scholarly journals Rheumatic immune-related adverse events from checkpoint inhibitor therapy: a case series

2021 ◽  
Vol 3 (2) ◽  
Author(s):  
Antonella Laria ◽  
Alfredomaria Lurati ◽  
Laura Castelnovo ◽  
Antonio Tamburello ◽  
Paola Maria Faggioli ◽  
...  
Keyword(s):  
Adverse Events ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Case Series ◽  
Hematologic Malignancies ◽  
Checkpoint Inhibitor Therapy ◽  
Cancer Immunotherapies ◽  
Cell Death Protein

Immune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte associated protein-4 (CTLA-4), programmed cell death protein-1 (PD-1), and its ligand PD-L1 are established cancer immunotherapies for solid tumor and hematologic malignancies. These therapies are involved in immune-related adverse events (irAE), both general and rheumatic ones. In general, immune-related adverse events (irAE) management includes drug-holding, tapering doses of corticosteroids, and specific immunosuppression for clinically severe cases, such as infliximab or mycophenolate.

scholarly journals Immune Checkpoint Inhibitor Therapy in Patients With Preexisting Inflammatory Bowel Disease

2020 ◽  
Vol 38 (6) ◽  
pp. 576-583 ◽  
Author(s):  
Hamzah Abu-Sbeih ◽  
David M. Faleck ◽  
Biagio Ricciuti ◽  
Robin B. Mendelsohn ◽  
Abdul R. Naqash ◽  
...  
Keyword(s):  
Adverse Events ◽  
T Lymphocyte ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Inhibitor Therapy ◽  
Checkpoint Inhibitor Therapy ◽  
Inflammatory Bowel

PURPOSE The risk of immune checkpoint inhibitor therapy–related GI adverse events in patients with cancer and inflammatory bowel disease (IBD) has not been well described. We characterized GI adverse events in patients with underlying IBD who received immune checkpoint inhibitors. PATIENTS AND METHODS We performed a multicenter, retrospective study of patients with documented IBD who received immune checkpoint inhibitor therapy between January 2010 and February 2019. Backward selection and multivariate logistic regression were conducted to assess risk of GI adverse events. RESULTS Of the 102 included patients, 17 received therapy targeting cytotoxic T-lymphocyte antigen-4, and 85 received monotherapy targeting programmed cell death 1 or its ligand. Half of the patients had Crohn’s disease, and half had ulcerative colitis. The median time from last active IBD episode to immunotherapy initiation was 5 years (interquartile range, 3-12 years). Forty-three patients were not receiving treatment of IBD. GI adverse events occurred in 42 patients (41%) after a median of 62 days (interquartile range, 33-123 days), a rate higher than that among similar patients without underlying IBD who were treated at centers participating in the study (11%; P < .001). GI events among patients with IBD included grade 3 or 4 diarrhea in 21 patients (21%). Four patients experienced colonic perforation, 2 of whom required surgery. No GI adverse event–related deaths were recorded. Anti–cytotoxic T-lymphocyte antigen-4 therapy was associated with increased risk of GI adverse events on univariable but not multivariable analysis (odds ratio, 3.19; 95% CI, 1.8 to 9.48; P = .037; and odds ratio, 4.72; 95% CI, 0.95 to 23.53; P = .058, respectively). CONCLUSION Preexisting IBD increases the risk of severe GI adverse events in patients treated with immune checkpoint inhibitors.

Hypohidrosis as an immune-related adverse event of checkpoint inhibitor therapy

Immunotherapy ◽  
2020 ◽  
Vol 12 (13) ◽  
pp. 951-956 ◽  
Author(s):  
Anna E Kersh ◽  
Lynn M Schuchter ◽  
Rosalie Elenitsas ◽  
Emily Y Chu
Keyword(s):  
T Lymphocyte ◽  
Adverse Reactions ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitor ◽  
Immune Checkpoint Blockade ◽  
Inhibitor Therapy ◽  
Lesional Skin ◽  
Checkpoint Inhibitor Therapy ◽  
Cutaneous Adverse Reactions ◽  
Cell Death Protein

Background: Immune checkpoint blockade therapies including cytotoxic-T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein-1 (PD-1) inhibitors have become indispensable tools for treating melanoma and other cancers. An increasing number of diverse cutaneous adverse reactions to immunotherapy have been documented in the literature and have been reported to affect up to 40% of patients treated with targeted therapies. Method & results: Herein, we report a case of a patient with metastatic melanoma treated with checkpoint inhibitor therapy who developed vitiligo, gastritis and hepatitis, all identified as adverse immune events and attributable to his immunotherapy regimen. He subsequently developed acquired idiopathic generalized hypohidrosis with biopsy of lesional skin demonstrating a peri-eccrine lymphocytic infiltrate. Conclusion: These findings suggest this acquired generalized hypohidrosis represents a lymphocyte-mediated adverse immune event related to this patient’s checkpoint inhibitor therapy.

scholarly journals Detect it so you can treat it: a case series and proposed checklist to detect neurotoxicity in checkpoint therapy

2020 ◽  
Author(s):  
Saskia Bolz ◽  
Thivyah Ramakrishnan ◽  
Michael Fleischer ◽  
Elisabeth Livingstone ◽  
Benjamin Stolte ◽  
...  
Keyword(s):  
Adverse Events ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Case Series ◽  
Transverse Myelitis ◽  
University Hospital ◽  
Life Threatening ◽  
Checkpoint Inhibitor Therapy ◽  
Cancer Types ◽  
Brachial Plexus Neuritis

Abstract Background: Checkpoint inhibitors show impressive and durable responses in various cancer types and provide new avenues for cancer immunotherapy. However, these drugs have a variety of adverse events. Common autoimmune-related adverse effects include fatigue, hepatitis, skin rash, endocrine deficiencies, and colitis. Neurotoxicity has been reported, but its incidence and course remain unclear.Methods: To illustrate the broad spectrum of neurotoxicity, we exemplarily report the neurological adverse events of five patients with melanoma and one patient with differentiated thyroid cancer who received checkpoint inhibitors at Essen University Hospital (Essen, Germany).Results: After treatment with ipilimumab, nivolumab or pembrolizumab, neurotoxic effects included hypophysitis-associated neck pain and headache, Guillain-Barré syndrome, transverse myelitis, acute brachial plexus neuritis, and ocular myasthenia gravis.Conclusions: Checkpoint inhibitor therapy remains a success story; however, neurological immune-related adverse events may cause severe life-threatening conditions. We propose a checklist for the early detection of neurological adverse events during routine clinical treatment to prevent more severe courses of checkpoint inhibitor-induced neurotoxicity.

scholarly journals Toxicidade Cutânea dos Inibidores de Checkpoint Imunológico: Uma Revisão Narrativa

2020 ◽  
Vol 33 (5) ◽  
pp. 335
Author(s):  
Nuno Gomes ◽  
Vincent Sibaud ◽  
Filomena Azevedo ◽  
Sofia Magina
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Adverse Events ◽  
T Lymphocyte ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Cutaneous Toxicity ◽  
Cell Death Protein

Introduction: Immune checkpoint inhibitors revolutionized anti-neoplastic treatment. Recently, the European Medicines Agency and the United States Food and Drug Administration approved inhibitors of various immune checkpoints, namely the cytotoxic T-lymphocyte-associated protein 4, programmed cell death protein 1 and its ligand. Despite the added benefits in the treatment of several neoplasms, immune checkpoint blockade may also be associated with multiple immune-related adverse events.Material and Methods: A literature review in PubMed database on the cutaneous toxicity of immune checkpoint inhibitors was performed until April 30, 2019.Results and Discussion: A total of 380 articles were initially screened, of which 75 are the basis of this bibliographic review. The immune checkpoint inhibitors monoclonal antibodies produce their beneficial effects by activating the patient’s immune system. This activation also results in adverse events that can affect any organ, whereas cutaneous toxicity is the most frequent and precocious. The adverse events of the programmed cell death protein 1 and its ligand and of the cytotoxic T-lymphocyte-associated protein 4 are similar (class effect), despite the apparent higher skin toxicity of inhibitors of the cytotoxic T-lymphocyte-associated protein 4 (or its use in combination with inhibitors of programmed cell death protein 1 and its ligand). The most common cutaneous toxicities are maculopapular exanthema and pruritus, but other more specific adverse effects (e.g. lichenoid or psoriasiform reaction, vitiligo, sarcoidosis, among others) or located in the oral mucosa and/or adnexa are underreported.Conclusion: Given the high rate of cutaneous toxicity associated with new immune checkpoint inhibitors and their impact on quality of life, their early recognition and appropriate approach are crucial in the treatment of cancer patients. Observation by a dermatologist should be provided in patients with certain toxicities.

scholarly journals Management of immune-related adverse events in patients treated with immune checkpoint inhibitors– Rheumatology point of view

2018 ◽  
Vol 18 (2) ◽  
pp. 56-60
Author(s):  
Cheuk Man Ho ◽  
Chi Chiu Mok
Keyword(s):  
Cell Death ◽  
Adverse Events ◽  
T Lymphocyte ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Standard Treatment ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Point Of View ◽  
Cell Death Protein

Abstract The development of immunotherapy has revolutionized the cancer treatment in the recent years. Immune checkpoint inhibitors (ICPis) such as anti-cytotoxic T-lymphocyte-associated antigen 4 (anti-CTLA-4) and anti-programmed cell death protein (anti-PD1) and its ligand (anti-PDL1) have become part of the standard treatment of various malignancies. Immune-related adverse events (irAEs) were common in patients treated with ICPis. Rheumatologists should be aware of the upcoming challenges in the management of irAEs in a patient receiving treatment with ICPis.

scholarly journals Susceptible loci associated with autoimmune disease as potential biomarkers for checkpoint inhibitor-induced immune-related adverse events

ESMO Open ◽  
2019 ◽  
Vol 4 (4) ◽  
pp. e000472 ◽  
Author(s):  
Esmée P. Hoefsmit ◽  
Elisa A. Rozeman ◽  
John B. A. G. Haanen ◽  
Christian U. Blank
Keyword(s):  
Adverse Events ◽  
Autoimmune Diseases ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Future Research ◽  
Early Stage Disease ◽  
Stage Disease ◽  
Cell Death Protein

Unprecedented successes regarding cancer immunotherapy have been achieved, in which therapeutic agents are used to target immune cells rather than cancer cells. The most effective immunotherapy to date is the group of immune checkpoint inhibitors (CPI), targeting, for example, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) or programmed cell death protein (PD-1). TThe combination of these therapies (anti-PD-1 with anti-CTLA-4) induces high response rates, and seem to be increased further when applied in early-stage disease. However, combined CTLA-4 plus PD-1 blockade causes frequent high-grade immune-related adverse events (irAE). To date, research on biological mechanism of irAEs is scarce and no widely accepted biomarkers predicting onset of severe irAEs have been identified. The similarity of irAEs to autoimmune disorders fuels the hypothesis that irAEs may be linked to susceptible genetic loci related to various autoimmune diseases. In this review, we extensively searched for susceptible loci associated with various autoimmune diseases, and pooled them in groups most likely to be associated with CPI-induced irAEs. These sets could be used in future research on predicting irAEs and guide physicians in a more refined and personal manner.

Liver Toxicity with Cancer Checkpoint Inhibitor Therapy

2018 ◽  
Vol 38 (04) ◽  
pp. 366-378 ◽  
Author(s):  
Brian Nadeau ◽  
Leslie Fecher ◽  
Scott Owens ◽  
Nataliya Razumilava
Keyword(s):  
Liver Toxicity ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Immunosuppressive Agents ◽  
Inhibitor Therapy ◽  
Significant Survival ◽  
The Us ◽  
Checkpoint Inhibitor Therapy ◽  
Clinically Significant

AbstractImmune checkpoint inhibition targeted against cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) has shown clinically significant survival benefit when used to treat multiple types of advanced cancer. These drugs have gained approval by the US Food and Drug Administration and their indications continue to increase. Checkpoint inhibitor therapy is associated with a unique side-effect profile characterized as immune-related adverse events (irAEs), which can result in significant morbidity and rarely mortality. Hepatotoxicity from checkpoint inhibitors is a less common irAE and often mild, while its incidence and severity vary based on the class and dose of checkpoint inhibitor, monotherapy versus combination therapy, and the type of cancer. Histological assessment of suspected irAEs is nonspecific and can show a variety of features. Hepatic irAEs can require discontinuation of checkpoint inhibitor therapy and treatment with immunosuppressive agents.

Biomarkers to predict immune-related adverse events with checkpoint inhibitors.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 131-131 ◽  
Author(s):  
Lia Head ◽  
Nicholas Gorden ◽  
Robert Van Gulick ◽  
Carol M. Amato ◽  
Ashley Frazer-Abel ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Inhibitor Therapy ◽  
Tnf Alpha ◽  
Immune Markers ◽  
Ifn Alpha ◽  
Checkpoint Inhibitor Therapy

131 Background: Immune-related adverse events (IRAE) occur commonly with immune checkpoint inhibitor therapy for the treatment of cancer, although the specific event and severity can vary widely. Little is known regarding factors that may predict which patients will develop an IRAE. The goal of this study is to identify blood biomarkers predictive of IRAE associated with immune checkpoint inhibitor therapy. Methods: Blood samples collected from patients with melanoma prior to receiving therapy with immune checkpoint inhibitors were obtained from the University of Colorado Skin Cancer Biorepository. Testing for a panel of autoantibodies and cytokines (ANA, CCP 3.1, IL-1 beta, IL-2, IL-6, IL-10, IL-12, IP-10, MCP-1, TNF alpha, IFN alpha 2, IFN gamma) in serum samples from patients who had at least one documented IRAE was performed by Exsera BioLabs. Descriptive statistics were used to evaluate biomarker levels in relation to type, grade, and number of adverse events. Results: Pre-treatment samples from 45 patients were evaluated. Median age was 55; 26 were male and 19 were female. The most common IRAEs were colitis (n = 22), thyroid dysfunction (n = 21), and dermatitis (n = 20). Most IRAEs were grade 2 in severity, and the majority of patients (n = 36) experienced more than 1 IRAE. TNF alpha was elevated in 60% of patient samples, while IFN alpha 2 was elevated in 44%. Borderline ANA was detected in 27% of samples and ANA was positive in 11%. No samples had elevation of IL-2. Between 9% and 18% of samples had elevation of the other immune markers tested (IFN gamma, IL-1 beta, IL-6, IL-10, IL-12, and CCP 3.1). Elevation of TNF alpha and IFN alpha 2 were associated with higher grades of IRAEs. No associations between immune markers and the number or type of adverse events in an individual patient were noted. Results from 15 patients who did not have a documented IRAE on immune checkpoint inhibitor therapy are currently pending to confirm these findings are unique to patients developing IRAE. Conclusions: This preliminary data suggests that baseline elevations of TNF alpha and IFN alpha 2 may predict development of IRAEs with immune checkpoint inhibitor therapy. Results from samples from patients who did not develop an IRAE on therapy will be reported at the meeting.

A phase II, open-label study of tomivosertib (eFT508) added on to continued checkpoint inhibitor therapy in patients (pts) with insufficient response to single-agent treatment.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3112-3112
Author(s):  
Anthony B. El-Khoueiry ◽  
Nishan Tchekmedyian ◽  
Rachel E. Sanborn ◽  
Julio Antonio Peguero ◽  
Kerry Pulver ◽  
...  
Keyword(s):  
Adverse Events ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Inhibitor Therapy ◽  
Dependent Manner ◽  
Recist 1.1 ◽  
Insufficient Response ◽  
Checkpoint Inhibitor Therapy ◽  
Nsclc Patients

3112 Background: Despite the broad activity of checkpoint inhibitors across tumor types, primary or secondary resistance after initial response represents a major challenge. Tomivosertib (T), a potent and highly selective inhibitor of the immunosuppressive kinases MNK-1 and 2, blocks expression of checkpoint proteins PD-1, PD-L1, and LAG-3 as well as immunosuppressive cytokines IL-6 and IL-8. In preclinical models, T was shown to trigger an anti-tumor immune response and enhance the activity of checkpoint inhibitors in a T-cell dependent manner. In prior clinical studies, T had an acceptable safety profile as a single agent and in combination with anti-PD-L1 agent avelumab. Methods: Patients experiencing insufficient response (progression or stable disease for 12 weeks or more) to any FDA-approved checkpoint inhibitor in any approved indication were eligible. T at 200 mg oral (PO) BID was added to the existing checkpoint inhibitor until disease progression or unacceptable toxicity was noted. Results: 39 pts (23 male, 16 female) were enrolled across seven cancer types. Median age was 68 (range 42-85). Median prior therapies were 2 (range 1-6). The most common cancers were lung (N = 17), urothelial (N = 6), renal (N = 5) and head and neck (N = 5). 36 pts continued on anti PD-1 antibody (Pembrolizumab and Nivolumab, 18 each) and 3 on anti PD-L-1 antibody (Durvalumab 2, Atezolizumab 1) . The most common grade 3/4 treatment related adverse events occurring in more than 1 pt were alanine aminotransferase increase (2), blood creatine phosphokinase increase (2) and maculo-papular rash (2). 7 patients discontinued treatment (18%) due to adverse events attributable to either drug. Three partial responses (PR) per RECIST 1.1 were observed in pts with previous progression on checkpoint inhibitor therapy, one each in NSCLC (1/17), gastric (1/1) and renal cancer (1/5). 7 NSCLC pts (41%) were progression free for ≥ 24 weeks. All NSCLC patients entered the study with progression by RECIST 1.1 on single agent checkpoint inhibitor prior to adding T. Conclusions: The addition of T to existing checkpoint therapy was well tolerated and manifested clinical activity including objective responses in pts with progression on existing checkpoint inhibitor. A Progression Free Survival rate at 24 weeks of 41% was noted in NSCLC patients. Additional studies evaluating the addition of T to checkpoint inhibitor therapy after progression on anti PD-1 or PD-L-1 therapy are planned. Clinical trial information: NCT03616834 .

scholarly journals The Central Role of Inflammation Associated with Checkpoint Inhibitor Treatments

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Cristina Vajaitu ◽  
Carmen Cristina Draghici ◽  
Iulia Solomon ◽  
Cristina Victoria Lisievici ◽  
Alexandra Victoria Popa ◽  
...  
Keyword(s):  
Response Rate ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Overall Survival Rate ◽  
Small Cell Lung ◽  
Cancer And Inflammation ◽  
Cell Death Protein ◽  
Free Rate

An important function of the immune system is its ability to differentiate between healthy cells in the organism and “foreign” cells, allowing the latest to be attacked and the first ones to be conserved. The most important molecules in this process are considered to be checkpoint inhibitors. This review is focused on the association between cancer and inflammation, underlying the mechanisms of action of monoclonal antibodies that are targeting checkpoint inhibitors: ipilimumab against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and pembrolizumab and nivolumab against programmed cell death protein 1 (PD-1), their indications for treatment, and side effects. Presence of antibodies against checkpoint inhibitors shows promising results in the clinical trials in patients with types of cancer difficult to treat until now such as melanoma, non-small-cell lung cancer (NSCLC), and renal cell carcinoma, offering an increase in the overall survival rate, response rate, and progression-free rate. Resistance is now observed to emerge in patients treated with this therapy, showing the need for more studies in order to design a biomarker that will predict the type of response to immunotherapy.

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