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Lerch M, Ramanathan S. The pathogenesis of neurological immune-related adverse events following immune checkpoint inhibitor therapy. Semin Immunol 2025; 78:101956. [PMID: 40294474 DOI: 10.1016/j.smim.2025.101956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 04/01/2025] [Accepted: 04/03/2025] [Indexed: 04/30/2025]
Abstract
Cancer is a leading cause of morbidity and mortality worldwide. The development of immune checkpoint inhibitors (ICI) has revolutionised cancer therapy, and patients who were previously incurable can now have excellent responses. These therapies work by blocking inhibitory immune pathways, like cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death-1 (PD-1), its ligand PD-L1, and lymphocyte activation gene 3 (LAG-3); which leads to increased anti-tumour immune responses. However, their use can lead to the development of immune-related adverse events (irAEs), which may result in severe disability, interruption of cancer therapy, and even death. Neurological autoimmune sequelae occur in 1-10 % of patients treated with ICIs and can be fatal. They encompass a broad spectrum of diseases, may affect the central and the peripheral nervous system, and include syndromes like encephalitis, cerebellitis, neuropathy, and myositis. In some cases, neurological irAEs can be associated with autoantibodies recognising neuronal or glial targets. In this review, we first describe the key targets in ICI therapy, followed by a formulation of irAEs and their clinical presentations, where we focus on neurological syndromes. We comprehensively formulate the current literature evaluating cell surface and intracellular autoantibodies, cytokines, chemokines, leukocyte patterns, other blood derived biomarkers, and immunogenetic profiles; and highlight their impact on our understanding of the pathogenesis of neurological irAEs. Finally, we describe therapeutic pathways and patient outcomes, and provide an overview on future aspects of ICI cancer therapy.
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Affiliation(s)
- Magdalena Lerch
- Translational Neuroimmunology Group, Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia
| | - Sudarshini Ramanathan
- Translational Neuroimmunology Group, Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, Australia; Department of Neurology and Concord Clinical School, Concord Hospital, Sydney, Australia.
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Feng J, Niu W, Zhang J, Ding Y, Li Z, Zhang J, Li B, Li C, Wang F, Wang G, Yu B. Pathological complete response after monotherapy with immune checkpoint inhibitors for bifocal colon cancer in a patient with lynch syndrome and situs inversus totalis: a case report. Front Immunol 2025; 16:1571607. [PMID: 40330463 PMCID: PMC12052791 DOI: 10.3389/fimmu.2025.1571607] [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: 02/05/2025] [Accepted: 04/03/2025] [Indexed: 05/08/2025] Open
Abstract
Background Lynch syndrome is the most common hereditary colorectal cancer (CRC) syndrome, accounting for 3-5% of all CRC cases. Situs inversus totalis (SIT) is a rare congenital malformation with an incidence of 1 in 8,000 to 1 in 25,000. The co-occurrence of Lynch syndrome and SIT is extremely uncommon. Immune checkpoint inhibitors (ICIs) have demonstrated significant efficacy in treating microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) CRC. Tumors associated with Lynch syndrome frequently exhibit MSI-H, providing a theoretical basis for ICI use. Case presentation We report a case of bifocal colon cancer associated with Lynch syndrome and SIT. After seven cycles of sintilimab, the patient developed gastrointestinal perforation due to tumor regression, necessitating emergency surgery. The anatomical variations associated with SIT required the surgical team to adopt an alternative approach. Postoperatively, the patient continued sintilimab treatment for 2 years. In June 2024, he underwent a colostomy reversal and proximal colectomy. Pathological examination revealed a tumor regression grade (TRG) of 0, indicating complete pathological remission (pCR), with no recurrence or metastasis detected upon follow-up. Conclusions The anatomical variations associated with SIT increase the complexity of surgical procedures. Advanced imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI) are essential for assessing fine anatomical details and facilitating surgery. ICIs are an effective treatment option for Lynch syndrome-associated CRC, as demonstrated in this case. Future studies should investigate the optimal timing of immunotherapy, combination treatment strategies, and methods to mitigate immune-related toxicities. Such research will help develop comprehensive and personalized treatment plans for Lynch syndrome-associated CRC.
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Affiliation(s)
- Jun Feng
- The Second Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Wenbo Niu
- The Second Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Juan Zhang
- The Second Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Yuanyi Ding
- The Second Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Zheng Li
- The Second Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Jianfeng Zhang
- The Second Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Baokun Li
- The Second Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Chenhui Li
- The Second Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Feifei Wang
- The Second Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Guiying Wang
- The Second Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- Hebei Key Laboratory of Etiology Tracing and Individualized Diagnosis and Treatment for Digestive System Carcinoma, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- Departments of General Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Bin Yu
- The Second Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
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Shatila M, Eshaghi F, Cruz CC, Machado AP, Mathew A, Zhao D, Siddiqui BA, Thomas AS, Chari ST, Wang Y. Differential Disease Behavior of Immune-Mediated Colitis Among Different Types of Immune Checkpoint Inhibition. Target Oncol 2025; 20:339-347. [PMID: 40038186 DOI: 10.1007/s11523-025-01135-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/11/2025] [Indexed: 03/06/2025]
Abstract
BACKGROUND Immune-checkpoint inhibitors (ICIs) enhance the immune response against cancer but can cause immune-related adverse events, with immune-mediated colitis (IMC) being among the most common. OBJECTIVE We investigated variations in gastrointestinal disease behavior and outcomes among patients receiving different ICI regimens. METHODS This retrospective chart review included patients who received ICIs and developed IMC. Groups were categorized by their last ICI regimen before IMC onset into either programmed cell death protein-1/ligand-1 monotherapy or cytotoxic T-lymphocyte antigen 4 (CTLA-4) monotherapy/combination immunotherapy. Demographic and IMC-related clinical information was collected. RESULTS There were 414 patients included in this study: 169 treated with programmed cell death protein-1/ligand-1 monotherapy and 245 treated with CTLA-4 mono/combination therapy. Patients treated with CTLA-4 therapy had an earlier onset of IMC (median 46 days vs 123 days, p < 0.001). They were more likely to present with fever (p = 0.02), abdominal pain (p = 0.049), or hematochezia (p < 0.001). They also had more severe colitis with 47.3% of patients in the CTLA-4 group presenting with grade ≥3 colitis versus 20.2% in the programmed cell death protein-1/ligand-1 group (p < 0.05). On endoscopy, CTLA-4 mono/combination therapy was associated with increased ulcerative findings (24.4 vs 8.4%, p = 0.002). On histology, the programmed cell death protein-1/ligand-1 group was more likely to have microscopic colitis (13.9 vs 5.8%, p < 0.045). CONCLUSIONS This study provides insight into the effect of ICI type on IMC disease course. Cytotoxic T-lymphocyte antigen 4 inhibition leads to an earlier and more severe IMC onset with distinct endoscopic and histologic features. Further research is needed to refine treatment algorithms and identify the mechanisms underlying the variability in IMC presentation among different ICI regimens.
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Affiliation(s)
- Malek Shatila
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1466, Houston, TX, 77030, USA
| | - Farzin Eshaghi
- Department of Internal Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Carolina Colli Cruz
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1466, Houston, TX, 77030, USA
| | - Antonio Pizuorno Machado
- Department of Internal Medicine, The University of Texas Health Science Center, Houston, TX, USA
| | - Antony Mathew
- Department of Internal Medicine, The University of Texas Health Science Center, Houston, TX, USA
| | - Dan Zhao
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Bilal A Siddiqui
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anusha Shirwaikar Thomas
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1466, Houston, TX, 77030, USA
| | - Suresh T Chari
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1466, Houston, TX, 77030, USA
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1466, Houston, TX, 77030, USA.
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Giesler S, Riemer R, Lowinus T, Zeiser R. Immune-mediated colitis after immune checkpoint inhibitor therapy. Trends Mol Med 2025; 31:265-280. [PMID: 39477757 DOI: 10.1016/j.molmed.2024.09.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 09/23/2024] [Accepted: 09/30/2024] [Indexed: 03/15/2025]
Abstract
Immune checkpoint inhibitors (ICIs) have led to improved outcome in patients with various types of cancer. Due to inhibition of physiological anti-inflammatory mechanisms, patients treated with ICIs may develop autoimmune inflammation of the colon, associated with morbidity, decreased quality of life (QoL), and mortality. In this review, we summarize clinical and pathophysiological aspects of immune-mediated colitis (ImC), highlighting novel treatment options. In the colon, ICIs trigger resident and circulating T cell activation and infiltration of myeloid cells. In addition, the gut microbiota critically contribute to intestinal immune dysregulation and loss of barrier function, thereby propagating local and systemic inflammation. Currently available therapies for ImC include corticosteroids, antitumor necrosis factor-α (TNF-α)- and anti-integrin α4β7 antibodies. Given that systemic immunosuppression might impair antitumor immune responses, novel therapeutic approaches are urgently needed.
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Affiliation(s)
- Sophie Giesler
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Roxane Riemer
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Theresa Lowinus
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Robert Zeiser
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
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Colli Cruz C, Moura Nascimento Santos MJ, Wali S, Varatharajalu K, Thomas A, Wang Y. Gastrointestinal toxicities associated with immune checkpoint inhibitors therapy: risks and management. Immunotherapy 2025; 17:293-303. [PMID: 40055892 PMCID: PMC12013428 DOI: 10.1080/1750743x.2025.2473305] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 02/25/2025] [Indexed: 04/22/2025] Open
Abstract
Immune checkpoint inhibitors (ICIs) have greatly improved cancer treatment by boosting the immune system's ability to target tumors. However, they can also cause serious side effects, particularly in the digestive system. These include immune-related diarrhea, inflammation of the intestines and, less commonly, inflammation of the stomach or esophagus. This review underscores the importance of early detection, accurate diagnosis, and timely treatment to improve patient outcomes. It also highlights the need for further research to develop strategies to reduce gastrointestinal toxicities and enhance the overall effectiveness of ICIs in cancer therapy.
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Affiliation(s)
- Carolina Colli Cruz
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Sharada Wali
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Krishnavathana Varatharajalu
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anusha Thomas
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology & Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Chen W, Wang Y, Zhao M, Zhang H, Zong Y, Zhao X. Incidence of and Risk Factors for Anti-PD-1/PD-L1- Associated Diarrhea and Colitis: A Retrospective Cohort Study of the Chinese Population. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:353. [PMID: 40005469 PMCID: PMC11857649 DOI: 10.3390/medicina61020353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 01/19/2025] [Accepted: 02/05/2025] [Indexed: 02/27/2025]
Abstract
Background and Objectives: The prevalence of and risk factors for immune checkpoint inhibitor-associated diarrhea and colitis (IMDC) in the Chinese population are unclear. This study aimed to estimate IMDC incidence and identify potential risk factors. Materials and Methods: We reviewed the electronic medical records from Beijing Friendship Hospital (2015-2022) to identify the patients treated with immune checkpoint inhibitors. The primary outcome was IMDC occurrence. The demographics, cancer type, baseline labs, and concurrent medications were analyzed. The univariable and multivariable analyses validated the associated factors. Results: Among 1186 patients (median follow-up: 217 days), the IMDC incidence was 4.6%, with colitis at 0.67%. Digestive system tumors increased the IMDC risk (OR 2.79, 95% CI 1.42-5.75, p = 0.004), while platinum agents decreased it (OR 0.41, 95% CI 0.21-0.78, p = 0.008). PPIs, antibiotics, NSAIDs, and glucocorticoids showed no significant association. Colitis was the third most common irAE, leading to ICI discontinuation (15.6%). Conclusions: IMDC prevalence is 4.6% in the Chinese population, the third most frequent irAE causing ICI discontinuation. Digestive tumors and platinum agents are risk and protective factors, respectively, while other medications show no significant impact.
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Affiliation(s)
- Wei Chen
- Beijing Digestive Disease Center, National Clinical Research Center for Digestive Disease, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; (W.C.); (Y.Z.)
| | - Yan Wang
- Liver Research Center, National Clinical Research Center for Digestive Disease, Key Laboratory on Translational Medicine on Cirrhosis, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; (Y.W.); (M.Z.)
| | - Mengyu Zhao
- Liver Research Center, National Clinical Research Center for Digestive Disease, Key Laboratory on Translational Medicine on Cirrhosis, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; (Y.W.); (M.Z.)
| | - Hong Zhang
- Department of Pharmacy, Wenzhou Integrated Traditional Chinese and Western Medicine Hospital, Wenzhou 325000, China;
| | - Ye Zong
- Beijing Digestive Disease Center, National Clinical Research Center for Digestive Disease, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; (W.C.); (Y.Z.)
| | - Xinyan Zhao
- Liver Research Center, National Clinical Research Center for Digestive Disease, Key Laboratory on Translational Medicine on Cirrhosis, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; (Y.W.); (M.Z.)
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Kim TK, Lee HS, Kim ES. Incidence and risk factors of immune checkpoint inhibitor-induced colitis in Korean patients with cancer. Korean J Intern Med 2025; 40:49-56. [PMID: 39778525 PMCID: PMC11725480 DOI: 10.3904/kjim.2024.135] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Revised: 07/25/2024] [Accepted: 08/05/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND/AIMS Immune checkpoint inhibitors (ICIs) are effective in treating cancer. However, various immune-related adverse events (irAEs) have become prevalent, with ICI-induced colitis being the most common gastrointestinal irAE. Thus, we aimed to investigate the incidence and risk factors of ICI-induced colitis in Korean patients with cancer. METHODS This retrospective study included patients treated with ICIs between October 2015 and June 2022 in two tertiary referral centers in Daegu, Korea. The incidence of ICI-induced colitis was determined using electronic medical records. Risk factors for ICI-induced colitis were identified using univariate and multivariate logistic regression analyses. RESULTS We included 1,478 patients with ICI-treated cancer. The incidence of ICI-induced colitis was 3.5% (n = 52/1,478). Multivariate logistic regression analysis showed that the combination of nivolumab and ipilimumab was a risk factor for ICI-induced colitis (p = 0.006; odds ratio, 9.768; 95% confidence interval, 1.93-49.30). CONCLUSION ICI-induced colitis had an incidence rate of 3.5% and was associated with the combination of nivolumab and ipilimumab. Most patients with ICI-induced colitis developed mild symptoms that improved with supportive care alone, making ICI therapy resumption possible.
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Affiliation(s)
- Tae Kyun Kim
- Department of Internal Medicine, Kyungpook National University Chilgok Hospital, Daegu,
Korea
| | - Hyun Seok Lee
- Department of Internal Medicine, Kyungpook National University Chilgok Hospital, Daegu,
Korea
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu,
Korea
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu,
Korea
| | - Eun Soo Kim
- Department of Internal Medicine, Kyungpook National University Hospital, Daegu,
Korea
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu,
Korea
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Wang S, Wang H. Treatment of immune checkpoint inhibitor-related colitis: a narrative review. Transl Cancer Res 2024; 13:7002-7014. [PMID: 39816545 PMCID: PMC11729759 DOI: 10.21037/tcr-24-2150] [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: 11/01/2024] [Accepted: 12/17/2024] [Indexed: 01/18/2025]
Abstract
Background and Objective Cancer is one of the most difficult diseases facing modern medicine, and increasing amounts of research and clinical treatments are being applied to the treatment of cancer. Immunotherapy, particularly immune checkpoint inhibitor (ICI) therapy, has revolutionized the treatment and overall survival of patients with several different types of cancer. Approximately one-third of patients treated with ICIs may experience immune-related adverse events (irAEs). Immune checkpoint inhibitor-associated colitis (ICIC) is the most common irAE with an incidence of approximately 8-10%, ICIC usually presents as watery or bloody diarrhea, and if the symptoms are severe, ICI treatment must be interrupted or even terminated. This review summarizes the epidemiology, pathogenesis, clinical characteristics, and therapies of ICIC, focusing on the use of biologics, in order to propose treatment options in different situations to control immune checkpoint inhibitor-related colitis as soon as possible. Methods To find relevant articles for this narrative review paper, a combination of keywords such as immune checkpoint inhibitor-related colitis, corticosteroids, biologics were searched for in PubMed databases. Key Content and Findings The pathogenesis of ICIC is complex and primarily involves antitumor effects and indirect damage to colonic tissues, as well as the activation of specific proinflammatory pathways. Corticosteroids (CSs) are the first line of treatment for ICIC, but steroid-refractory or steroid-resistant cases often occur. Patients with irAE colitis respond favorably to biologics, and patients with CS-resistant/refractory enterocolitis can benefit from the early use of biologics. Conclusions Biologics are currently recommended for the treatment of ICIC but are usually used as a supplement after the failure of first-line CS therapy. Patients with irAE colitis respond favorably to biologics, and patients with CS-resistant/refractory enterocolitis can benefit from the early use of biologics. Biologics (alone or in combination with CS) should be considered as an early therapy option for high-risk patients rather than just an escalation after a failure to respond to CS.
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Affiliation(s)
- Shiyang Wang
- Division of Pulmonary and Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Hanping Wang
- Division of Pulmonary and Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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Kim MK, Son HN, Hong SW, Park SH, Yang DH, Ye BD, Byeon JS, Myung SJ, Yang SK, Yoon S, Hwang SW. CD8+ cell dominance in immune checkpoint inhibitor-induced colitis and its heterogeneity across endoscopic features. Therap Adv Gastroenterol 2024; 17:17562848241309445. [PMID: 39735350 PMCID: PMC11672375 DOI: 10.1177/17562848241309445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 12/06/2024] [Indexed: 12/31/2024] Open
Abstract
Background Immune checkpoint inhibitor (ICI)-induced colitis is a significant adverse event associated with ICI therapy, known to be linked to increased cytotoxic T-cell activity. Objectives To compare T-cell subsets based on the endoscopic features of ICI-induced colitis and to compare these findings with those of inflammatory bowel disease (IBD). Design Prospective cohort study. Methods We analyzed patients with ICI-induced colitis, confirmed through both endoscopic and histological evaluation. Biopsy specimens were examined using multiplex immunohistochemistry to assess their immune cell profile. Clinical outcomes were analyzed. Immune cell profiles were compared based on their endoscopic features and contrasted with those of patients with IBD. Results Seventeen patients with ICI-induced colitis were included in the study. All patients showed clinical improvement after treatment, and steroids were administered to 11 patients (64.7%). Based on endoscopic features, the patients were classified as Crohn's disease (CD)-like (n = 3, 17.6%), ulcerative colitis (UC)-like (n = 9, 52.9%), or microscopic colitis (MC)-like (n = 5, 29.4%). In ICI-induced colitis, cytotoxic T cells (Tc cells) were more predominant than helper T cells (Th cells) (p = 0.053), and this trend was most pronounced in the MC-like subtype (p = 0.020). When comparing the number of CD8+ cells infiltrating the crypts, both the UC-like and MC-like subtypes had significantly more infiltrating cells than the CD-like subtype (p = 0.008 and p = 0.016, respectively). In comparison to IBD, IBD exhibited a Th-dominant profile, whereas CD-like ICI-induced colitis had a lower Th cell density than CD (p = 0.032) and UC-like ICI-induced colitis had a higher Tc density than UC (p = 0.045). Conclusion Analysis of T-cell subsets of ICI-induced colitis revealed a Tc-dominant profile, contrasting with the Th dominance observed in patients with IBD. The Tc-dominant profile was evident in UC-like and MC-like subtypes, with significant crypt infiltration by CD8+ cells. Tc may play an important role in the pathophysiology of ICI-induced colitis.
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Affiliation(s)
- Min Kyu Kim
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hye-Nam Son
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seung Wook Hong
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sang Hyoung Park
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Dong-Hoon Yang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Byong Duk Ye
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jeong-Sik Byeon
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seung-Jae Myung
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Suk-Kyun Yang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Shinkyo Yoon
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea
| | - Sung Wook Hwang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea
- Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Cheema PK, Iafolla MAJ, Abdel-Qadir H, Bellini AB, Chatur N, Chandok N, Comondore VR, Cunningham M, Halperin I, Hu AB, Jaskolka D, Darvish-Kazem S, Khandaker MH, Kitchlu A, Sachdeva JS, Shapera S, Woolnough NRJ, Nematollahi M. Managing Select Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitors. Curr Oncol 2024; 31:6356-6383. [PMID: 39451777 PMCID: PMC11506662 DOI: 10.3390/curroncol31100473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 10/12/2024] [Accepted: 10/16/2024] [Indexed: 10/26/2024] Open
Abstract
The increased use of immune checkpoint inhibitors (ICIs) across cancer programs has created the need for standardized monitoring and management of immune-related adverse events (irAEs). Delayed recognition without appropriate treatment can have serious and life-threatening consequences. The management of irAEs presents a unique set of challenges that must be addressed at a multidisciplinary level. Although various national and international guidelines and working groups provide high-level recommendations for the management of irAEs, practical guidance is lacking. Furthermore, timely collaboration between specialists requires institutional protocols that enable the early recognition, assessment, and treatment of irAEs. Such protocols should be developed by institution specialists and include algorithms for all healthcare providers involved in the care of patients treated with ICIs. At William Osler Health System in Brampton, Ontario, practical step-by-step multidisciplinary treatment approaches with recommendations for the management of irAEs were developed in collaboration with experts across Canada. Here, we provide an in-depth description of the approaches, outlining baseline investigations prior to the initiation of ICIs, as well as the monitoring and management of irAEs based on symptoms, severity, and involved organ systems. We encourage other centres to adapt and modify our approaches according to their specific needs and requirements.
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Affiliation(s)
- Parneet K. Cheema
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Marco A. J. Iafolla
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Husam Abdel-Qadir
- Women’s College Hospital Research Institute, Toronto, ON M5S 1B2, Canada;
- Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, ON M5G 2N2, Canada
| | - Andrew B. Bellini
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Nazira Chatur
- Division of Gastroenterology, Faculty of Medicine, Vancouver General Hospital (Sanders), University of British Columbia, Vancouver, BC V5Z 1M9, Canada;
| | - Natasha Chandok
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Vikram R. Comondore
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Morven Cunningham
- Toronto Centre for Liver Disease, University Health Network, Toronto, ON M5G 2C4, Canada;
| | - Ilana Halperin
- Division of Endocrinology, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada;
| | - Anne B. Hu
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Diana Jaskolka
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Saeed Darvish-Kazem
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Masud H. Khandaker
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Abhijat Kitchlu
- Division of Nephrology, Department of Medicine, University Health Network, University of Toronto, Toronto, ON M5G 2C4, Canada;
| | - Jasdip S. Sachdeva
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Shane Shapera
- Department of Medicine, University of Toronto, Toronto, ON M5G 2N2, Canada;
| | - Nicholas R. J. Woolnough
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
| | - Massey Nematollahi
- William Osler Health System, Brampton, ON L6R 3J7, Canada; (M.A.J.I.); (A.B.B.); (N.C.); (V.R.C.); (A.B.H.); (D.J.); (S.D.-K.); (M.H.K.); (J.S.S.); (N.R.J.W.); (M.N.)
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11
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Huang J, Xiong L, Tang S, Zhao J, Zuo L. Balancing Tumor Immunotherapy and Immune-Related Adverse Events: Unveiling the Key Regulators. Int J Mol Sci 2024; 25:10919. [PMID: 39456702 PMCID: PMC11507008 DOI: 10.3390/ijms252010919] [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: 08/28/2024] [Revised: 10/04/2024] [Accepted: 10/09/2024] [Indexed: 10/28/2024] Open
Abstract
Tumor immunotherapy has emerged as a promising approach in cancer treatment in recent years, offering vast potential. This method primarily involves targeting and inhibiting the suppressive checkpoints present in different immune cells to enhance their activation, ultimately leading to tumor regression. However, tumor cells exploit the surrounding immune cells and tissues to establish a tumor microenvironment (TME) that supports their survival and growth. Within the TME, the efficacy of effector immune cells is compromised, as tumor cells exploit inhibitory immune cells to suppress their function. Furthermore, certain immune cells can be co-opted by tumor cells to facilitate tumor growth. While significantly enhancing the body's tumor immunity can lead to tumor regression, it can also result in severe toxic side effects and an inflammatory factor storm. As a consequence, patients often discontinue treatment due to immune-related adverse events (irAEs) or, in extreme cases, succumb to toxic side effects before experiencing tumor regression. In this analysis, we examined several remission regimens for irAEs, each with its own drawbacks, including toxic side effects or suppression of tumor immunotherapy, which is undesirable. A recent research study, specifically aimed at downregulating intestinal epithelial barrier permeability, has shown promising results in reducing the severity of inflammatory bowel disease (IBD) while preserving immune function. This approach effectively reduces the severity of IBD without compromising the levels of TNF-α and IFN-γ, which are crucial for maintaining the efficacy of tumor immunotherapy. Based on the substantial similarities between IBD and ICI colitis (combo immune checkpoint inhibitors-induced colitis), this review proposes that targeting epithelial cells represents a crucial research direction for mitigating irAEs in the future.
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Affiliation(s)
- Jianshang Huang
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Sciences, Anhui Medical University, No.81, Meishan Rd., Hefei 230032, China; (J.H.)
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, No.81, Meishan Rd., Hefei 230032, China
| | - Lei Xiong
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Sciences, Anhui Medical University, No.81, Meishan Rd., Hefei 230032, China; (J.H.)
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, No.81, Meishan Rd., Hefei 230032, China
| | - Sainan Tang
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Sciences, Anhui Medical University, No.81, Meishan Rd., Hefei 230032, China; (J.H.)
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, No.81, Meishan Rd., Hefei 230032, China
| | - Junhao Zhao
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Sciences, Anhui Medical University, No.81, Meishan Rd., Hefei 230032, China; (J.H.)
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, No.81, Meishan Rd., Hefei 230032, China
| | - Li Zuo
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Sciences, Anhui Medical University, No.81, Meishan Rd., Hefei 230032, China; (J.H.)
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, No.81, Meishan Rd., Hefei 230032, China
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12
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Zoghbi M, Burk KJ, Haroun E, Saade M, Carreras MTC. Immune checkpoint inhibitor-induced diarrhea and colitis: an overview. Support Care Cancer 2024; 32:680. [PMID: 39311981 PMCID: PMC11420271 DOI: 10.1007/s00520-024-08889-2] [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: 05/13/2024] [Accepted: 09/17/2024] [Indexed: 09/26/2024]
Abstract
Immune checkpoint inhibitors (ICIs) have emerged as an integral component of the management of various cancers and have contributed to significant improvements in overall survival. Most available ICIs target anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4), and anti-programmed cell death 1/programmed cell death ligand 1 (anti-PD1/PDL1). Gastrointestinal immune-related adverse events remain a common complication of ICIs. The predominant manifestations include diarrhea and colitis, which often manifest concurrently as immune-mediated diarrhea and colitis (IMDC). Risk factors for developing these side effects include baseline gut microbiota, preexisting autoimmune disorders, such as inflammatory bowel disease, and type of neoplasm. The hallmark symptom of colitis is diarrhea which may be accompanied by mucus or blood in stools. Patients may also experience abdominal pain, fever, vomiting, and nausea. If not treated rapidly, ICI-induced colitis can lead to serious life-threatening complications. Current management is based on corticosteroids as first-line, and immunosuppressants like infliximab or vedolizumab for refractory cases. Microbiota transplantation and specific cytokines and lymphocyte replication inhibitors are being investigated. Optimal patient care requires maintaining a balance between treatment toxicity and efficacy, hence the aim of this review is to enhance readers' comprehension of the gastrointestinal adverse events associated with ICIs, particularly IMDC. In addition to identifying the risk factors, we discuss the incidence, clinical presentation, workup, and management options of IMDC.
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Affiliation(s)
- Marianne Zoghbi
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Kathryn J Burk
- Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Elio Haroun
- Faculty of Medicine, Saint Joseph University of Beirut, Beirut, 1100, Lebanon
| | - Maria Saade
- Faculty of Medicine, Saint Joseph University of Beirut, Beirut, 1100, Lebanon
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13
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Adiwinata R, Tandarto K, Tanadi C, Waleleng BJ, Haroen H, Rotty L, Gosal F, Rotty L, Hendratta C, Lasut P, Winarta J, Waleleng A, Simadibrata P, Simadibrata M. Immune checkpoint inhibitor colitis, a rising issue in targeted cancer therapy era: A literature review. ROMANIAN JOURNAL OF INTERNAL MEDICINE = REVUE ROUMAINE DE MEDECINE INTERNE 2024; 62:219-230. [PMID: 38595047 DOI: 10.2478/rjim-2024-0015] [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: 11/29/2023] [Indexed: 04/11/2024]
Abstract
Research advances in the oncology treatment field have led to the widespread use of immunotherapy. The usage of immune checkpoint inhibitor (ICI) has improved the survival of cancer patients with metastases. This has also led to the rapidly expanding indications for ICI use. However, ICI usage may lead to toxicity, which may be immune-related, in different organ-specific targets. The immune-related adverse events (irAEs) of ICI may lead to increased morbidity, decreased quality of life, and early termination of ICI. The clinical manifestations of irAEs in the gastrointestinal system are variable, ranging from self-limited to life-threatening or fatal events. In this review article, we would like to focus on discussing ICI-induced colitis, which is one of the most common ICI irAEs in the gastrointestinal tract.
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Affiliation(s)
- Randy Adiwinata
- 1Department of Internal Medicine, Faculty of Medicine, Universitas Sam Ratulangi "Prof. dr. R. D. Kandou" Hospital, Manado, Indonesia
- 2Gastrointestinal Cancer Center, MRCCC Siloam Hospital Semanggi, Jakarta, Indonesia
| | - Kevin Tandarto
- 3Intensive Care Unit, Columbia Asia Hospital, Semarang, Indonesia
| | | | - Bradley Jimmy Waleleng
- 5Division of Gastroenterology-Hepatology, Department of Internal Medicine, Faculty of Medicine, Universitas Sam Ratulangi "Prof. dr. R. D. Kandou" Hospital, Manado, Indonesia
| | - Harlinda Haroen
- 6Division of Hematology and Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Universitas Sam Ratulangi/Prof. dr. R. D. Kandou Hospital, Manado, Indonesia
| | - Linda Rotty
- 6Division of Hematology and Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Universitas Sam Ratulangi/Prof. dr. R. D. Kandou Hospital, Manado, Indonesia
| | - Fandy Gosal
- 5Division of Gastroenterology-Hepatology, Department of Internal Medicine, Faculty of Medicine, Universitas Sam Ratulangi "Prof. dr. R. D. Kandou" Hospital, Manado, Indonesia
| | - Luciana Rotty
- 5Division of Gastroenterology-Hepatology, Department of Internal Medicine, Faculty of Medicine, Universitas Sam Ratulangi "Prof. dr. R. D. Kandou" Hospital, Manado, Indonesia
| | - Cecilia Hendratta
- 6Division of Hematology and Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Universitas Sam Ratulangi/Prof. dr. R. D. Kandou Hospital, Manado, Indonesia
| | - Pearla Lasut
- 6Division of Hematology and Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Universitas Sam Ratulangi/Prof. dr. R. D. Kandou Hospital, Manado, Indonesia
| | - Jeanne Winarta
- 5Division of Gastroenterology-Hepatology, Department of Internal Medicine, Faculty of Medicine, Universitas Sam Ratulangi "Prof. dr. R. D. Kandou" Hospital, Manado, Indonesia
| | - Andrew Waleleng
- 5Division of Gastroenterology-Hepatology, Department of Internal Medicine, Faculty of Medicine, Universitas Sam Ratulangi "Prof. dr. R. D. Kandou" Hospital, Manado, Indonesia
| | - Paulus Simadibrata
- 2Gastrointestinal Cancer Center, MRCCC Siloam Hospital Semanggi, Jakarta, Indonesia
- 7Abdi Waluyo Hospital, Jakarta, Indonesia
| | - Marcellus Simadibrata
- 8Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo Hospital, Jakarta, Indonesia
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14
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Lukin R, Ciner A. Fulminant immune-related colitis after dual checkpoint inhibitor therapy: case report. Immunotherapy 2024; 16:943-948. [PMID: 39155794 PMCID: PMC11485820 DOI: 10.1080/1750743x.2024.2386234] [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: 04/24/2024] [Accepted: 07/26/2024] [Indexed: 08/20/2024] Open
Abstract
Aim: Immune-related (IR) colitis is a potentially life-threatening complication of checkpoint inhibitors. Its presentation often includes diarrhea, abdominal pain and rectal bleeding and the median time to onset is 6-10 weeks post initiation of immunotherapy.Case study: We report an unusual case of fulminant IR-colitis beginning 3 days after the first dose of dual checkpoint blockade. IR-colitis was refractory to high-dose corticosteroids and was further complicated by sigmoid diverticulum perforation.Conclusion: Early-onset IR-colitis can occur, particularly in the context of combined anti-PD1 and anti-CTLA4 blockade, and clinicians should maintain a high-index of suspicion even when timing of symptom onset is atypical. Further research is needed to elucidate risk factors for early-onset IR-colitis.
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Affiliation(s)
- Robert Lukin
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD21201, USA
| | - Aaron Ciner
- Department of Medicine, Division of Hematology/Oncology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
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15
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Ortega MA, Boaru DL, De Leon-Oliva D, Fraile-Martinez O, García-Montero C, Rios L, Garrido-Gil MJ, Barrena-Blázquez S, Minaya-Bravo AM, Rios-Parra A, Álvarez-Mon M, Jiménez-Álvarez L, López-González L, Guijarro LG, Diaz R, Saez MA. PD-1/PD-L1 axis: implications in immune regulation, cancer progression, and translational applications. J Mol Med (Berl) 2024; 102:987-1000. [PMID: 38935130 DOI: 10.1007/s00109-024-02463-3] [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: 03/11/2024] [Revised: 06/17/2024] [Accepted: 06/18/2024] [Indexed: 06/28/2024]
Abstract
The PD-1/PD-L1 axis is a complex signaling pathway that has an important role in the immune system cells. Programmed cell death protein 1 (PD-1) acts as an immune checkpoint on the T lymphocytes, B lymphocytes, natural killer (NK), macrophages, dendritic cells (DCs), monocytes, and myeloid cells. Its ligand, the programmed cell death 1 ligand (PD-L1), is expressed in the surface of the antigen-presenting cells (APCs). The binding of both promotes the downregulation of the T cell response to ensure the activation to prevent the onset of chronic immune inflammation. This axis in the tumor microenvironment (TME) performs a crucial role in the tumor progression and the escape of the tumor by neutralizing the immune system, the engagement of PD-L1 with PD-1 in the T cell causes dysfunctions, neutralization, and exhaustion, providing the tumor mass production. This review will provide a comprehensive overview of the functions of the PD-1/PD-L1 system in immune function, cancer, and the potential therapeutic implications of the PD-1/PD-L1 pathway for cancer management.
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Affiliation(s)
- Miguel A Ortega
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, CIBEREHD, University of Alcalá, 28801, Alcala de Henares, Spain.
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain.
- Cancer Registry and Pathology Department, Principe de, Asturias University Hospital, Alcala de Henares, Spain.
| | - Diego Liviu Boaru
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, CIBEREHD, University of Alcalá, 28801, Alcala de Henares, Spain
| | - Diego De Leon-Oliva
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, CIBEREHD, University of Alcalá, 28801, Alcala de Henares, Spain
| | - Oscar Fraile-Martinez
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, CIBEREHD, University of Alcalá, 28801, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
| | - Cielo García-Montero
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, CIBEREHD, University of Alcalá, 28801, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
| | - Laura Rios
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, CIBEREHD, University of Alcalá, 28801, Alcala de Henares, Spain
| | - Maria J Garrido-Gil
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, CIBEREHD, University of Alcalá, 28801, Alcala de Henares, Spain
| | - Silvestra Barrena-Blázquez
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
- Department of Nursing and Physiotherapy, Faculty of Medicine and Health Sciences, University of Alcalá, 28801, Alcala de Henares, Spain
| | - Ana M Minaya-Bravo
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, CIBEREHD, University of Alcalá, 28801, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
| | - Antonio Rios-Parra
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, CIBEREHD, University of Alcalá, 28801, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
- Cancer Registry and Pathology Department, Principe de, Asturias University Hospital, Alcala de Henares, Spain
| | - Melchor Álvarez-Mon
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, CIBEREHD, University of Alcalá, 28801, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
- Immune System Diseases-Rheumatology Service, University Hospital Principe de Asturias, CIBEREHD, 28801, Alcala de Henares, Spain
| | - Laura Jiménez-Álvarez
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, CIBEREHD, University of Alcalá, 28801, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
- Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, 28801, Alcala de Henares, Spain
| | - Laura López-González
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
- Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, 28801, Alcala de Henares, Spain
| | - Luis G Guijarro
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, CIBEREHD, University of Alcalá, 28801, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
| | - Raul Diaz
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain.
- Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, 28801, Alcala de Henares, Spain.
- Surgery Service, University Hospital Principe de Asturias, 28801, Alcala de Henares, Spain.
| | - Miguel A Saez
- Department of Medicine and Medical Specialties, Faculty of Medicine and Health Sciences, CIBEREHD, University of Alcalá, 28801, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034, Madrid, Spain
- Pathological Anatomy Service, Central University Hospital of Defence-University of Alcalá (UAH) Madrid, Alcala de Henares, Spain
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16
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Hong N, Wang B, Zhou HC, Wu ZX, Fang HY, Song GQ, Yu Y. Multidisciplinary management of ulcerative colitis complicated by immune checkpoint inhibitor-associated colitis with life-threatening gastrointestinal hemorrhage: A case report. World J Gastrointest Surg 2024; 16:2329-2336. [PMID: 39087117 PMCID: PMC11287687 DOI: 10.4240/wjgs.v16.i7.2329] [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: 02/24/2024] [Revised: 05/26/2024] [Accepted: 06/18/2024] [Indexed: 07/22/2024] Open
Abstract
BACKGROUND Programmed cell death 1 (PD-1) inhibitors are immune checkpoint inhibitors (ICI) that have demonstrated significant efficacy in treating various advanced malignant tumors. While most patients tolerate treatment well, several adverse drug reactions, such as fatigue, myelosuppression, and ICI-associated colitis, have been reported. CASE SUMMARY This case involved a 57-year-old male patient with ulcerative colitis complicated by hepatocarcinoma who underwent treatment with tirelizumab (a PD-1 inhibitor) for six months. The treatment led to repeated life-threatening lower gastrointestinal hemorrhage. The patient received infliximab, vedolizumab, and other salvage procedures but ultimately required subtotal colectomy due to uncontrollable massive lower gastrointestinal bleeding. Currently, postoperative gastrointestinal bleeding has stopped, the patient's stool has turned yellow, and his full blood cell count has returned to normal. CONCLUSION This case highlights the necessity of early identification, timely and adequate treatment of ICI-related colitis, and rapid escalation to achieve the goal of improving prognosis.
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Affiliation(s)
- Na Hong
- Department of Gastroenterology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China
| | - Bo Wang
- Department of Gastroenterology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China
| | - Hang-Cheng Zhou
- Department of Pathology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230036, Anhui Province, China
- Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230036, Anhui Province, China
| | - Zheng-Xiang Wu
- Department of Gastroenterology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China
| | - Hua-Ying Fang
- Department of Gastroenterology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China
| | - Geng-Qing Song
- Department of Gastroenterology and Hepatology, Metro Health Medical Center, Case Western Reserve University, Cleveland, OH 44109, United States
| | - Yue Yu
- Department of Gastroenterology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui Province, China
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17
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Koshiishi T, Nishioka N, Yoshimoto K. Immune-Related Adverse Events due to Concomitant Use of Immune Checkpoint Inhibitors and Chinese Herbal Medicines: A Study Based on a Japanese Adverse Event Database. Asian Pac J Cancer Prev 2024; 25:2291-2295. [PMID: 39068560 PMCID: PMC11480620 DOI: 10.31557/apjcp.2024.25.7.2291] [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: 11/12/2023] [Indexed: 07/30/2024] Open
Abstract
BACKGROUND Fatigue is an immune-related adverse event (irAE) associated with immune checkpoint inhibitors (ICIs) used for cancer treatment. Chinese herbal medicines (Ho-zai) are used to treat cancer-related fatigue. However, no interactions between ICIs and Ho-zai have been reported. Herein, we investigated the risk of irAEs associated with the concomitant use of ICIs and Ho-zai. METHODS We extracted data of patients who used ICI and Ho-zai from the Japanese Adverse Event Reporting Database. The proportional reporting ratio (PRR) was calculated for patients using ICI, Ho-zai, or both. We focused on cases of interstitial lung disease (ILD) and colitis, which were among the most severe cases of irAEs among these patients. The shrinkage method used by the World Health Organization-Uppsala Monitoring Center was used to detect the interactions. RESULTS Of the 799,670 patients in the database, 77,219, 2060, and 92 were using ICIs, Ho-zai, and combination treatment, respectively. The ILD and colitis groups included 39,388 and 17,522 patients, respectively. ILD signals were detected for both ICIs and Ho-zai. There were 24 cases of patients treated with concomitant ICIs and Ho-zai who developed ILD. For all combinations of all ICIs and all Ho-zai, Ω025 was negative, which suggested no ILD-related interactions. Colitis signals were detected for ICIs except for atezolizumab, avelumab, and durvalumab. There were eight patients treated with concomitant ICI and Ho-zai who developed colitis. For all combinations of all ICIs and all Ho-zai, Ω025 was negative, which suggested no colitis-related interactions. CONCLUSION To our knowledge, this is the first study to investigate interactions between ICIs and Ho-zai. Signals were detected for ILD in both ICI and Ho-zai groups, and colitis in the ICI group. However, the combined use of these treatments did not increase the risk of irAEs.
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Affiliation(s)
- Toru Koshiishi
- Department of Pharmacy, Tokyo Medical University Hachioji Medical Center, Tokyo Japan
| | - Nanako Nishioka
- Department of Pharmacy, Tokyo Medical University Hachioji Medical Center, Tokyo Japan
| | - Koichi Yoshimoto
- Department of Pharmacy, Tokyo Medical University Hachioji Medical Center, Tokyo Japan
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18
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Lenti MV, Ribaldone DG, Borrelli de Andreis F, Vernero M, Barberio B, De Ruvo M, Savarino EV, Kav T, Blesl A, Franzoi M, Gröchenig HP, Pugliese D, Ianiro G, Porcari S, Cammarota G, Gasbarrini A, Spagnuolo R, Ellul P, Foteinogiannopoulou K, Koutroubakis I, Argyriou K, Cappello M, Jauregui-Amezaga A, Demarzo MG, Silvestris N, Armuzzi A, Sottotetti F, Bertani L, Festa S, Eder P, Pedrazzoli P, Lasagna A, Vanoli A, Gambini G, Santacroce G, Rossi CM, Delliponti M, Klersy C, Corazza GR, Di Sabatino A. A 1-year follow-up study on checkpoint inhibitor-induced colitis: results from a European consortium. ESMO Open 2024; 9:103632. [PMID: 38970840 PMCID: PMC11360400 DOI: 10.1016/j.esmoop.2024.103632] [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: 04/13/2024] [Revised: 05/22/2024] [Accepted: 06/10/2024] [Indexed: 07/08/2024] Open
Abstract
BACKGROUND Data regarding the clinical outcome of patients with immune checkpoint inhibitor (ICI)-induced colitis are scant. We aimed to describe the 12-month clinical outcome of patients with ICI-induced colitis. MATERIALS AND METHODS This was a retrospective, European, multicentre study. Endoscopy/histology-proven ICI-induced colitis patients were enrolled. The 12-month clinical remission rate, defined as a Common Terminology Criteria for Adverse Events diarrhoea grade of 0-1, and the correlates of 12-month remission were assessed. RESULTS Ninety-six patients [male:female ratio 1.5:1; median age 65 years, interquartile range (IQR) 55.5-71.5 years] were included. Lung cancer (41, 42.7%) and melanoma (30, 31.2%) were the most common cancers. ICI-related gastrointestinal symptoms occurred at a median time of 4 months (IQR 2-7 months). An inflammatory bowel disease (IBD)-like pattern was present in 74 patients (77.1%) [35 (47.3%) ulcerative colitis (UC)-like, 11 (14.9%) Crohn's disease (CD)-like, 28 (37.8%) IBD-like unclassified], while microscopic colitis was present in 19 patients (19.8%). As a first line, systemic steroids were the most prescribed drugs (65, 67.7%). The 12-month clinical remission rate was 47.7 per 100 person-years [95% confidence interval (CI) 33.5-67.8). ICI was discontinued due to colitis in 66 patients (79.5%). A CD-like pattern was associated with remission failure (hazard ratio 3.84, 95% CI 1.16-12.69). Having histopathological signs of microscopic colitis (P = 0.049) and microscopic versus UC-/CD-like colitis (P = 0.014) were associated with a better outcome. Discontinuing the ICI was not related to the 12-month remission (P = 0.483). Four patients (3.1%) died from ICI-induced colitis. CONCLUSIONS Patients with IBD-like colitis may need an early and more aggressive treatment. Future studies should focus on how to improve long-term clinical outcomes.
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Affiliation(s)
- M V Lenti
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy; First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - D G Ribaldone
- Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - F Borrelli de Andreis
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy; Digestive Endoscopy Unit, Isola Tiberina - Gemelli Isola Hospital, Rome, Italy
| | - M Vernero
- Division of Gastroenterology, Department of Medical Sciences, University of Turin, Turin, Italy
| | - B Barberio
- Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - M De Ruvo
- Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - E V Savarino
- Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - T Kav
- Department of Gastroenterology, Hacettepe University School of Medicine, Ankara, Türkiye
| | - A Blesl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - M Franzoi
- Department of Internal Medicine and Gastroenterology, Academic Teaching Hospital Brothers of St John of God, St Veit an der Glan, Austria
| | - H P Gröchenig
- Department of Internal Medicine and Gastroenterology, Academic Teaching Hospital Brothers of St John of God, St Veit an der Glan, Austria
| | - D Pugliese
- Department of Medical and Surgical Sciences, CEMAD (Digestive Disease Center), Policlinico Universitario 'A. Gemelli' IRCCS Foundation, Rome, Italy; Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore Roma, Rome, Italy; UOS Gastroenterologia, Ospedale Isola Tiberina Gemelli Isola, Rome, Italy
| | - G Ianiro
- Department of Medical and Surgical Sciences, CEMAD (Digestive Disease Center), Policlinico Universitario 'A. Gemelli' IRCCS Foundation, Rome, Italy; Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore Roma, Rome, Italy
| | - S Porcari
- Department of Medical and Surgical Sciences, CEMAD (Digestive Disease Center), Policlinico Universitario 'A. Gemelli' IRCCS Foundation, Rome, Italy; Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore Roma, Rome, Italy
| | - G Cammarota
- Department of Medical and Surgical Sciences, CEMAD (Digestive Disease Center), Policlinico Universitario 'A. Gemelli' IRCCS Foundation, Rome, Italy; Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore Roma, Rome, Italy
| | - A Gasbarrini
- Department of Medical and Surgical Sciences, CEMAD (Digestive Disease Center), Policlinico Universitario 'A. Gemelli' IRCCS Foundation, Rome, Italy; Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore Roma, Rome, Italy
| | - R Spagnuolo
- Department of Health Sciences, University 'Magna Graecia', Catanzaro, Italy
| | - P Ellul
- Division of Gastroenterology, Department of Medicine, Mater Dei Hospital, Msida, Malta
| | - K Foteinogiannopoulou
- Department of Gastroenterology, University Hospital of Heraklion, Heraklion, Crete, Greece
| | - I Koutroubakis
- Department of Gastroenterology, University Hospital of Heraklion, Heraklion, Crete, Greece
| | - K Argyriou
- Department of Gastroenterology, University Hospital of Larisa, Larisa, Greece
| | - M Cappello
- Gastroenterology & Hepatology Section, PROMISE, University of Palermo, Palermo, Italy
| | - A Jauregui-Amezaga
- Department of Gastroenterology and Hepatology, University Hospital Antwerp, Antwerp, Belgium; Laboratory of Experimental Medicine and Pediatrics (LEMP), Division of Gastroenterology-Hepatology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
| | - M G Demarzo
- Department of Internal Medicine, Ospedale Policlinico San Martino-IRCCS per l'Oncologia, Gastroenterology Unit, University of Genoa, Genoa, Italy
| | - N Silvestris
- Medical Oncology Unit, Department of Human Pathology of Adulthood and Childhood DETEV 'G. Barresi', University of Messina, Messina, Italy
| | - A Armuzzi
- IBD Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - F Sottotetti
- Istituti Clinici Scientifici Maugeri IRCCS, Medical Oncology Unit, Pavia, Italy
| | - L Bertani
- Department of General Surgery and Gastroenterology, Tuscany North West ASL, Pontedera Hospital, Pontedera, Italy
| | - S Festa
- IBD Unit, Ospedale S. Filippo Neri, Rome, Italy
| | - P Eder
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - P Pedrazzoli
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy; Medical Oncology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - A Lasagna
- Medical Oncology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - A Vanoli
- Unit of Anatomic Pathology, Department of Molecular Medicine, University of Pavia, and IRCCS San Matteo Hospital Foundation, Pavia, Italy
| | - G Gambini
- Clinical Epidemiology and Biometry Service, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - G Santacroce
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy; First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - C M Rossi
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy; First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - M Delliponti
- First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - C Klersy
- Clinical Epidemiology and Biometry Service, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - G R Corazza
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy; First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - A Di Sabatino
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy; First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
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Del Gaudio A, Di Vincenzo F, Petito V, Giustiniani MC, Gasbarrini A, Scaldaferri F, Lopetuso LR. Focus on Immune Checkpoint Inhibitors-related Intestinal Inflammation: From Pathogenesis to Therapeutical Approach. Inflamm Bowel Dis 2024; 30:1018-1031. [PMID: 37801695 PMCID: PMC11144981 DOI: 10.1093/ibd/izad229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Indexed: 10/08/2023]
Abstract
Recently, antitumor immunotherapies have witnessed a breakthrough with the emergence of immune checkpoint inhibitors (ICIs) including programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors. Unfortunately, the use of ICIs has also led to the advent of a novel class of adverse events that differ from those of classic chemotherapeutics and are more reminiscent of autoimmune diseases, the immune-related adverse events (IRAEs). Herein, we performed an insight of the main IRAEs associated with ICIs, focusing on gastroenterological IRAEs and specifically on checkpoint inhibitor colitis, which represents the most widely reported IRAE to date. We comprehensively dissected the current evidence regarding pathogenesis, diagnosis, and management of ICIs-induced colitis, touching upon also on innovative therapies.
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Affiliation(s)
- Angelo Del Gaudio
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
| | - Federica Di Vincenzo
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
| | - Valentina Petito
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
| | | | - Antonio Gasbarrini
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
| | - Franco Scaldaferri
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
| | - Loris Riccardo Lopetuso
- UOS Malattie Infiammatorie Croniche Intestinali, Centro di Malattie dell’Apparato Digerente (CEMAD), Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- UOC di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, 00168, Italy
- Department of Medicine and Ageing Sciences, G. d’Annunzio University of Chieti-Pescara, Chieti, 66100, Italy
- Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, Chieti, 66100, Italy
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Liang X, Xiao H, Li H, Chen X, Li Y. Adverse events associated with immune checkpoint inhibitors in non-small cell lung cancer: a safety analysis of clinical trials and FDA pharmacovigilance system. Front Immunol 2024; 15:1396752. [PMID: 38745663 PMCID: PMC11091284 DOI: 10.3389/fimmu.2024.1396752] [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: 03/06/2024] [Accepted: 04/17/2024] [Indexed: 05/16/2024] Open
Abstract
Objectives Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC). However, the application of ICIs can also cause treatment-related adverse events (trAEs) and immune-related adverse events (irAEs). This study was to evaluate both the irAEs and trAEs of different ICI strategies for NSCLC based on randomized clinical trials (RCTs). The study also examined real-world pharmacovigilance data from the Food and Drug Administration Adverse Event Reporting System (FAERS) regarding claimed ICI-associated AEs in clinical practice. Methods Based on Pubmed, Embase, Medline, and the Cochrane CENTRAL, we retrieved RCTs comparing ICIs with chemotherapy drugs or with different ICI regimens for the treatment of NSCLC up to October 20, 2023. Bayesian network meta-analysis (NMA) was performed using odds ratios (ORs) with 95% credible intervals (95%CrI). Separately, a retrospective pharmacovigilance study was performed based on FAERS database, extracting ICI-associated AEs in NSCLC patients between the first quarter (Q1) of 2004 and Q4 of 2023. The proportional reports reporting odds ratio was calculated to analyze the disproportionality. Results The NMA included 51 RCTs that involved a total of 26,958 patients with NSCLC. Based on the lowest risk of any trAEs, cemiplimab, tislelizumab, and durvalumab were ranked as the best. Among the agents associated with the lowest risk of grades 3-5 trAEs, tislelizumab, avelumab, and nivolumab were most likely to rank highest. As far as any or grades 3-5 irAEs are concerned, atezolizumab plus bevacizumab plus chemotherapy is considered the most safety option. However, it is associated with a high risk of grades 3-5 trAEs. As a result of FAERS pharmacovigilance data analysis, 9,420 AEs cases have been identified in 7,339 NSCLC patients treated with ICIs, and ICIs were related to statistically significant positive signal with 311 preferred terms (PTs), and comprehensively investigated and identified those AEs highly associated with ICIs. In total, 152 significant signals were associated with Nivolumab, with malignant neoplasm progression, death, and hypothyroidism being the most frequent PTs. Conclusion These findings revealed that ICIs differed in their safety profile. ICI treatment strategies can be improved and preventive methods can be developed for NSCLC patients based on our results.
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Affiliation(s)
- Xueyan Liang
- Phase 1 Clinical Trial Laboratory, Guangxi Academy of Medical Sciences and the People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Hewei Xiao
- Department of Scientific Research, Guangxi Academy of Medical Sciences and the People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Huijuan Li
- Phase 1 Clinical Trial Laboratory, Guangxi Academy of Medical Sciences and the People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Xiaoyu Chen
- Phase 1 Clinical Trial Laboratory, Guangxi Academy of Medical Sciences and the People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
- Department of Clinical Pharmacy, Guangxi Academy of Medical Sciences and the People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Yan Li
- Department of Clinical Pharmacy, Guangxi Academy of Medical Sciences and the People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
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Saowapa S, Polpichai N, Siladech P, Wannaphut C, Tanariyakul M, Wattanachayakul P, Bernal DO, Garcia Pleitez H, Tijani L. Immunotherapy-induced colitis in metastatic colorectal cancer: a systematic review and meta-analysis. Proc AMIA Symp 2024; 37:613-622. [PMID: 38910824 PMCID: PMC11188800 DOI: 10.1080/08998280.2024.2342723] [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: 03/09/2024] [Accepted: 03/28/2024] [Indexed: 06/25/2024] Open
Abstract
Colorectal cancer (CRC) presents significant mortality risks, underscoring the urgency of timely diagnosis and intervention. Advanced stages of CRC are managed through chemotherapy, targeted therapy, immunotherapy, radiotherapy, and surgery. Immunotherapy, while effective in bolstering the immune system against cancer cells, often carries toxic side effects, including colitis. This study aimed to evaluate the incidence of colitis in patients with metastatic CRC (mCRC) undergoing various immunotherapy treatments. Through a systematic search of Google Scholar and PubMed databases from inception until November 2023, nine relevant studies were identified. Subgroup analyses revealed a higher incidence of colitis, particularly in patients treated with anti-cytotoxic T-lymphocyte-associated molecule-4 (anti-CTLA-4) and combination therapies compared to monotherapy with programmed cell death receptor-1 (PD-1) or programmed cell death ligand receptor-1 (PDL-1) inhibitors. Notably, naive-treated metastatic CRC patients exhibited elevated colitis incidences compared to those previously treated. In conclusion, anti-CTLA-4 and combination therapies, such as nivolumab plus ipilimumab, were associated with increased colitis occurrences in metastatic CRC patients, highlighting the need for vigilant monitoring and management strategies, especially in immunotherapy-naive individuals.
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Affiliation(s)
- Sakditad Saowapa
- Department of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
| | - Natchaya Polpichai
- Department of Internal Medicine, Weiss Memorial Hospital, Chicago, Illinois, USA
| | - Pharit Siladech
- Department of Internal Medicine, Mahidol University, Bangkok, Thailand
| | - Chalothorn Wannaphut
- Department of Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA
| | - Manasawee Tanariyakul
- Department of Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii, USA
| | | | - Diego Olavarria Bernal
- Department of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
| | - Hector Garcia Pleitez
- Department of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
| | - Lukman Tijani
- Hematology and Oncology Department, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
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22
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Wang J, Guo Z, Shen M, Xie Q, Xiang H. Potential application mechanism of traditional Chinese medicine in treating immune checkpoint inhibitor-induced colitis. Front Immunol 2024; 15:1366489. [PMID: 38660314 PMCID: PMC11039877 DOI: 10.3389/fimmu.2024.1366489] [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: 01/06/2024] [Accepted: 03/08/2024] [Indexed: 04/26/2024] Open
Abstract
Cancer ranks among the foremost causes of mortality worldwide, posing a significant threat to human lives. The advent of tumor immunotherapy has substantially transformed the therapeutic landscape for numerous advanced malignancies, notably non-small cell lung cancer and melanoma. However, as immune checkpoint inhibitors (ICIs) are increasingly applied in clinical settings, a spectrum of undesired reactions, termed immune-related adverse events (irAEs), has emerged. These adverse reactions are associated with immunotherapy and can result in varying degrees of harm to the human body. Among these reactions, Immune checkpoint inhibitor-induced colitis (ICIIC) stands out as one of the most prevalent clinical adverse events. In contemporary times, traditional Chinese medicine (TCM) has demonstrated remarkable efficacy in addressing various maladies. Consequently, investigating the potential application and mechanisms of Chinese medicine in countering immune checkpoint inhibitor-induced colitis assumes significant importance in the treatment of this condition.
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Affiliation(s)
- Jing Wang
- College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang, China
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Ziyue Guo
- College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang, China
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Mengyi Shen
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Shangdong First Medical University & Shangdong Academy of Medical Sciences, Jinan, China
| | - Qi Xie
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
| | - Hongjie Xiang
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Shandong Lung Cancer Institute, Jinan, China
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23
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Casagrande S, Sopetto GB, Bertalot G, Bortolotti R, Racanelli V, Caffo O, Giometto B, Berti A, Veccia A. Immune-Related Adverse Events Due to Cancer Immunotherapy: Immune Mechanisms and Clinical Manifestations. Cancers (Basel) 2024; 16:1440. [PMID: 38611115 PMCID: PMC11011060 DOI: 10.3390/cancers16071440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 04/02/2024] [Accepted: 04/03/2024] [Indexed: 04/14/2024] Open
Abstract
The landscape of cancer treatment has undergone a significant transformation with the introduction of Immune Checkpoint Inhibitors (ICIs). Patients undergoing these treatments often report prolonged clinical and radiological responses, albeit with a potential risk of developing immune-related adverse events (irAEs). Here, we reviewed and discussed the mechanisms of action of ICIs and their pivotal role in regulating the immune system to enhance the anti-tumor immune response. We scrutinized the intricate pathogenic mechanisms responsible for irAEs, arising from the evasion of self-tolerance checkpoints due to drug-induced immune modulation. We also summarized the main clinical manifestations due to irAEs categorized by organ types, detailing their incidence and associated risk factors. The occurrence of irAEs is more frequent when ICIs are combined; with neurological, cardiovascular, hematological, and rheumatic irAEs more commonly linked to PD1/PD-L1 inhibitors and cutaneous and gastrointestinal irAEs more prevalent with CTLA4 inhibitors. Due to the often-nonspecific signs and symptoms, the diagnosis of irAEs (especially for those rare ones) can be challenging. The differential with primary autoimmune disorders becomes sometimes intricate, given the clinical and pathophysiological similarities. In conclusion, considering the escalating use of ICIs, this area of research necessitates additional clinical studies and practical insights, especially the development of biomarkers for predicting immune toxicities. In addition, there is a need for heightened education for both clinicians and patients to enhance understanding and awareness.
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Affiliation(s)
- Silvia Casagrande
- Unit of Neurology, Rovereto Hospital, Azienda Provinciale per i Servizi Sanitari-APSS, 38122 Trento, Italy; (S.C.); (B.G.)
| | - Giulia Boscato Sopetto
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38122 Trento, Italy; (G.B.S.); (G.B.); (V.R.)
| | - Giovanni Bertalot
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38122 Trento, Italy; (G.B.S.); (G.B.); (V.R.)
- Center for Medical Sciences (CISMed), University of Trento, 38122 Trento, Italy
- Multizonal Unit of Pathology, APSS, 38122 Trento, Italy
| | - Roberto Bortolotti
- Unit of Rheumatology, Santa Chiara Regional Hospital, APSS, 38122 Trento, Italy;
| | - Vito Racanelli
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38122 Trento, Italy; (G.B.S.); (G.B.); (V.R.)
- Center for Medical Sciences (CISMed), University of Trento, 38122 Trento, Italy
- Unit of Internal Medicine, Santa Chiara Regional Hospital, APSS, 38122 Trento, Italy
| | - Orazio Caffo
- Unit of Oncology, Santa Chiara Regional Hospital, APSS, 38122 Trento, Italy; (O.C.); (A.V.)
| | - Bruno Giometto
- Unit of Neurology, Rovereto Hospital, Azienda Provinciale per i Servizi Sanitari-APSS, 38122 Trento, Italy; (S.C.); (B.G.)
- Center for Medical Sciences (CISMed), University of Trento, 38122 Trento, Italy
- Department of Psychology and Cognitive Sciences (DIPSCO), University of Trento, 38122 Trento, Italy
| | - Alvise Berti
- Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, 38122 Trento, Italy; (G.B.S.); (G.B.); (V.R.)
- Center for Medical Sciences (CISMed), University of Trento, 38122 Trento, Italy
- Unit of Rheumatology, Santa Chiara Regional Hospital, APSS, 38122 Trento, Italy;
| | - Antonello Veccia
- Unit of Oncology, Santa Chiara Regional Hospital, APSS, 38122 Trento, Italy; (O.C.); (A.V.)
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24
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Velikova T, Krastev B, Gulinac M, Zashev M, Graklanov V, Peruhova M. New strategies in the diagnosis and treatment of immune-checkpoint inhibitor-mediated colitis. World J Clin Cases 2024; 12:1050-1062. [PMID: 38464930 PMCID: PMC10921308 DOI: 10.12998/wjcc.v12.i6.1050] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/20/2023] [Accepted: 01/19/2024] [Indexed: 02/20/2024] Open
Abstract
Immune-checkpoint inhibitor-mediated colitis (IMC) is an increasingly recognized adverse event in cancer immunotherapy, particularly associated with immune checkpoint inhibitors (ICIs) such as anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed cell death protein-1 antibodies. As this revolutionary immunotherapy gains prominence in cancer treatment, understanding, diagnosing, and effectively managing IMC becomes paramount. IMC represents a unique challenge due to its immune-mediated nature and potential for severe complications. However, a precise picture of IMC pathophysiology is currently unavailable. Therefore, we aimed to summarize the existing data while acknowledging the need for further research. This comprehensive review explores the mechanisms underlying ICIs, gastrointestinal adverse effects, and, in particular, IMC's incidence, prevalence, and features. Our review also emphasizes the importance of recognizing IMC's distinct clinical and histopathological features to differentiate it from other forms of colitis. Furthermore, this paper highlights the urgent need for evolving diagnostic methods, therapeutic strategies, and a multidisciplinary approach to effectively manage IMC.
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Affiliation(s)
- Tsvetelina Velikova
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
| | - Boris Krastev
- Medical Center Nadezhda, Medical Center Nadezhda, Sofia 1407, Bulgaria
| | - Milena Gulinac
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
- General and Clinical Pathology, Medical University of Plovdiv, Plovdiv 4002, Bulgaria
| | - Miroslav Zashev
- Department of General Surgery, University Hospital “Heart and Brain”, Burgas 8000, Bulgaria
| | - Vasko Graklanov
- First Department of Internal Diseases, Medical University of Plovdiv, Plovdiv 4000, Bulgaria
- Department of Hematology, University Hospital “St. George”, Plovdiv 4000, Bulgaria
| | - Milena Peruhova
- Division of Gastroenterology, University Hospital “Heart and Brain”, Burgas 1000, Bulgaria
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25
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Jungbauer F, Affolter A, Brochhausen C, Lammert A, Ludwig S, Merx K, Rotter N, Huber L. Risk factors for immune-related adverse effects during CPI therapy in patients with head and neck malignancies - a single center study. Front Oncol 2024; 14:1287178. [PMID: 38420014 PMCID: PMC10899674 DOI: 10.3389/fonc.2024.1287178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 01/30/2024] [Indexed: 03/02/2024] Open
Abstract
Introduction Checkpoint inhibitors, such as PD1 inhibitors, represent an important pillar in the therapy of advanced malignancies of the head and neck region. The most relevant complications are immune-related adverse effects (irAEs), which represent an immense burden for patients. Currently, no sufficient stratification measures are available to identify patients at increased risk of irAEs. The aim of this retrospective study was to examine whether demographic, histopathological, clinical, or laboratory values at the start of CPI therapy represent a risk factor for the later occurrence of autoimmune complications. Material and methods Data from 35 patients between 2018 and 2021 who received therapy with nivolumab or pembrolizumab for head and neck malignancy were analyzed and assessed for any associations with the subsequent occurrence of irAEs. Results IrAE developed in 37% of patients, with pneumonitis being the most common form (14%). Pneumonitis was found in patients with an average significantly lower T-stage of primary tumors. An increase in basophilic leukocytes was found in patients with dermatitis later in the course. When thyroiditis developed later, the patients had a higher CPS score and lower monocyte levels. Discussion Even though individual laboratory values at the beginning of therapy might show a statistical association with the later occurrence of irAEs, neither demographic, histopathological, nor laboratory chemistry values seem to be able to generate a sound and reliable risk profile for this type of complication. Therefore, patients need to be educated and sensitized to irAEs, and regular screening for irAEs should be carried out.
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Affiliation(s)
- Frederic Jungbauer
- Department of Otorhinolaryngology, Head- and Neck-Surgery, University Medical Centre Mannheim, Heidelberg University, Mannheim, Germany
| | - Annette Affolter
- Department of Otorhinolaryngology, Head- and Neck-Surgery, University Medical Centre Mannheim, Heidelberg University, Mannheim, Germany
| | - Christoph Brochhausen
- Department of Pathology, University Medical Centre Mannheim, Heidelberg University, Mannheim, Germany
| | - Anne Lammert
- Department of Otorhinolaryngology, Head- and Neck-Surgery, University Medical Centre Mannheim, Heidelberg University, Mannheim, Germany
| | - Sonja Ludwig
- Department of Otorhinolaryngology, Head- and Neck-Surgery, University Medical Centre Mannheim, Heidelberg University, Mannheim, Germany
| | - Kirsten Merx
- Department of Hematology and Oncology, University Medical Centre Mannheim, Heidelberg University, Mannheim, Germany
| | - Nicole Rotter
- Department of Otorhinolaryngology, Head- and Neck-Surgery, University Medical Centre Mannheim, Heidelberg University, Mannheim, Germany
| | - Lena Huber
- Department of Otorhinolaryngology, Head- and Neck-Surgery, University Medical Centre Mannheim, Heidelberg University, Mannheim, Germany
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26
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Yan T, Yu L, Zhang J, Chen Y, Fu Y, Tang J, Liao D. Achilles' Heel of currently approved immune checkpoint inhibitors: immune related adverse events. Front Immunol 2024; 15:1292122. [PMID: 38410506 PMCID: PMC10895024 DOI: 10.3389/fimmu.2024.1292122] [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: 09/11/2023] [Accepted: 01/04/2024] [Indexed: 02/28/2024] Open
Abstract
Immunotherapy has revolutionized the cancer treatment landscape by opening up novel avenues for intervention. As the use of immune checkpoint inhibitors (ICIs) has exponentially increased, so have immune-related adverse events (irAEs). The mechanism of irAEs may involve the direct damage caused by monoclonal antibodies and a sequence of immune responses triggered by T cell activation. Common side effects include dermatologic toxicity, endocrine toxicity, gastrointestinal toxicity, and hepatic toxicity. While relatively rare, neurotoxicity, cardiotoxicity, and pulmonary toxicity can be fatal. These toxicities pose a clinical dilemma regarding treatment discontinuation since they can result in severe complications and necessitate frequent hospitalization. Vigilant monitoring of irAEs is vital in clinical practice, and the principal therapeutic strategy entails the administration of oral or intravenous glucocorticoids (GSCs). It may be necessary to temporarily or permanently discontinue the use of ICIs in severe cases. Given that irAEs can impact multiple organs and require diverse treatment approaches, the involvement of a multidisciplinary team of experts is imperative. This review aims to comprehensively examine the pathogenesis, clinical manifestations, incidence, and treatment options for various irAEs.
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Affiliation(s)
- Ting Yan
- Department of Pharmacy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Lun Yu
- Department of Positron Emission Tomography–Computed Tomography (PET-CT) Center, Chenzhou No. 1 People’s Hospital, Chenzhou, China
| | - Jiwen Zhang
- Department of Pharmacy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
- School of Pharmacy, University of South China, Hengyang, China
| | - Yun Chen
- Department of Pharmacy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Yilan Fu
- Department of Pharmacy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Jingyi Tang
- Department of Pharmacy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Dehua Liao
- Department of Pharmacy, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
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27
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Ishihara H, Watanabe T, Kumei S, Kume K, Yoshikawa I, Harada M. A case of refractory immune checkpoint inhibitor-induced colitis improved by the treatment with vedolizumab and granulocyte-monocyte apheresis combination therapy. Clin J Gastroenterol 2024; 17:46-51. [PMID: 38041760 DOI: 10.1007/s12328-023-01887-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 10/23/2023] [Indexed: 12/03/2023]
Abstract
A 68-year-old man developed immune-related adverse event (irAE) colitis after the initiation of nivolumab and ipilimumab combination therapy for malignant melanoma. We diagnosed the patient with grade 3 irAE colitis and started prednisolone (1 mg/kg/day). Although the symptom improved once, it worsened along with the tapering of prednisolone. Therefore, we started infliximab (IFX). However, symptoms did not improve after two doses of IFX. We discontinued IFX and initiated vedolizumab (VED). Because VED alone did not improve the symptom, we started granulocyte-monocyte apheresis (GMA). Twelve weeks after the onset, the colitis was in remission. Therefore, in addition to vedolizumab, GMA may be considered in cases refractory to treatment.
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Affiliation(s)
- Hikaru Ishihara
- Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan.
| | - Tatsuyuki Watanabe
- Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Shinsuke Kumei
- Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Keiichiro Kume
- Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Ichiro Yoshikawa
- Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Masaru Harada
- Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
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28
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Newman KL, Allegretti JR. Emerging Noninfectious Indications for Live Biotherapeutic Products in Gastroenterology. Am J Gastroenterol 2024; 119:S30-S35. [PMID: 38153224 DOI: 10.14309/ajg.0000000000002584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 10/22/2023] [Indexed: 12/29/2023]
Affiliation(s)
- Kira L Newman
- Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Jessica R Allegretti
- Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
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29
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Gómez Escudero O. Enterocolitis and other immunotherapy and targeted therapy-related gastrointestinal manifestations: A review for gastroenterologist. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2024; 89:89-105. [PMID: 38485558 DOI: 10.1016/j.rgmxen.2023.11.001] [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: 07/21/2023] [Accepted: 11/08/2023] [Indexed: 04/20/2024]
Abstract
New oncologic treatments, particularly immunotherapy (IT), have revolutionized the treatment of advanced-stage malignant tumors. Immune checkpoint inhibitors are the main form of IT and act by increasing T cell activity and the organism's immune response against neoplastic cells. Targeted therapy is another form of IT that acts by inhibiting oncogenes or inflammation signaling and tumor angiogenesis pathways. However, these mechanisms of tumor destruction can interfere with the host's immune self-tolerance or with the mechanisms of epithelial tissue repair and predispose to immune system-mediated adverse events that can affect multiple organs, including the digestive tract. The gastrointestinal manifestations of damage caused by IT can range from low-grade mucositis to ulceration, and in some cases, necrosis and perforation. Any part of the gastrointestinal tract can be affected, but there is greater involvement of the small bowel and colon, with a pattern similar to that seen in inflammatory bowel disease. The most common clinical manifestation is chronic diarrhea. The differential diagnosis includes enteropathogenic infections, especially those caused by opportunistic microorganisms; adverse drug reactions; and other inflammatory and malabsorption disorders. Treatment is guided by damage severity. Mild cases can be treated with antidiarrheals and rehydration in the outpatient setting; moderate cases with hospitalization, systemic steroids, and temporary suspension of IT; and severe cases with immunosuppressants or biologic agents and definitive suspension of IT.
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Affiliation(s)
- O Gómez Escudero
- Clínica de Gastroenterología, Endoscopia Digestiva y Motilidad Gastrointestinal «Endoneurogastro», Hospital Ángeles, Puebla, Mexico.
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30
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Gómez-Escudero O. Enterocolitis y otras manifestaciones de toxicidad gastrointestinal asociada a inmunoterapia y terapia blanco: una revisión para el gastroenterólogo. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2024; 89:89-105. [DOI: 10.1016/j.rgmx.2023.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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31
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Ding M, Zhang X, Wang J, Gao F, Zheng X, Yuan J, Qi X. Treatment and outcomes of immune checkpoint inhibitors-associated colitis/diarrhea: A systematic review and meta-analysis. Dig Liver Dis 2023; 55:1621-1631. [PMID: 36894390 DOI: 10.1016/j.dld.2023.02.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 02/15/2023] [Accepted: 02/20/2023] [Indexed: 03/11/2023]
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) have improved the outcomes of cancer patients. However, ICIs often lead to colitis/diarrhea. This study aimed to assess the treatment of ICIs-associated colitis/diarrhea and outcomes. METHODS PubMed, EMBASE, and Cochrane Library databases were searched for eligible studies which investigated the treatment and outcomes of colitis/diarrhea developing in patients who received ICIs. The pooled incidences of any-grade colitis/diarrhea, low-grade colitis, high-grade colitis, low-grade diarrhea, and high-grade diarrhea as well as the pooled rates of response to treatment, mortality, and ICIs permanent discontinuation and restarts in patients with ICIs-associated colitis/diarrhea were estimated using a random-effects model. RESULTS Among the 11,492 papers initially identified, 27 studies were included. The pooled incidences of any-grade colitis/diarrhea, low-grade colitis, high-grade colitis, low-grade diarrhea, and high-grade diarrhea were 17%, 3%, 17%, 13%, and 15%, respectively. The pooled rates of overall response, response to corticosteroid therapy, and response to biological agents were 88%, 50%, and 96%, respectively. The pooled short-term mortality in patients with ICIs-associated colitis/diarrhea was 2%. The pooled incidences of ICIs permanent discontinuation and restarts were 43% and 33%, respectively. CONCLUSION ICIs-associated colitis/diarrhea is common, but rarely lethal. Half of them are responsive to corticosteroid therapy. There is a fairly high rate of response to biological agents in steroid-refractory colitis/diarrhea patients.
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Affiliation(s)
- Min Ding
- Meta-Analysis Interest Group, Department of Gastroenterology, The General Hospital of Northern Theater Command (formerly General Hospital of Shenyang Military Area), Shenyang, China; Postgraduate College, China Medical University, Shenyang, China
| | - Xianxian Zhang
- Meta-Analysis Interest Group, Department of Gastroenterology, The General Hospital of Northern Theater Command (formerly General Hospital of Shenyang Military Area), Shenyang, China; Department of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
| | - Jing Wang
- Meta-Analysis Interest Group, Department of Gastroenterology, The General Hospital of Northern Theater Command (formerly General Hospital of Shenyang Military Area), Shenyang, China; Department of Gastroenterology, The 960th Hospital of the PLA, Jinan, China
| | - Fangbo Gao
- Meta-Analysis Interest Group, Department of Gastroenterology, The General Hospital of Northern Theater Command (formerly General Hospital of Shenyang Military Area), Shenyang, China; Department of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
| | - Xiaojie Zheng
- Meta-Analysis Interest Group, Department of Gastroenterology, The General Hospital of Northern Theater Command (formerly General Hospital of Shenyang Military Area), Shenyang, China; Postgraduate College, China Medical University, Shenyang, China
| | - Jinqiu Yuan
- Clinical Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Xingshun Qi
- Meta-Analysis Interest Group, Department of Gastroenterology, The General Hospital of Northern Theater Command (formerly General Hospital of Shenyang Military Area), Shenyang, China; Postgraduate College, China Medical University, Shenyang, China; Department of Life Sciences and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China.
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32
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Krasnow NA, Chute DF, Falade AS, North CM, Reynolds KL, Dougan ML. Evaluation of appendectomy as a potential risk factor for immune checkpoint inhibitor-associated enterocolitis. Immunotherapy 2023; 15:913-920. [PMID: 37292001 PMCID: PMC10346134 DOI: 10.2217/imt-2022-0245] [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: 09/27/2022] [Accepted: 05/23/2023] [Indexed: 06/10/2023] Open
Abstract
Aims: The relationship between appendectomy and immune checkpoint inhibitor (ICI) enterocolitis was explored. Methods: Patients who began ICIs between July 2010 and September 2020 (n = 10,907) were included. The exposure group included patients with evidence of appendectomy prior to ICIs in operative notes (n = 380). The control group included patients with evidence of normal appendix in radiologic reports (n = 3602). ICI enterocolitis was defined as histopathologic evidence of colitis or enteritis attributed to ICIs. The association between appendectomy and ICI enterocolitis was characterized by multivariate logistic regression. Results: 248 patients (6.2%) developed ICI enterocolitis. The odds of ICI enterocolitis were similar among those with prior appendectomy and those without appendectomy (adjusted odds ratio: 0.82; 95% CI: 0.49-1.36; p = 0.449). Conclusion: No association was found between prior appendectomy and ICI enterocolitis.
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Affiliation(s)
| | - Donald F Chute
- Department of Vascular Surgery, UMass Memorial Medical Center, Worcester, MA 01605, USA
| | - Ayo S Falade
- Department of Medicine, Mass General Brigham Salem Hospital, Salem, MA 01970, USA
| | - Crystal M North
- Harvard Medical School, Boston, MA 02115, USA
- Division of Pulmonology/Critical Care, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Kerry L Reynolds
- Harvard Medical School, Boston, MA 02115, USA
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA
| | - Michael L Dougan
- Harvard Medical School, Boston, MA 02115, USA
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA
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33
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Lee RV, Melstrom KA, Mannan R, Idos GE, Kidambi T. Severe Immune-Mediated Colitis Induced by Checkpoint Inhibitors in an Adolescent With Lynch Syndrome. Cureus 2023; 15:e43246. [PMID: 37692727 PMCID: PMC10491925 DOI: 10.7759/cureus.43246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/09/2023] [Indexed: 09/12/2023] Open
Abstract
Lynch syndrome is a hereditary colorectal cancer caused by mutations in DNA mismatch repair genes. Immune checkpoint therapies have shown promise in treating Lynch syndrome-associated cancers but can lead to immune-related adverse events, such as colitis. In this report, we present a severe case of immune-mediated colitis (IMC) induced by checkpoint inhibitors in a young patient with Lynch syndrome. This 20-year-old male with Lynch syndrome and a history of glioblastoma underwent dual checkpoint therapy, after initial treatment with systemic steroids. Despite this, his condition worsened, resulting in complications, such as toxic megacolon and small bowel obstruction. He was subjected to various treatments, including infliximab and vedolizumab, but ultimately required total abdominal colectomy with J-pouch creation. This case highlights the challenges of managing severe IMC in patients with Lynch syndrome. The patient's suboptimal response to standard treatments and the development of complications emphasizes the need for a better understanding and alternative therapeutic options for IMC. This case also calls into question whether a subset of patients with IMC should be "treated to target," even though the current standard of care for IMC is guided by symptom response, and if so, further research is necessary to identify potential therapeutic targets. Further research is also required to understand the mechanisms of IMC and develop effective treatment strategies tailored to patients with Lynch syndrome and immune-related adverse events.
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Affiliation(s)
- Rachel V Lee
- Center for Precision Medicine, City of Hope Comprehensive Cancer Center, Duarte, USA
| | - Kurt A Melstrom
- Department of Surgery, Division of Colorectal Surgery, City of Hope Comprehensive Cancer Center, Duarte, USA
| | - Rifat Mannan
- Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, USA
| | - Gregory E Idos
- Department of Internal Medicine, Division of Gastroenterology, City of Hope Comprehensive Cancer Center, Duarte, USA
| | - Trilokesh Kidambi
- Department of Internal Medicine, Division of Gastroenterology, City of Hope Comprehensive Cancer Center, Duarte, USA
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34
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Karna R, S Deliwala S, Ramgopal B, Asawa P, Mishra R, P Mohan B, Jayakrishnan T, Grover D, Kalra T, Bhalla J, Saraswati U, K Gangwani M, Dhawan M, G Adler D. Gastrointestinal treatment-related adverse events of combined immune checkpoint inhibitors: a meta-analysis. Immunotherapy 2023. [PMID: 37190949 DOI: 10.2217/imt-2023-0001] [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] [Indexed: 05/17/2023] Open
Abstract
Introduction: Combined immune checkpoint inhibitors can cause gastrointestinal adverse events. Methods: We performed a meta-analysis of pooled colonic, hepatic and pancreatic treatment-related adverse events of combined ICI. Results: 53 trials reporting treatment-related adverse events in 6581 patients. All grade diarrhea was the most common adverse event seen in 25.4% patients, followed by all grade hepatitis in nearly 13% patients and pancreatitis in nearly 7.5% patients. Conclusion: Our study provides pooled data of treatment-related adverse events from different combination immune checkpoint inhibitors use in solid tumors and demonstrates a high incidence of all grades and ≥3 grade gastrointestinal adverse events. Further studies are required to characterize these adverse events and assess their overall impact on treatment course and outcomes.
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Affiliation(s)
- Rahul Karna
- Internal Medicine, Allegheny Health Network, Pittsburgh, PA, USA
| | - Smit S Deliwala
- Division of Digestive Diseases, Emory University School of Medicine, Atlanta, GA, USA
| | - Balasubramanian Ramgopal
- Foundation Fellowship Doctor, University Hospital, Southampton NHS Foundation Trust, Southampton, Hampshire, UK
| | - Palash Asawa
- Internal Medicine, Allegheny Health Network, Pittsburgh, PA, USA
| | - Rahul Mishra
- Postdoctoral research fellow, Cleveland Clinic, OH, USA
| | - Babu P Mohan
- Gastroenterology & Hepatology, University of Utah Health School of Medicine, Salt Lake City, UT, USA
| | | | - Dheera Grover
- Internal Medicine, University of Connecticut, Hartford, CT, USA
| | - Tanisha Kalra
- Internal Medicine, SUNY Downstate Health Science University, NY, USA
| | | | | | - Manesh K Gangwani
- Internal Medicine, University of Toledo Medical Center, Toledo, OH, USA
| | - Manish Dhawan
- Gastroenterology & Hepatology, Allegheny Health Network, Pittsburgh, PA, USA
| | - Douglas G Adler
- Center for Advanced Therapeutic Endoscopy, Centura Health, Denver, CO, USA
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35
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Mallio CA, Bernetti C, Cea L, Buoso A, Stiffi M, Vertulli D, Greco F, Zobel BB. Adverse Effects of Immune-Checkpoint Inhibitors: A Comprehensive Imaging-Oriented Review. Curr Oncol 2023; 30:4700-4723. [PMID: 37232813 DOI: 10.3390/curroncol30050355] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 04/22/2023] [Accepted: 05/01/2023] [Indexed: 05/27/2023] Open
Abstract
Immune-checkpoint inhibitors (ICIs) are immunomodulatory monoclonal antibodies, which increase antitumor immunity of the host and facilitate T-cell-mediated actions against tumors. These medications have been used in recent years as a weapon against advanced stage malignancies, such as melanoma, renal cell carcinoma, lymphoma, small or non-small cell lung cancer, and colorectal cancer. Unfortunately, they are not free from possible adverse effects (immune-related adverse events-irAEs) that mainly affect skin, gastrointestinal, hepatic, and endocrine systems. Early diagnosis of irAEs is essential to correctly and rapidly manage patients, with ICIs suspension and therapies administration. Deep knowledge of the imaging and clinical patterns of irAEs is the key to promptly rule out other diagnoses. Here, we performed a review of the radiological signs and differential diagnosis, based on the organ involved. The aim of this review is to provide guidance to recognize the most significant radiological findings of the main irAEs, based on incidence, severity, and the role of imaging.
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Affiliation(s)
- Carlo Augusto Mallio
- Department of Medicine and Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
- Department of Medicine and Surgery, Research Unit of Radiology, Università Campus Bio-Medico di Roma, 00128 Roma, Italy
| | - Caterina Bernetti
- Department of Medicine and Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
- Department of Medicine and Surgery, Research Unit of Radiology, Università Campus Bio-Medico di Roma, 00128 Roma, Italy
| | - Laura Cea
- Department of Medicine and Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
- Department of Medicine and Surgery, Research Unit of Radiology, Università Campus Bio-Medico di Roma, 00128 Roma, Italy
| | - Andrea Buoso
- Department of Medicine and Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
- Department of Medicine and Surgery, Research Unit of Radiology, Università Campus Bio-Medico di Roma, 00128 Roma, Italy
| | - Massimo Stiffi
- Department of Medicine and Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
- Department of Medicine and Surgery, Research Unit of Radiology, Università Campus Bio-Medico di Roma, 00128 Roma, Italy
| | - Daniele Vertulli
- Department of Medicine and Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
- Department of Medicine and Surgery, Research Unit of Radiology, Università Campus Bio-Medico di Roma, 00128 Roma, Italy
| | - Federico Greco
- Unità Operativa Complessa Diagnostica per Immagini Territoriale Aziendale, Cittadella della Salute Azienda Sanitaria Locale di Lecce, Piazza Filippo Bottazzi, 73100 Lecce, Italy
| | - Bruno Beomonte Zobel
- Department of Medicine and Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
- Department of Medicine and Surgery, Research Unit of Radiology, Università Campus Bio-Medico di Roma, 00128 Roma, Italy
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36
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Childers BG, Donovan E, Lo WM, Janowak LM, Sussman J, Janowak CF. Operative management of immune checkpoint colitis following in-transit melanoma: Case report. Front Oncol 2023; 13:1120808. [PMID: 37152059 PMCID: PMC10157394 DOI: 10.3389/fonc.2023.1120808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Accepted: 03/27/2023] [Indexed: 05/09/2023] Open
Abstract
Immune checkpoint inhibitors are increasingly used as powerful anti-neoplastic therapies in the setting of melanoma. Colitis is a known complication of immune checkpoint inhibitors that if often medically managed. We present a patient with stage IV melanoma with demonstrated in-transit disease undergoing immune checkpoint inhibitor therapy. The patient subsequently developed recalcitrant severe colitis that necessitated operative intervention and bowel resection. The association of immune check point inhibitors and immune related adverse effects are discussed as well as treatments of advanced colitis, including the possibility of surgical management in the setting of severe colitis with complications.
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Affiliation(s)
| | - Eileen Donovan
- College of Medicine, University of Cincinnati, Cincinnati, OH, United States
| | - Winifred M. Lo
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Lauren M. Janowak
- College of Nursing, University of Cincinnati, Cincinnati, OH, United States
| | - Jeffrey Sussman
- College of Medicine, University of Cincinnati, Cincinnati, OH, United States
| | - Christopher F. Janowak
- College of Medicine, University of Cincinnati, Cincinnati, OH, United States
- *Correspondence: Christopher F. Janowak,
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Cheng S, Yang Y, Yu J, Chen W, Li X. Immune-Related Colitis Induced by Camrelizumab: A Case Report. J Inflamm Res 2023; 16:1727-1731. [PMID: 37096128 PMCID: PMC10122477 DOI: 10.2147/jir.s405023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 04/11/2023] [Indexed: 04/26/2023] Open
Abstract
In recent years, immunotherapy has become a major research focus in the field of cancer treatment. Because of its good efficacy and lasting immune response, immune checkpoint inhibitors have benefited the long-term survival of many types of cancer patients. However, overactivation of the immune system may attack normal organs and cause a series of immune related adverse reactions. Among them, due to the high incidence of immune-related colitis, it deserves special attention. Camrelizumab is a programmed cell death 1 (PD-1) inhibitor that was developed by Jiangsu Hengrui Medicine Company. We reported the clinical data of a case of hepatocellular carcinoma with immune-related colitis after treatment with camrelizumab. A 63-year-old man with hepatocellular carcinoma developed diarrhea and hematochezia after receiving 4 cycles of camrelizumab. Endoscopy showed multiple flake congestion and edema in the terminal ileum and total colon mucosa with bright red surface. Pathological evaluation showed chronic inflammation of colonic mucosa. After giving 0.25g bid of enteric-coated sulfasalazine tablets orally for 6 weeks, his colitis improved. Camrelizumab can induce immune-related colitis. Sulfasalazine could be used to reduce adverse reactions of glucocorticoids.
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Affiliation(s)
- Sheng Cheng
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Yun Yang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Junxian Yu
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Wei Chen
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China
| | - Xingang Li
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, People’s Republic of China
- Correspondence: Xingang Li, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, People’s Republic of China, Email
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Kuang AG, Mohajir W, Panneerselvam K, McQuade JL, Oliva ICG, Khan MA, Zhang HC, Thomas AS, Wang Y. Diarrhea and colitis related to immune checkpoint inhibitor and BRAF/MEK inhibitor therapy. Ann Gastroenterol 2023; 36:45-53. [PMID: 36593813 PMCID: PMC9756030 DOI: 10.20524/aog.2023.0762] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 10/21/2022] [Indexed: 01/04/2023] Open
Abstract
Background Immune checkpoint inhibitor (ICI) therapy can be complicated by gastrointestinal adverse events (AEs). Similarly, gastrointestinal AEs have been reported with the use of serine/threonine-protein kinase B-Raf (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitor therapy. We investigated the characteristics and management of gastrointestinal AEs related to sequential ICI and BRAF/MEK inhibitor therapy. Methods We identified 255 adult cancer patients who received both BRAF/MEK inhibitor therapy and ICI therapy between 2014 and 2021. Thirty-two eligible patients had gastrointestinal AEs after receiving both therapies and were categorized based on the order of their administration. Their clinical characteristics, evaluation, treatment and outcomes were compared. Results Of the 32 eligible patients, 18 (56.3%) received ICI therapy followed by BRAF/MEK inhibitors (early ICI group), and 14 (44.8%) received BRAF/MEK inhibitor therapy followed by ICI (early BRAF/MEK inhibitor group). Compared with the early BRAF/MEK inhibitor group, the early ICI group had higher rates of grade 3-4 diarrhea (50.0% vs. 14.3%, P=0.047) and grade 3-4 colitis (38.9% vs. 0%, P=0.010). The early ICI group had a later onset of colitis (347.5 vs. 84.5 days, P=0.011) and a higher rate of hospitalization at initial colitis presentation (100% vs. 71.4%, P=0.028). Patients in the early ICI group were more likely to have diarrhea or colitis recurrence (69.2% vs. 9.1%, P=0.019) and re-hospitalization for colitis (38.9% vs. 0%, P=0.010). Conclusion The sequential exposure of BRAF/MEK therapy after ICI may contribute to a more aggressive clinical profile of gastrointestinal toxicities that may warrant a more aggressive management strategy.
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Affiliation(s)
- Andrew G. Kuang
- Department of Medicine, Baylor College of Medicine (Andrew G. Kuang, Kavea Panneerselvam)
| | - Wasay Mohajir
- Department of Internal Medicine, The University of Texas Health Science Center at Houston (Wasay Mohajir)
| | - Kavea Panneerselvam
- Department of Medicine, Baylor College of Medicine (Andrew G. Kuang, Kavea Panneerselvam)
| | - Jennifer L. McQuade
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center (Jennifer L. McQuade, Isabella C. Glitz Oliva)
| | - Isabella C. Glitz Oliva
- Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center (Jennifer L. McQuade, Isabella C. Glitz Oliva)
| | - Muhammad Ali Khan
- Department of Gastroenterology, Hepatology, and Nutrition, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center (Muhammad Ali Khan, Hao Chi Zhang, Anusha S. Thomas, Yinghong Wang), Houston, TX, USA
| | - Hao Chi Zhang
- Department of Gastroenterology, Hepatology, and Nutrition, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center (Muhammad Ali Khan, Hao Chi Zhang, Anusha S. Thomas, Yinghong Wang), Houston, TX, USA
| | - Anusha S. Thomas
- Department of Gastroenterology, Hepatology, and Nutrition, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center (Muhammad Ali Khan, Hao Chi Zhang, Anusha S. Thomas, Yinghong Wang), Houston, TX, USA
| | - Yinghong Wang
- Department of Gastroenterology, Hepatology, and Nutrition, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center (Muhammad Ali Khan, Hao Chi Zhang, Anusha S. Thomas, Yinghong Wang), Houston, TX, USA
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Refractory Checkpoint Inhibitor Colitis Responsive to Ustekinumab. ACG Case Rep J 2022; 9:e00946. [PMID: 36600789 PMCID: PMC9794264 DOI: 10.14309/crj.0000000000000946] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Accepted: 11/28/2022] [Indexed: 01/06/2023] Open
Abstract
Immune checkpoint inhibitors have transformed the treatment of cancer. Nonetheless, multiple immune-related adverse events have been reported, including checkpoint inhibitor colitis. Severe colitis can be complicated by ileus, megacolon, intestinal perforation, and death. Current appropriate treatment includes steroids, followed by antitumor necrosis factor biologic therapy, infliximab. Alternatively, vedolizumab and fecal microbiota transplantation have reported efficacy for refractory cases. In this study, we present the first case report of a patient with steroid-refractory checkpoint inhibitor-induced colitis due to pembrolizumab for Stage IV anaplastic thyroid carcinoma successfully treated with ustekinumab after failure of infliximab, vedolizumab, and fecal microbiota transplantation. This may lead to a better understanding of treatment options for refractory checkpoint inhibitor colitis.
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40
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Saha A, Dreyfuss I, Sarfraz H, Friedman M, Markowitz J. Dietary Considerations for Inflammatory Bowel Disease Are Useful for Treatment of Checkpoint Inhibitor-Induced Colitis. Cancers (Basel) 2022; 15:84. [PMID: 36612082 PMCID: PMC9817715 DOI: 10.3390/cancers15010084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/13/2022] [Accepted: 12/19/2022] [Indexed: 12/28/2022] Open
Abstract
Checkpoint molecules are cell surface receptors on immune cells that mitigate excessive immune responses, but they have increased expression levels in cancer to facilitate immune escape. Checkpoint blockade therapies (e.g., anti-PD-1, anti-CTLA-4, and anti-LAG-3 therapy, among others) have been developed for multiple cancers. Colitis associated with checkpoint blockade therapy has pathophysiological similarities to inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis. Current therapeutic guidelines for checkpoint blockade-induced colitis include corticosteroids and, if the patient is refractory to steroids, immunomodulating antibodies, such as anti-TNF and anti-integrin agents. Interestingly, immunomodulatory molecules, such as TNFα, are upregulated in both IBD and checkpoint-mediated colitis. The inflammatory colitis toxicity symptoms from checkpoint blockade are similar to clinical symptoms experienced by patients with IBD. The pathophysiologic, dietary, and genetic factors associated with IBD will be reviewed. We will then explain how the principles developed for the treatment of IBD can be applied to patients experiencing inflammatory bowel toxicity secondary to checkpoint blockade.
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Affiliation(s)
- Aditi Saha
- Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Isabella Dreyfuss
- Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Humaira Sarfraz
- Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Mark Friedman
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Joseph Markowitz
- Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
- Department of Oncologic Sciences, University of South Florida School of Medicine, Tampa, FL 33612, USA
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41
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Lu L, Sha L, Feng Y, Yan L. Multidisciplinary treatment of a patient with severe immune checkpoint inhibitor-induced colitis: A case report. World J Clin Cases 2022; 10:13108-13114. [PMID: 36569020 PMCID: PMC9782922 DOI: 10.12998/wjcc.v10.i35.13108] [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: 10/02/2022] [Revised: 11/02/2022] [Accepted: 11/23/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) are a new class of antitumor drugs that have been approved to treat a variety of malignant tumors. However, the occurrence of immune related adverse events (irAEs) has become an important reason for terminating treatment. ICIs sometimes lead to diarrhea and colitis, with severe enterocolitis potentially causing the hemorrhage of the lower gastrointestinal tract and colonic perforation. ICI-associated colitis is primarily treated with glucorticosteroids and/or agents targeting tumor necrosis factor-α. Here, we describe a case of severe ICI-associated colitis due to anti-programmed cell death ligand 1 (PD-L1) (durvalumab) treatment for small cell lung cancer with liver metastasis. The patient exhibited a poor response to rescuable therapy, and eventually received a laparoscopic subtotal colectomy and ileostomy. The data presented here will contribute to optimizing current treatment strategies for patients with severe ICI-associated colitis.
CASE SUMMARY A 71-year-old man was admitted for a second course of anti-PD-L1 + IP (durvalumab + irinotecan + cisplatin) treatment to manage lung cancer with liver metastasis, diagnosed 1 mo previously. Four days after the second dose, the patient developed abdominal pain and bloody diarrhea. Due to the anti-PD-L1 medication history and colonoscopy findings of the patient, he was diagnosed with a colitis associated with ICI treatment. After treatment with sufficient glucocorticoids and two courses of infliximab, the patient developed severe lower gastrointestinal bleeding. After adequate assessment, the patient was treated by laparoscopic surgery, and was discharged in stable condition.
CONCLUSION The early screening and hierarchical management of irAEs need the joint participation of a multidisciplinary team. For ICI-related colitis with ineffective medical treatment, timely surgical intervention could prevent the death of patients.
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Affiliation(s)
- Lu Lu
- Department of Gastroenterology, Longhua Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Li Sha
- Department of General Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200021, China
| | - Yu Feng
- Department of General Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200021, China
| | - Liang Yan
- Department of General Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 200021, China
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42
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Immunotherapy for Cancer: Common Gastrointestinal, Liver, and Pancreatic Side Effects and Their Management. Am J Gastroenterol 2022; 117:1917-1932. [PMID: 36455219 DOI: 10.14309/ajg.0000000000001983] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 07/29/2022] [Indexed: 12/03/2022]
Abstract
Cancer cells can block the activation of T lymphocytes by deploying inhibitory signals to cell surface receptors that downregulate the immune response. Immune checkpoint inhibitors (ICI) are monoclonal antibodies that regulate the immune response by acting on these receptors. The use of ICI has been successful for cancer types that do not respond well to conventional chemotherapy, showing clinical benefit in various advanced and metastatic cancers and supporting the promise of cancer immunotherapy. However, in some cases, these treatments are associated with immune-related adverse events, many of which affect the digestive system. The treatment of immune-related adverse events depends on the affected organ and the severity of symptoms. Here, we review the commonly used US FDA-approved ICI and briefly outline their mechanism of action. We also describe the resulting collateral effects on the gastrointestinal tract, liver, and pancreas and discuss their management and prognosis.
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43
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Kelly-Goss MR, Badran YR, Dougan M. Update on Immune Checkpoint Inhibitor Enterocolitis. Curr Gastroenterol Rep 2022; 24:171-181. [PMID: 36264425 PMCID: PMC9583048 DOI: 10.1007/s11894-022-00852-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/29/2022] [Indexed: 12/13/2022]
Abstract
PURPOSE OF REVIEW Immune checkpoint inhibitor (ICI) therapy revolutionized the treatment of multiple solid and hematologic malignancies. Yet, with it came profound inflammatory toxicities that mimic autoimmune diseases, termed immune-related adverse events (irAEs). Prominent among these is gastrointestinal inflammation, including a spectrum of gastritis, enteritis, and colitis. Here we synthesize an approach to immune checkpoint related enterocolitis (irEC) - including diagnostics and therapeutics - underpinned by new insights into the mechanism behind these phenomena. RECENT FINDINGS This review presents updated insights on how to approach irEC, including novel approaches to selective immunosuppressive therapy, the role of fecal microbiota transplant, and the underlying cellular mechanisms of irEC. This review provides an update on irEC diagnosis and therapy, with considerations of new therapies and special patient populations. The field of gastrointestinal irAEs requires additional investigation, which will ultimately provide the tools required for patients to continue to receive life-saving ICI therapy.
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Affiliation(s)
- Molly R. Kelly-Goss
- Department of Medicine, Massachusetts General Hospital, Boston, MA 02114 USA
- Harvard Medical School, Boston, MA 02115 USA
| | - Yousef R. Badran
- Department of Medicine, Massachusetts General Hospital, Boston, MA 02114 USA
- Harvard Medical School, Boston, MA 02115 USA
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114 USA
| | - Michael Dougan
- Harvard Medical School, Boston, MA 02115 USA
- Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114 USA
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44
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Huang G, Liu S, Dong J, Xi X, Kong R, Li W, Du Q. PD-1 inhibitor-based adverse events in solid tumors: A retrospective real-world study. Front Pharmacol 2022; 13:974376. [PMID: 36438818 PMCID: PMC9681783 DOI: 10.3389/fphar.2022.974376] [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] [Received: 06/21/2022] [Accepted: 10/31/2022] [Indexed: 12/21/2023] Open
Abstract
Background & Aims: Immune checkpoint inhibitors (ICIs) have transformed the landscape of cancer treatment, and ICI-related toxicities (i.e., immune-related adverse events (irAEs) have been reported in many clinical studies. However, the toxicity data of real-world have not been fully assessed. Methods: Patients with histologically confirmed solid tumors who had been treated with PD-1 inhibitors were included in the study. Patient data were collected from electronic medical records, including basic characteristics, data of irAEs, management and outcome. Incidences of irAEs were pooled and compared, and the risk of irAEs was also analyzed. Results: A total of 362 solid tumor patients treated with sintilimab (n = 171), camrelizumab (n = 60), toripalimab (n = 72), and pembrolizumab (n = 59) were included. In total, any grade irAEs, grade 1-2 irAEs, and grade ≥3 irAEs accounted for 47.24%, 38.67% and 8.56% of cases, reapectively. Further, 29.24% of patients discontinued immunotherapy due to irAEs, with pneumonitis being the main reason for discontinuation. By comparing the toxicity profiles between different ICIs, we found that reactive capillary haemangiomas were camrelizumab-specific. Additionally, the frequency of irAEs was association with ICIs type, the pooled incidence (standardized rate) of irAEs related to sintilimab, camrelizumab, toripalimab and pembrolizumab were 55.56% (52.81%), 48.33% (55.55%), 33.33% (29.23%) and 38.98% (38.29%), respectively. Sintilimab and camrelizumab had higher incidences of any grade and grade 1-2 than toripalimab (55.56% vs. 33.33%, p = 0.002; 48.54% vs. 25.00%, p = 0.0001) and pembrolizumab (55.56% vs. 38.98%, p = 0.0028; 48.54% vs. 25.42%, p = 0.002), while the grade ≥3 irAEs of pembrolizumab (13.56%) were approximately 1.63- to 1.93-fold higher than other ICIs, and the standardized grade ≥3 of pembrolizumab was significantly higher than that of sintilimab (13.21% vs. 7.12%, p = 0.026), especially for grade ≥3 pneumonitis. Multivariate analysis found that cumulative cycles of ICI (OR = 1.081; 95% CI: 1.023-1.142; p = 0.006), and lung cancer (OR = 1.765; 95% CI: 1.105-2.820; p = 0.017) were independent risk factors for irAEs. Conclusion: The frequency of irAEs is associated with ICI type. The pooled incidence of irAEs related to sintilimab and pneumonitis caused by pembrolizumab were higher. These data indicate the importance of having different monitoring priorities for different PD-1 inhibitors.
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Affiliation(s)
- Guili Huang
- Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Songqing Liu
- Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jie Dong
- Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xin Xi
- Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Rui Kong
- Department of Oncology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Wenjun Li
- Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qian Du
- Department of Pharmacy, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Nahar KJ, Marsh-Wakefield F, Rawson RV, Gide TN, Ferguson AL, Allen R, Quek C, da Silva IP, Tattersal S, Kiely CJ, Sandanayake N, Carlino MS, McCaughan G, Wilmott JS, Scolyer RA, Long GV, Menzies AM, Palendira U. Distinct pretreatment innate immune landscape and posttreatment T cell responses underlie immunotherapy-induced colitis. JCI Insight 2022; 7:157839. [PMID: 36173679 PMCID: PMC9675442 DOI: 10.1172/jci.insight.157839] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 09/21/2022] [Indexed: 12/15/2022] Open
Abstract
Immune-related adverse events represent a major hurdle to the success of immunotherapy. The immunological mechanisms underlying their development and relation to antitumor responses are poorly understood. By examining both systemic and tissue-specific immune changes induced by combination anti-CTLA-4 and anti-PD-1 immunotherapy, we found distinct repertoire changes in patients who developed moderate-severe colitis, irrespective of their antitumor response to therapy. The proportion of circulating monocytes were significantly increased at baseline in patients who subsequently developed colitis compared with patients who did not develop colitis, and biopsies from patients with colitis showed monocytic infiltration of both endoscopically and histopathologically normal and inflamed regions of colon. The magnitude of systemic expansion of T cells following commencement of immunotherapy was also greater in patients who developed colitis. Importantly, we show expansion of specific T cell subsets within inflamed regions of the colon, including tissue-resident memory CD8+ T cells and Th1 CD4+ T cells in patients who developed colitis. Our data also suggest that CD8+ T cell expansion was locally induced, while Th1 cell expansion was systemic. Together, our data show that exaggerated innate and T cell responses to combination immunotherapy synergize to propel colitis in susceptible patients.
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Affiliation(s)
- Kazi J. Nahar
- Melanoma Institute Australia,,Faculty of Medicine and Health,,Charles Perkins Centre, and
| | - Felix Marsh-Wakefield
- Faculty of Medicine and Health,,Charles Perkins Centre, and,Centenary Institute, The University of Sydney, Sydney, New South Wales, Australia
| | - Robert V. Rawson
- Melanoma Institute Australia,,Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, New South Wales, Australia
| | - Tuba N. Gide
- Melanoma Institute Australia,,Faculty of Medicine and Health,,Charles Perkins Centre, and
| | - Angela L. Ferguson
- Faculty of Medicine and Health,,Charles Perkins Centre, and,Centenary Institute, The University of Sydney, Sydney, New South Wales, Australia
| | - Ruth Allen
- Faculty of Medicine and Health,,Charles Perkins Centre, and
| | - Camelia Quek
- Melanoma Institute Australia,,Faculty of Medicine and Health,,Charles Perkins Centre, and
| | - Ines Pires da Silva
- Melanoma Institute Australia,,Faculty of Medicine and Health,,Charles Perkins Centre, and
| | | | | | | | - Matteo S. Carlino
- Melanoma Institute Australia,,Crown Princess Mary Cancer Centre and Westmead Hospitals, New South Wales, Australia
| | - Geoff McCaughan
- Faculty of Medicine and Health,,Centenary Institute, The University of Sydney, Sydney, New South Wales, Australia
| | - James S. Wilmott
- Melanoma Institute Australia,,Faculty of Medicine and Health,,Charles Perkins Centre, and
| | - Richard A. Scolyer
- Melanoma Institute Australia,,Faculty of Medicine and Health,,Charles Perkins Centre, and,Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, New South Wales, Australia
| | - Georgina V. Long
- Melanoma Institute Australia,,Faculty of Medicine and Health,,Royal North Shore Hospital, Sydney, New South Wales Australia.,Mater Hospital, North Sydney, New South Wales, Australia
| | - Alexander M. Menzies
- Melanoma Institute Australia,,Faculty of Medicine and Health,,Royal North Shore Hospital, Sydney, New South Wales Australia.,Mater Hospital, North Sydney, New South Wales, Australia
| | - Umaimainthan Palendira
- Melanoma Institute Australia,,Faculty of Medicine and Health,,Charles Perkins Centre, and
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46
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Fuji T, Arai J, Otoyama Y, Nio Y, Sugiura I, Nakajima Y, Kajiwara A, Ichikawa Y, Uozumi S, Shimozuma Y, Uchikoshi M, Sakaki M, Nozawa H, Momo K, Sasaki T, Yoshida H. A Case of Hepatocellular Carcinoma Successfully Resumed Atezolizumab and Bevacizumab After Associated Grade 3 Diarrhea and Grade 2 Colitis: Case Report and Literature Review. Onco Targets Ther 2022; 15:1281-1288. [PMID: 36303951 PMCID: PMC9594877 DOI: 10.2147/ott.s383769] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 09/10/2022] [Indexed: 11/16/2022] Open
Abstract
Systemic chemotherapy has shown a significant survival benefit in patients with hepatocellular carcinoma (HCC). However, it is associated with various immune-related adverse events (irAEs). We report a case with grade 3 diarrhea and grade 2 colitis following systemic chemotherapy, successfully treated with prednisolone. An 89-year-old man was incidentally detected with a 140-mm hypervascular intrahepatic nodule on contrast-enhanced computed tomography (CECT). Washout of the contrast medium was also detected, and protein induced by vitamin K deficiency or antagonists-II (PIVKA-II) was elevated. Since the Albumin-Bilirubin (ALBI) grade was 2a without any distant metastasis, transarterial chemoembolization (TACE) was performed to treat the HCC, but several intrahepatic nodules were seen in both lobes. Therefore, the patient was treated with lenvatinib for 1 year and 4 months. A complete response according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria was achieved in 2 months; however, multiple hypervascular nodules were detected again. Since the ALBI grade was 1, a second round of chemotherapy with atezolizumab and bevacizumab was initiated. Although a complete response was achieved, the therapy was discontinued due to grade 3 diarrhea and grade 2 colitis after the sixth course. Based on the stool analysis and culture, CECT, and colonoscopy, the diagnosis was atezolizumab-associated colitis. Diarrhea was controlled following the oral administration of 0.5 mg/kg/day of prednisolone, and atezolizumab-bevacizumab therapy was successfully reinitiated without recurrence of colitis. The management of irAEs is important for a significant survival benefit. Systemic chemotherapy with atezolizumab and bevacizumab can be resumed despite a grade 3 irAE due to atezolizumab.
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Affiliation(s)
- Takahiro Fuji
- Department of Medicine, Division of Gastroenterology, Showa University School of Medicine, Tokyo, Japan
| | - Jun Arai
- Department of Medicine, Division of Gastroenterology, Showa University School of Medicine, Tokyo, Japan,Correspondence: Jun Arai, Department of Medicine, Division of Gastroenterology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8666, Japan, Tel +81-3-3784-8535, Fax +81-3-3784-7553, Email
| | - Yumi Otoyama
- Department of Medicine, Division of Gastroenterology, Showa University School of Medicine, Tokyo, Japan
| | - Yuta Nio
- Department of Hospital Pharmaceutics, School of Pharmacy, Showa University Hospital, Tokyo, Japan,Department of Pharmacy, Showa University Hospital, Tokyo, Japan
| | - Ikuya Sugiura
- Department of Medicine, Division of Gastroenterology, Showa University School of Medicine, Tokyo, Japan
| | - Yoko Nakajima
- Department of Medicine, Division of Gastroenterology, Showa University School of Medicine, Tokyo, Japan
| | - Atsushi Kajiwara
- Department of Medicine, Division of Gastroenterology, Showa University School of Medicine, Tokyo, Japan
| | - Yuki Ichikawa
- Department of Medicine, Division of Gastroenterology, Showa University School of Medicine, Tokyo, Japan
| | - Shojiro Uozumi
- Department of Medicine, Division of Gastroenterology, Showa University School of Medicine, Tokyo, Japan
| | - Yuu Shimozuma
- Department of Medicine, Division of Gastroenterology, Showa University School of Medicine, Tokyo, Japan
| | - Manabu Uchikoshi
- Department of Medicine, Division of Gastroenterology, Showa University School of Medicine, Tokyo, Japan
| | - Masashi Sakaki
- Department of Medicine, Division of Gastroenterology, Showa University School of Medicine, Tokyo, Japan
| | - Hisako Nozawa
- Department of Medicine, Division of Gastroenterology, Showa University School of Medicine, Tokyo, Japan
| | - Kenji Momo
- Department of Hospital Pharmaceutics, School of Pharmacy, Showa University Hospital, Tokyo, Japan
| | - Tadanori Sasaki
- Department of Pharmacy, Showa University Hospital, Tokyo, Japan
| | - Hitoshi Yoshida
- Department of Medicine, Division of Gastroenterology, Showa University School of Medicine, Tokyo, Japan
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47
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Weingarden AR, Gubatan J, Singh S, Balabanis TC, Patel A, Sharma A, Habtezion A. Immune checkpoint inhibitor-mediated colitis is associated with cancer overall survival. World J Gastroenterol 2022; 28:5750-5763. [PMID: 36338892 PMCID: PMC9627421 DOI: 10.3748/wjg.v28.i39.5750] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 09/24/2022] [Accepted: 10/10/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Immune checkpoint inhibitor-mediated colitis (IMC) is a common adverse event following immune checkpoint inhibitor (ICI) therapy for cancer. IMC has been associated with improved overall survival (OS) and progression-free survival (PFS), but data are limited to a single site and predominantly for melanoma patients.
AIM To determine the association of IMC with OS and PFS and identify clinical predictors of IMC.
METHODS We performed a retrospective case-control study including 64 ICI users who developed IMC matched according to age, sex, ICI class, and malignancy to a cohort of ICI users without IMC, from May 2011 to May 2020. Using univariate and multivariate logistic regression, we determined association of presence of IMC on OS, PFS, and clinical predictors of IMC. Kaplan-Meier curves were generated to compare OS and PFS between ICI users with and without IMC.
RESULTS IMC was significantly associated with a higher OS (mean 24.3 mo vs 17.7 mo, P = 0.05) but not PFS (mean 13.7 mo vs 11.9 mo, P = 0.524). IMC was significantly associated with OS greater than 12 mo [Odds ratio (OR) 2.81, 95% confidence interval (CI) 1.17-6.77]. Vitamin D supplementation was significantly associated with increased risk of IMC (OR 2.48, 95%CI 1.01-6.07).
CONCLUSION IMC was significantly associated with OS greater than 12 mo. In contrast to prior work, we found that vitamin D use may be a risk factor for IMC.
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Affiliation(s)
- Alexa R Weingarden
- Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94305, United States
| | - John Gubatan
- Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94305, United States
| | - Sundeep Singh
- Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94305, United States
| | - Tatiana Clorice Balabanis
- Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94305, United States
| | - Akshar Patel
- Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94305, United States
| | - Arpita Sharma
- Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94305, United States
| | - Aida Habtezion
- Medicine, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94305, United States
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48
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Shroff GS, Strange CD, Ahuja J, Altan M, Sheshadri A, Unlu E, Truong MT, Vlahos I. Imaging of Immune Checkpoint Inhibitor Immunotherapy for Non-Small Cell Lung Cancer. Radiographics 2022; 42:1956-1974. [PMID: 36240075 DOI: 10.1148/rg.220108] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The normal immune system identifies and eliminates precancerous and cancerous cells. However, tumors can develop immune resistance mechanisms, one of which involves the exploitation of pathways, termed immune checkpoints, that normally suppress T-cell function. The goal of immune checkpoint inhibitor (ICI) immunotherapy is to boost T-cell-mediated immunity to mount a more effective attack on cancer cells. ICIs have changed the treatment landscape of advanced non-small cell lung cancer (NSCLC), and numerous ICIs have now been approved as first-line treatments for NSCLC by the U.S. Food and Drug Administration. ICIs can cause atypical response patterns such as pseudoprogression, whereby the tumor burden initially increases but then decreases. Therefore, response criteria have been developed specifically for patients receiving immunotherapy. Because ICIs activate the immune system, they can lead to inflammatory side effects, termed immune-related adverse events (irAEs). Usually occurring within weeks to months after the start of therapy, irAEs range from asymptomatic abnormal laboratory results to life-threatening conditions such as encephalitis, pneumonitis, myocarditis, hepatitis, and colitis. It is important to be aware of the imaging appearances of the various irAEs to avoid misinterpreting them as metastatic disease, progressive disease, or infection. The basic principles of ICI therapy; indications for ICI therapy in the setting of NSCLC; response assessment and atypical response patterns of ICI therapy, as compared with conventional chemotherapy; and the spectrum of irAEs seen at imaging are reviewed. An invited commentary by Nishino is available online. ©RSNA, 2022.
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Affiliation(s)
- Girish S Shroff
- From the Departments of Thoracic Imaging (G.S.S., C.D.S., J.A., E.U., M.T.T., I.V.), Thoracic/Head and Neck Medical Oncology (M.A.), and Pulmonary Medicine (A.S.), The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1478, Houston, TX 77030
| | - Chad D Strange
- From the Departments of Thoracic Imaging (G.S.S., C.D.S., J.A., E.U., M.T.T., I.V.), Thoracic/Head and Neck Medical Oncology (M.A.), and Pulmonary Medicine (A.S.), The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1478, Houston, TX 77030
| | - Jitesh Ahuja
- From the Departments of Thoracic Imaging (G.S.S., C.D.S., J.A., E.U., M.T.T., I.V.), Thoracic/Head and Neck Medical Oncology (M.A.), and Pulmonary Medicine (A.S.), The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1478, Houston, TX 77030
| | - Mehmet Altan
- From the Departments of Thoracic Imaging (G.S.S., C.D.S., J.A., E.U., M.T.T., I.V.), Thoracic/Head and Neck Medical Oncology (M.A.), and Pulmonary Medicine (A.S.), The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1478, Houston, TX 77030
| | - Ajay Sheshadri
- From the Departments of Thoracic Imaging (G.S.S., C.D.S., J.A., E.U., M.T.T., I.V.), Thoracic/Head and Neck Medical Oncology (M.A.), and Pulmonary Medicine (A.S.), The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1478, Houston, TX 77030
| | - Ebru Unlu
- From the Departments of Thoracic Imaging (G.S.S., C.D.S., J.A., E.U., M.T.T., I.V.), Thoracic/Head and Neck Medical Oncology (M.A.), and Pulmonary Medicine (A.S.), The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1478, Houston, TX 77030
| | - Mylene T Truong
- From the Departments of Thoracic Imaging (G.S.S., C.D.S., J.A., E.U., M.T.T., I.V.), Thoracic/Head and Neck Medical Oncology (M.A.), and Pulmonary Medicine (A.S.), The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1478, Houston, TX 77030
| | - Ioannis Vlahos
- From the Departments of Thoracic Imaging (G.S.S., C.D.S., J.A., E.U., M.T.T., I.V.), Thoracic/Head and Neck Medical Oncology (M.A.), and Pulmonary Medicine (A.S.), The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1478, Houston, TX 77030
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49
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Alorfi NM, Alourfi MM. Biologic Therapy for Refractory Immune Checkpoint Inhibitor Colitis. Biologics 2022; 16:119-127. [PMID: 35957978 PMCID: PMC9362776 DOI: 10.2147/btt.s367675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 07/08/2022] [Indexed: 11/23/2022]
Abstract
Immune checkpoint inhibitors (ICI) are treatments for several cancer types. Pathogenesis of ICI-induced colitis is not yet clearly explained as it can be disguised as another form such as inflammatory bowel disease or IBD. Recent studies revealed that ICI-induced colitis is a unique form of colitis wherein the synergy of regulatory T cells with the gut microbiome is involved. Diagnosis of colitis can be done via endoscopic lesions and histopathological methods. A patient with colitis can be compared with someone who has IBD. Initial treatment is a corticosteroid. Cooperation between gastroenterologists and oncologists is required to understand further the complete diagnosis and management of different behaviors of ICI-induced colitis. Although immunotherapy provides breakthroughs in treating cancer, adverse effects cannot be prevented and have to be carefully addressed. This study aimed to discuss different biologic therapeutic perspectives in treating refractory immune checkpoint inhibitor-induced colitis. This review provided guidelines, challenges, and suggested protocols for drug immunosuppression.
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Affiliation(s)
- Nasser M Alorfi
- Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
- Correspondence: Nasser M Alorfi, Umm Al Qura University, Al Abdeyah, Mecca, 24381, Saudi Arabia, Tel +966500644261, Email
| | - Mansour Marzouq Alourfi
- Internal Medicine Department, King Faisal Medical City for Southern Region, Abha, Saudi Arabia
- Internal Medicine Department, Khamis Mushait General Hospital, Khamis Mushait, Saudi Arabia
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50
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Immunotherapy-induced Colitis: A Comprehensive Review of Epidemiology, Clinical Presentation, Diagnostic Workup, and Management Plan. J Clin Gastroenterol 2022; 56:555-564. [PMID: 35470301 DOI: 10.1097/mcg.0000000000001705] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of a variety of malignancies including advanced melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancers among others. Since their introduction, there has been significant improvement in survival and prognosis in patients with advanced malignancies. Unfortunately, improved outcomes have come at a price of significant immune-related adverse events, with those of the gastrointestinal tract being the most common. Gastrointestinal immune-related adverse events frequently present as diarrhea and colitis, the severity of which can range from mild diarrhea to fulminant colitis with intestinal perforation. Currently, management of ICI-induced colitis is primarily guided by retrospective studies and expert opinion. A significant number of ICI-induced colitis responds to high-dose corticosteroids; however, some patients require further therapy with biologics. There is limited information on the factors which may predispose patients to ICI-induced colitis. Future research elucidating these risk factors along with development of a scoring system could allow for risk-stratification of patients before initiation of ICI therapy. Such a system may help clinicians and patients keep a high index of suspicion regarding ICI-induced colitis and could hopefully reduce the incidence of severe cases. Similarly, future studies should investigate protective factors against ICI-induced colitis, which could potentially allow more patients to safely benefit from ICI therapy.
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