basel) 2023; 15:1629. [PMID: 36900420 PMCID: PMC10000735 DOI: 10.3390/cancers15051629] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/24/2023] [Accepted: 02/28/2023] [Indexed: 03/09/2023] Open
Abstract
Immune-checkpoint inhibitors (ICIs) are antagonists of inhibitory receptors in the immune system, such as the cytotoxic T-lymphocyte-associated antigen-4, the programmed cell death protein-1 and its ligand PD-L1, and they are increasingly used in cancer treatment. By blocking certain suppressive pathways, ICIs promote T-cell activation and antitumor activity but may induce so-called immune-related adverse events (irAEs), which mimic traditional autoimmune disorders. With the approval of more ICIs, irAE prediction has become a key factor in improving patient survival and quality of life. Several biomarkers have been described as potential irAE predictors, some of them are already available for clinical use and others are under development; examples include circulating blood cell counts and ratios, T-cell expansion and diversification, cytokines, autoantibodies and autoantigens, serum and other biological fluid proteins, human leucocyte antigen genotypes, genetic variations and gene profiles, microRNAs, and the gastrointestinal microbiome. Nevertheless, it is difficult to generalize the application of irAE biomarkers based on the current evidence because most studies have been retrospective, time-limited and restricted to a specific type of cancer, irAE or ICI. Long-term prospective cohorts and real-life studies are needed to assess the predictive capacity of different potential irAE biomarkers, regardless of the ICI type, organ involved or cancer site.
Collapse
Affiliation(s)
- Iñigo Les
- Internal Medicine Department, Navarre University Hospital, 31008 Pamplona, Spain
- Autoimmune Diseases Unit, Internal Medicine Department, Navarre University Hospital, 31008 Pamplona, Spain
- Inflammatory and Immune-Mediated Diseases Group, Instituto de Investigación Sanitaria de Navarra (IdISNA), Navarrabiomed-Public University of Navarre, 31008 Pamplona, Spain
| | - Mireia Martínez
- Osakidetza Basque Health Service, Department of Medical Oncology, Araba University Hospital, 01009 Vitoria-Gasteiz, Spain
- Lung Cancer Research Group, Bioaraba Health Research Institute, 01006 Vitoria-Gasteiz, Spain
| | - Inés Pérez-Francisco
- Breast Cancer Research Group, Bioaraba Health Research Institute, 01006 Vitoria-Gasteiz, Spain
| | - María Cabero
- Clinical Trials Platform, Bioaraba Health Research Institute, 01006 Vitoria-Gasteiz, Spain
| | - Lucía Teijeira
- Medical Oncology Department, Navarre University Hospital, 31008 Pamplona, Spain
| | - Virginia Arrazubi
- Medical Oncology Department, Navarre University Hospital, 31008 Pamplona, Spain
| | - Nuria Torrego
- Osakidetza Basque Health Service, Department of Medical Oncology, Araba University Hospital, 01009 Vitoria-Gasteiz, Spain
- Lung Cancer Research Group, Bioaraba Health Research Institute, 01006 Vitoria-Gasteiz, Spain
| | - Ana Campillo-Calatayud
- Inflammatory and Immune-Mediated Diseases Group, Instituto de Investigación Sanitaria de Navarra (IdISNA), Navarrabiomed-Public University of Navarre, 31008 Pamplona, Spain
| | - Iñaki Elejalde
- Internal Medicine Department, Navarre University Hospital, 31008 Pamplona, Spain
- Autoimmune Diseases Unit, Internal Medicine Department, Navarre University Hospital, 31008 Pamplona, Spain
- Inflammatory and Immune-Mediated Diseases Group, Instituto de Investigación Sanitaria de Navarra (IdISNA), Navarrabiomed-Public University of Navarre, 31008 Pamplona, Spain
| | - Grazyna Kochan
- Oncoimmunology Group, Instituto de Investigación Sanitaria de Navarra (IdISNA), Navarrabiomed-Public University of Navarre, 31008 Pamplona, Spain
| | - David Escors
- Oncoimmunology Group, Instituto de Investigación Sanitaria de Navarra (IdISNA), Navarrabiomed-Public University of Navarre, 31008 Pamplona, Spain
| |
Collapse
|
31
|
Xin Z, You L, Na F, Li J, Chen M, Song J, Bai L, Chen J, Zhou J, Ying B. Immunogenetic variations predict immune-related adverse events for PD-1/PD-L1 inhibitors. Eur J Cancer 2023; 184:124-136. [PMID: 36917924 DOI: 10.1016/j.ejca.2023.01.034] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Accepted: 01/30/2023] [Indexed: 02/24/2023]
Abstract
BACKGROUND PD-1/PD-L1 inhibitors have brought remarkable benefits but can cause profound immune-related adverse events (irAEs). The host immunogenetic background is likely to play a role in irAE susceptibility. In this study, we aimed to identify potential immunogenetic biomarkers to predict irAEs. METHODS Patients with solid tumours receiving PD-1/PD-L1 blockade were recruited and followed up. Genes considered pivotal contributors to tumour-immunity and autoimmune diseases were screened out via protein-protein interaction network and Cytoscape. Consequently, thirty-nine variants in eighteen genes were genotyped using the multiplex genotyping assay. Association analysis between genetic variants and irAEs as well as irAEs-free survival was performed. RESULTS Four immunogenetic variants as predictive biomarkers of irAEs were identified. The C allele of Mitogen-Activated Protein Kinase 1 (MAPK1) rs3810610 (odds ratio [OR] = 1.495, 95% confidence interval [CI] = 1.093-2.044, P = 0.012) was a risk predictor while the A allele of PTPRC rs6428474 (OR = 0.717, 95% CI = 0.521-0.987, P = 0.041) was a protective factor for all-grade irAEs. The A allele of ADAD1 rs17388568 (OR = 2.599, 95% CI = 1.355-4.983, P = 0.003) increased the risk while the G allele of IL6 rs1800796 (OR = 0.425, 95% CI = 0.205-0.881, P = 0.018) protected patients from high-grade irAEs. Significant immunogenetic variants reached a similar tendency in PD-1 blockade or lung cancer subgroups. In multivariate Cox regression analysis, the MAPK1 rs3810610 was an independent factor regarding all-grade irAEs-free survival (CC versus CT or TT: hazard ratio [HR] = 0.71, 95% CI = 0.52-0.99, P = 0.042). ADAD1 rs17388568 (AA versus AG or GG: HR = 0.11, 95% CI = 0.025-0.49, P = 0.004) and IL6 rs1800796 (GG or GC versus CC: HR = 3.10, 95% CI = 1.315-7.29, P = 0.01) were independent variables for high-grade irAEs-free survival. CONCLUSION We first identified several immunogenetic polymorphisms associated with irAEs and irAEs-free survival in PD-1/PD-L1 blockade-treated tumour patients, and they may serve as potential predictive biomarkers.
Collapse
Affiliation(s)
- Zhaodan Xin
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, 610041, PR China
| | - Liting You
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, 610041, PR China; Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, PR China
| | - Feifei Na
- Department of Thoracic Cancer, West China Hospital, Sichuan University, Chengdu, 610041, PR China
| | - Jin Li
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, 610041, PR China
| | - Min Chen
- Department of Laboratory Medicine, The First Affiliated Hospital of Hainan Medical College, Haikou, Hainan Province 570100, PR China
| | - Jiajia Song
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, 610041, PR China
| | - Ling Bai
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, 610041, PR China
| | - Jie Chen
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, 610041, PR China.
| | - Juan Zhou
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, 610041, PR China.
| | - Binwu Ying
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, 610041, PR China.
| |
Collapse
|
32
|
Germline genetic variation and predicting immune checkpoint inhibitor induced toxicity. NPJ Genom Med 2022; 7:73. [PMID: 36564402 PMCID: PMC9789157 DOI: 10.1038/s41525-022-00345-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 12/07/2022] [Indexed: 12/25/2022] Open
Abstract
Immune checkpoint inhibitor (ICI) therapy has revolutionised the treatment of various cancer types. ICIs reinstate T-cell function to elicit an anti-cancer immune response. The resulting immune response can however have off-target effects which manifest as autoimmune type serious immune-related adverse events (irAE) in ~10-55% of patients treated. It is currently challenging to predict both who will experience irAEs and to what severity. Identification of patients at high risk of serious irAE would revolutionise patient care. While the pathogenesis driving irAE development is still unclear, host genetic factors are proposed to be key determinants of these events. This review presents current evidence supporting the role of the host genome in determining risk of irAE. We summarise the spectrum and timing of irAEs following treatment with ICIs and describe currently reported germline genetic variation associated with expression of immuno-modulatory factors within the cancer immunity cycle, development of autoimmune disease and irAE occurrence. We propose that germline genetic determinants of host immune function and autoimmune diseases could also explain risk of irAE development. We also endorse genome-wide association studies of patients being treated with ICIs to identify genetic variants that can be used in polygenic risk scores to predict risk of irAE.
Collapse
|
33
|
Luo J, Chen H, Ma F, Xiao C, Sun B, Liu Y, Tang H, Yang Y, Liu W, Luo Z. Vitamin D metabolism pathway polymorphisms are associated with efficacy and safety in patients under anti-PD-1 inhibitor therapy. Front Immunol 2022; 13:937476. [PMID: 36172344 PMCID: PMC9510606 DOI: 10.3389/fimmu.2022.937476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 08/09/2022] [Indexed: 11/16/2022] Open
Abstract
AIM Vitamin D (VitD) signaling has been increasingly investigated for its role in stimulating the innate and adaptive immune systems and suppressing inflammatory responses. Therefore, we examined the associations between VitD-related genetic polymorphisms, plasma 25-hydroxyvitamin D (25(OH)D), and the efficacy and safety of immune checkpoint inhibitors (ICIs). PATIENTS AND METHODS A total of 13 single-nucleotide polymorphisms (SNPs) in VitD metabolic pathway genes were genotyped in 343 cancer patients receiving ICI treatment using the MassARRAY platform. In 65 patients, the associations between plasma 25(OH)D levels and ICI treatment outcomes were investigated further. RESULTS We found that the CYP24A1 rs6068816TT and rs2296241AA genotypes were significantly higher in patients who responded to ICIs. Furthermore, patients with higher plasma 25(OH)D levels had a better treatment response. The distribution of allele and genotype frequencies showed that three SNPs (rs10877012, rs2762934, and rs8018720) differed significantly between patients who had immune-related adverse events (irAEs) and those who did not. There was no statistically significant relationship between plasma 25(OH)D levels and the risk of irAEs. CONCLUSION In summary, our findings showed that genetic variations in the VitD metabolism pathway were associated with ICI treatment outcomes, and VitD supplementation may be useful in improving ICI treatment efficacy.
Collapse
Affiliation(s)
- Jianquan Luo
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Huiqing Chen
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Fang Ma
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Chenlin Xiao
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Bao Sun
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Yiping Liu
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Haoneng Tang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Yue Yang
- Department of Spine Surgery, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Wenhui Liu
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Zhiying Luo
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| |
Collapse
|
34
|
Issa M, Tang J, Guo Y, Coss C, Mace TA, Bischof J, Phelps M, Presley CJ, Owen DH. Risk factors and predictors of immune-related adverse events: implications for patients with non-small cell lung cancer. Expert Rev Anticancer Ther 2022; 22:861-874. [PMID: 35786142 DOI: 10.1080/14737140.2022.2094772] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Immune checkpoint inhibitors (ICI) are now utilized as a standard of care treatment for multiple cancers, including in both the metastatic setting as well as in earlier stages of disease. The identification of unique immune-related adverse events (irAE) that occur during ICI treatment has led to intense research to identify potential risk factors and biomarkers that may assist in clinical decision making. Although initial studies in ICI were primarily in advanced stage disease, the use of ICI in earlier stages of disease as adjuvant therapies requires a better understanding of patient risk stratification to mitigate or prevent serious irAE. AREAS COVERED In this review, we set out to describe the current state of research regarding potential risk factors for irAE in patients with non-small cell lung cancer, as well as explore the barriers to understanding irAE. We review data from irAE that occur in large phase 3 trials and prospective studies focusing on irAE, as well as the many retrospective studies that currently form the bulk of our understanding of irAE.
Collapse
Affiliation(s)
- Majd Issa
- Division of Medical Oncology, Department of Internal Medicine, the Ohio State University Wexner Medical Center - Comprehensive Cancer Center, Columbus, USA
| | - Joy Tang
- Division of Medical Oncology, Department of Internal Medicine, the Ohio State University Wexner Medical Center - Comprehensive Cancer Center, Columbus, USA
| | - Yizhen Guo
- College of Pharmacy, the Ohio State University Wexner Medical Center - Comprehensive Cancer Center, Columbus, USA
| | - Chris Coss
- College of Pharmacy, the Ohio State University Wexner Medical Center - Comprehensive Cancer Center, Columbus, USA
| | - Thomas A Mace
- Division of Gastroenterology, Hepatology & Nutrition, Department of Internal Medicine, the Ohio State University Wexner Medical Center, Columbus, USA
| | - Jason Bischof
- Department of Emergency Medicine, the Ohio State University Wexner Medical Center - Comprehensive Cancer Center, Columbus, USA
| | - Mitch Phelps
- College of Pharmacy, the Ohio State University Wexner Medical Center - Comprehensive Cancer Center, Columbus, USA
| | - Carolyn J Presley
- Division of Medical Oncology, Department of Internal Medicine, the Ohio State University Wexner Medical Center - Comprehensive Cancer Center, Columbus, USA
| | - Dwight H Owen
- Division of Medical Oncology, Department of Internal Medicine, the Ohio State University Wexner Medical Center - Comprehensive Cancer Center, Columbus, USA
| |
Collapse
|
35
|
Les I, Pérez-Francisco I, Cabero M, Sánchez C, Hidalgo M, Teijeira L, Arrazubi V, Domínguez S, Anaut P, Eguiluz S, Elejalde I, Herrera A, Martínez M. Prediction of Immune-Related Adverse Events Induced by Immune Checkpoint Inhibitors With a Panel of Autoantibodies: Protocol of a Multicenter, Prospective, Observational Cohort Study. Front Pharmacol 2022; 13:894550. [PMID: 35721217 PMCID: PMC9198493 DOI: 10.3389/fphar.2022.894550] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 04/27/2022] [Indexed: 11/13/2022] Open
Abstract
Introduction: Immune checkpoint inhibitor (ICI) therapy is markedly improving the prognosis of patients with several types of cancer. On the other hand, the growth in the use of these drugs in oncology is associated with an increase in multiple immune-related adverse events (irAEs), whose optimal prevention and management remain unclear. In this context, there is a need for reliable and validated biomarkers to predict the occurrence of irAEs in patients treated with ICIs. Thus, the main objective of this study is to evaluate the diagnostic performance of a sensitive routinely available panel of autoantibodies consisting of antinuclear antibodies, rheumatoid factor, and antineutrophil cytoplasmic antibodies to identify patients at risk of developing irAEs. Methods and Analysis: A multicenter, prospective, observational, cohort study has been designed to be conducted in patients diagnosed with cancer amenable to ICI therapy. Considering the percentage of ICI-induced irAEs to be 25% and a loss to follow-up of 5%, it has been estimated that a sample size of 294 patients is required to detect an expected sensitivity of the autoantibody panel under study of 0.90 with a confidence interval (95%) of no less than 0.75. For 48 weeks, patients will be monitored through the oncology outpatient clinics of five hospitals in Spain. Immune-related adverse events will be defined and categorized according to CTCAE v. 5.0. All the patients will undergo ordinary blood tests at specific moments predefined per protocol and extraordinary blood tests at the time of any irAE being detected. Ordinary and extraordinary samples will be frozen and stored in the biobank until analysis in the same autoimmunity laboratory when the whole cohort reaches week 48. A predictive model of irAEs will be constructed with potential risk factors of immune-related toxicity including the autoantibody panel under study. Ethics and Dissemination: This protocol was reviewed and approved by the Ethical Committee of the Basque Country and the Spanish Agency of Medicines and Medical Devices. Informed consent will be obtained from all participants before their enrollment. The authors declare that the results will be submitted to an international peer-reviewed journal for their prompt dissemination.
Collapse
Affiliation(s)
- Iñigo Les
- Internal Medicine Department, Navarra University Hospital, Pamplona, Spain.,Autoimmune Diseases Unit, Internal Medicine Department, Navarra University Hospital, Pamplona, Spain
| | - Inés Pérez-Francisco
- Bioaraba Health Research Institute, Breast Cancer Research Group, Vitoria-Gasteiz, Spain
| | - María Cabero
- Bioaraba Health Research Institute, Clinical Trials Platform, Vitoria-Gasteiz, Spain
| | - Cristina Sánchez
- Osakidetza Basque Health Service, Araba University Hospital, Department of Internal Medicine, Vitoria-Gasteiz, Spain
| | - María Hidalgo
- Osakidetza Basque Health Service, Araba University Hospital, Department of Medical Oncology, Vitoria-Gasteiz, Spain
| | - Lucía Teijeira
- Medical Oncology Department, Navarra University Hospital, Pamplona, Spain
| | - Virginia Arrazubi
- Medical Oncology Department, Navarra University Hospital, Pamplona, Spain
| | - Severina Domínguez
- Bioaraba Health Research Institute, Breast Cancer Research Group, Vitoria-Gasteiz, Spain.,Osakidetza Basque Health Service, Araba University Hospital, Department of Medical Oncology, Vitoria-Gasteiz, Spain
| | - Pilar Anaut
- Osakidetza Basque Health Service, Araba University Hospital, Department of Internal Medicine, Vitoria-Gasteiz, Spain
| | - Saioa Eguiluz
- Osakidetza Basque Health Service, Araba University Hospital, Department of Internal Medicine, Vitoria-Gasteiz, Spain
| | - Iñaki Elejalde
- Internal Medicine Department, Navarra University Hospital, Pamplona, Spain.,Autoimmune Diseases Unit, Internal Medicine Department, Navarra University Hospital, Pamplona, Spain
| | - Alberto Herrera
- Osakidetza Basque Health Service, Araba University Hospital, Department of Immunology, Vitoria-Gasteiz, Spain
| | - Mireia Martínez
- Osakidetza Basque Health Service, Araba University Hospital, Department of Medical Oncology, Vitoria-Gasteiz, Spain.,Bioaraba Health Research Institute, Lung Cancer Research Group, Vitoria-Gasteiz, Spain
| |
Collapse
|
36
|
Chennamadhavuni A, Abushahin L, Jin N, Presley CJ, Manne A. Risk Factors and Biomarkers for Immune-Related Adverse Events: A Practical Guide to Identifying High-Risk Patients and Rechallenging Immune Checkpoint Inhibitors. Front Immunol 2022; 13:779691. [PMID: 35558065 PMCID: PMC9086893 DOI: 10.3389/fimmu.2022.779691] [Citation(s) in RCA: 187] [Impact Index Per Article: 62.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Accepted: 03/31/2022] [Indexed: 12/19/2022] Open
Abstract
Immune-related adverse events (irAEs) are a range of complications associated with the use of immune-checkpoint inhibitors (ICIs). Two major classes of ICIs widely used are Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) and Programmed Cell death-1 (PD-1)/Programmed death-ligand 1 (PD-L1) inhibitors. High-grade irAEs are life-threatening and often cause a severe decline in performance status in such that patients do not qualify for any further anticancer treatments. It is difficult to generalize the evidence in the current literature on risk factors or biomarkers for the entire class of ICIs as the studies so far are either disease-specific (e.g., lung cancer or melanoma) or ICI agent-specific (e.g., pembrolizumab, ipilimumab) or irAE-specific (e.g., pneumonitis or gastritis). In this review, risk factors and biomarkers to consider before initiating or monitoring ICI are listed with a practical purpose in day-to-day practice. Risk factors are grouped into demographics and social history, medical history, and medication history, tumor-specific and agent-specific risk factors. A higher risk of irAE is associated with age <60 years, high body mass index, women on CTLA4 and men on PD-1/PD-L1 agents, and chronic smokers. Patients with significant kidney (Stage IV-V), cardiac (heart failure, coronary artery disease, myocardial infarction, hypertension), and lung (asthma, pulmonary fibrosis, and chronic obstructive pulmonary disease) are at a higher risk of respective organ-specific irAEs. Pre-existing autoimmune disease and chronic use of certain drugs (proton pump inhibitors, diuretics, anti-inflammatory drugs) also increase the irAE-risk. Biomarkers are categorized into circulating blood counts, cytokines, autoantibodies, HLA genotypes, microRNA, gene expression profiling, and serum proteins. The blood counts and certain protein markers (albumin and thyroid-stimulating hormone) are readily accessible in current practice. High neutrophil-lymphocyte ratio, eosinophil/monocyte/lymphocyte counts; TSH and troponins at diagnosis and drop in the white count and lymphocyte count can predict irAE. Other biomarkers with limited evidence are cytokines, autoantibodies, HLA genotypes, microRNA, and gene expression profiling. With fast-expanding approvals for ICIs in various cancer types, knowledge on risk factors and biomarkers can help providers assess the irAE-risk of their patients. Prospective disease and agent-specific studies are needed to provide further insight on this essential aspect of ICI therapy.
Collapse
Affiliation(s)
- Adithya Chennamadhavuni
- University of Iowa Hospitals and Clinics, Holden Comprehensive Cancer Center, Iowa City, IA, United States
| | - Laith Abushahin
- Department of Internal Medicine, Division of Medical Oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
| | - Ning Jin
- Department of Internal Medicine, Division of Medical Oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
| | - Carolyn J. Presley
- Department of Internal Medicine, Division of Medical Oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
| | - Ashish Manne
- Department of Internal Medicine, Division of Medical Oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
| |
Collapse
|
37
|
Can Immune-related adverse events serve as clinical biomarkers of PD-1/PD-L1 inhibitor efficacy in Pan-Cancer Patients? Int Immunopharmacol 2022; 108:108738. [PMID: 35395468 DOI: 10.1016/j.intimp.2022.108738] [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: 01/29/2022] [Revised: 03/16/2022] [Accepted: 03/25/2022] [Indexed: 11/21/2022]
Abstract
Although PD-1/PD-L1 inhibitors are widely used as first-line treatment for patients with advanced tumors or as adjuvant therapy for patients with early-stage tumors, their efficacy is only 15-60%. Increasing evidence has demonstrated that biomarkers such as PD-L1 expression levels, microsatellite instability, and tumor mutation burden may assist in predicting the anti-tumor efficacy of PD-1/PD-L1 inhibitors. However, their clinical application value is limited, and there is currently a dearth of specific clinical markers to monitor or predict the efficacy of PD-1/PD-L1 inhibitors. Recently, studies have exposed that the efficacy of PD-1/PD-L1 inhibitors is positively correlated with immune-related adverse events (irAEs), suggesting that the latter may effectively predict anti-tumor efficacy. While there are controversies, a systematic understanding of the reasons and influencing factors of its correlation is still lacking. Therefore, this review aimed to introduce and discuss the latest research on the correlation between the efficacy of PD-1/PD-L1 inhibitors and irAEs. We identified that this positive correlation might be related to adipose tissue, T cells, pharmacokinetic characteristics, and antigen spread. In addition, the severity of irAEs, the duration of the use of PD-1/PD-L1 inhibitors, the comprehensive evaluation method of the severity of irAEs, and the genetic determinants are potentially the most significant bias factors when evaluating this correlation.
Collapse
|
38
|
Vaddepally R, Doddamani R, Sodavarapu S, Madam NR, Katkar R, Kutadi AP, Mathew N, Garje R, Chandra AB. Review of Immune-Related Adverse Events (irAEs) in Non-Small-Cell Lung Cancer (NSCLC)—Their Incidence, Management, Multiorgan irAEs, and Rechallenge. Biomedicines 2022; 10:biomedicines10040790. [PMID: 35453540 PMCID: PMC9027181 DOI: 10.3390/biomedicines10040790] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 03/08/2022] [Accepted: 03/16/2022] [Indexed: 11/16/2022] Open
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced malignancies, including non-small cell lung cancer (NSCLC). These agents have improved clinical outcomes and have become quite an attractive alternative alone or combined with other treatments. Although ICIs are tolerated better, they also lead to unique toxicities, termed immune-related adverse events (irAEs). A reconstituted immune system may lead to dysregulation in normal immune self-tolerance and cause inflammatory side effects (irAEs). Although any organ system can be affected, immune-related adverse events most commonly involve the gastrointestinal tract, endocrine glands, skin, and liver. They can occur anytime during the treatment course and rarely even after completion. Owen and colleagues showed that approximately 30% of patients with NSCLC treated with ICIs develop irAEs. Kichenadasse et al. conducted a thorough evaluation of multiorgan irAEs, which is of particular interest because information regarding these types of irAEs is currently sparse. It is important to delineate between infectious etiologies and symptom progression during the management of irAEs. Close consultation with disease-specific subspecialties is encouraged. Corticosteroids are the mainstay of treatment of most irAEs. Early intervention with corticosteroids is crucial in the general management of immune-mediated toxicity. Grade 1–2 irAEs can be closely monitored; hypothyroidism and other endocrine irAEs may be treated with hormone supplementation without the need for corticosteroid therapy. Moderate- to high-dose steroids and other additional immunosuppressants such as tocilizumab and cyclophosphamide might be required in severe, grade 3–4 cases. Recently, increasing research on irAEs after immunotherapy rechallenge has garnered much attention. Dolladille and colleagues assessed the safety in patients with cancer who resumed therapy with the same ICIs and found that rechallenge was associated with about 25–30% of the same irAEs experienced previously (4). However, such data should be carefully considered. Further pooled analyses may be required before we conclude about ICIs’ safety in rechallenge.
Collapse
Affiliation(s)
- Raju Vaddepally
- Yuma Regional Medical Center, 2400 S Avenue A, Yuma, AZ 85364, USA; (N.R.M.); (R.K.); (A.P.K.); (N.M.); (A.B.C.)
- Correspondence:
| | - Rajiv Doddamani
- Slidell Memorial Hospital, 1001 Gause Blvd, Slidell, LA 70458, USA;
| | - Soujanya Sodavarapu
- San Joaquin General Hospital, 500 W Hospital Road, French Camp, CA 95231, USA;
| | - Narasa Raju Madam
- Yuma Regional Medical Center, 2400 S Avenue A, Yuma, AZ 85364, USA; (N.R.M.); (R.K.); (A.P.K.); (N.M.); (A.B.C.)
| | - Rujuta Katkar
- Yuma Regional Medical Center, 2400 S Avenue A, Yuma, AZ 85364, USA; (N.R.M.); (R.K.); (A.P.K.); (N.M.); (A.B.C.)
| | - Anupama P. Kutadi
- Yuma Regional Medical Center, 2400 S Avenue A, Yuma, AZ 85364, USA; (N.R.M.); (R.K.); (A.P.K.); (N.M.); (A.B.C.)
| | - Nibu Mathew
- Yuma Regional Medical Center, 2400 S Avenue A, Yuma, AZ 85364, USA; (N.R.M.); (R.K.); (A.P.K.); (N.M.); (A.B.C.)
| | - Rohan Garje
- Department of Internal Medicine-Hematology/Oncology, University of Iowa, Iowa, IA 52242, USA;
| | - Abhinav B. Chandra
- Yuma Regional Medical Center, 2400 S Avenue A, Yuma, AZ 85364, USA; (N.R.M.); (R.K.); (A.P.K.); (N.M.); (A.B.C.)
| |
Collapse
|
39
|
Smithy JW, Faleck DM, Postow MA. Facts and Hopes in Prediction, Diagnosis, and Treatment of Immune-Related Adverse Events. Clin Cancer Res 2021; 28:1250-1257. [PMID: 34921018 DOI: 10.1158/1078-0432.ccr-21-1240] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/20/2021] [Accepted: 12/07/2021] [Indexed: 11/16/2022]
Abstract
Over the past decade, the use of immune checkpoint inhibitors (ICI) has expanded across a wide spectrum of oncology indications. Immune-related adverse events (irAE) from ICIs represent a significant source of morbidity, and in rare instances, can lead to treatment-related mortality. There are significant opportunities to better identify patients at increased risk for immune-related toxicity, diagnose irAEs more accurately and earlier in their course, and develop more individualized therapeutic strategies once complications arise. Clinical characteristics, germline and somatic genetic features, microbiome composition, and circulating biomarkers have all been associated with higher risk of developing irAEs in retrospective series. Many of these data suggest that both antitumor and anti-host ICI-associated immune reactions may be driven by common features of either the tumor or the patient's preexisting immune milieu. While irAE diagnosis is currently based on clinical history, exclusion of alternative etiologies, and sometimes pathologic confirmation, novel blood-based and radiographic assays are in development to identify these complications more precisely. Anecdotal reports and small case series have highlighted the potential role of targeted immunomodulatory agents to treat irAEs, though further prospective investigation is needed to evaluate more rigorously their use in these settings. In this review, we highlight the current state of knowledge about predicting, diagnosing, and treating irAEs with a translational focus and discuss emerging strategies which aim to improve each of these domains.
Collapse
Affiliation(s)
- James W Smithy
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - David M Faleck
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Medical College, New York, New York
| | - Michael A Postow
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. .,Weill Cornell Medical College, New York, New York
| |
Collapse
|
40
|
Immune Checkpoint Blockade and Skin Toxicity Pathogenesis. J Invest Dermatol 2021; 142:951-959. [PMID: 34844731 DOI: 10.1016/j.jid.2021.06.040] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 06/18/2021] [Accepted: 06/29/2021] [Indexed: 12/12/2022]
Abstract
Immune checkpoint blockade has revolutionized the treatment of multiple tumor types, including melanoma and nonmelanoma skin cancers. The use of immune checkpoint blockade is curtailed by tissue toxicities termed immune-related adverse events (irAEs), which occur most quickly and most often in the skin. We review the rationale for immune checkpoint blockade use, current agents, use in skin cancers, autoimmune manifestations in the skin, and considerations for predictive biomarkers and treatment options on the basis of skin pathogenesis. We also highlight major gaps in the field and the lack of preclinical modeling in the skin. A deeper understanding of irAE pathophysiology may help to uncouple toxicity and efficacy but mandates an interdisciplinary approach, including foundational skin immunology and autoimmune pathogenesis.
Collapse
|
41
|
Luo J, Martucci VL, Quandt Z, Groha S, Murray MH, Lovly CM, Rizvi H, Egger JV, Plodkowski AJ, Abu-Akeel M, Schulze I, Merghoub T, Cardenas E, Huntsman S, Li M, Hu D, Gubens MA, Gusev A, Aldrich MC, Hellmann MD, Ziv E. Immunotherapy-Mediated Thyroid Dysfunction: Genetic Risk and Impact on Outcomes with PD-1 Blockade in Non-Small Cell Lung Cancer. Clin Cancer Res 2021; 27:5131-5140. [PMID: 34244291 PMCID: PMC8815444 DOI: 10.1158/1078-0432.ccr-21-0921] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/28/2021] [Accepted: 07/06/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Genetic differences in immunity may contribute to toxicity and outcomes with immune checkpoint inhibitor (CPI) therapy, but these relationships are poorly understood. We examined the genetics of thyroid immune-related adverse events (irAE). EXPERIMENTAL DESIGN In patients with non-small cell lung cancer (NSCLC) treated with CPIs at Memorial Sloan Kettering (MSK) and Vanderbilt University Medical Center (VUMC), we evaluated thyroid irAEs. We typed germline DNA using genome-wide single-nucleotide polymorphism (SNP) arrays and imputed genotypes. Germline SNP imputation was also performed in an independent Dana-Farber Cancer Institute (DFCI) cohort. We developed and validated polygenic risk scores (PRS) for hypothyroidism in noncancer patients using the UK and VUMC BioVU biobanks. These PRSs were applied to thyroid irAEs and CPI response in patients with NSCLC at MSK, VUMC, and DFCI. RESULTS Among 744 patients at MSK and VUMC, thyroid irAEs occurred in 13% and were associated with improved outcomes [progression-free survival adjusted HR (PFS aHR) = 0.68; 95% confidence interval (CI), 0.52-0.88]. The PRS for hypothyroidism developed from UK Biobank predicted hypothyroidism in the BioVU dataset in noncancer patients [OR per standard deviation (SD) = 1.33, 95% CI, 1.29-1.37; AUROC = 0.6]. The same PRS also predicted development of thyroid irAEs in both independent cohorts of patients treated with CPIs (HR per SD = 1.34; 95% CI, 1.08-1.66; AUROC = 0.6). The results were similar in the DFCI cohort. However, PRS for hypothyroidism did not predict CPI benefit. CONCLUSIONS Thyroid irAEs were associated with response to anti-PD-1 therapy. Genetic risk for hypothyroidism was associated with risk of developing thyroid irAEs. Additional studies are needed to determine whether other irAEs also have shared genetic risk with known autoimmune disorders and the association with treatment response.
Collapse
Affiliation(s)
- Jia Luo
- Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Victoria L Martucci
- Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Zoe Quandt
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, California
- Diabetes Center, University of California, San Francisco, California
| | - Stefan Groha
- Dana-Farber Cancer Institute, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
- Broad Institute of MIT and Harvard, Boston, Massachusetts
| | - Megan H Murray
- Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Christine M Lovly
- Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, Tennessee
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Hira Rizvi
- Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jacklynn V Egger
- Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Andrew J Plodkowski
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Mohsen Abu-Akeel
- Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center, New York, New York
- Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Isabell Schulze
- Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center, New York, New York
- Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Taha Merghoub
- Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center, New York, New York
- Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Eduardo Cardenas
- Department of Medicine, University of California San Francisco, San Francisco, California
| | - Scott Huntsman
- Department of Medicine, University of California San Francisco, San Francisco, California
| | - Min Li
- Department of Medicine, University of California San Francisco, San Francisco, California
| | - Donglei Hu
- Department of Medicine, University of California San Francisco, San Francisco, California
| | - Matthew A Gubens
- Medical Oncology, University of California San Francisco, San Francisco, California
- Department of Medicine, Weill Cornell Medical Center, New York, New York
| | - Alexander Gusev
- Dana-Farber Cancer Institute, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
- Broad Institute of MIT and Harvard, Boston, Massachusetts
| | - Melinda C Aldrich
- Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Matthew D Hellmann
- Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
- Parker Institute for Cancer Immunotherapy at Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Medicine, Weill Cornell Medical Center, New York, New York
| | - Elad Ziv
- Department of Medicine, University of California San Francisco, San Francisco, California.
- Helen Diller Family Comprehensive Cancer Center, Center for Genes, Environment and Health and Institute for Human Genetics, University of California San Francisco, San Francisco, California
| |
Collapse
|