Immune-Related Adverse Effects of Checkpoint Inhibitors in Cancer Patients

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 20 April 2024 | Viewed by 7867

Special Issue Editor

Integrated Cancer Center Ghent, AZ Maria Middelares, Buitenring Sint Denijs 30, 9000 Ghent, Belgium
Interests: checkpoint inhibitors; immune-related adverse events

Special Issue Information

Dear Colleagues,

The development of immune checkpoint inhibitors (ICIs) has significantly altered the field of oncology by achieving durable anti-tumor responses in a number of advanced malignancies with previously poor prognoses. Currently, up to 50% of all cancer patients can potentially benefit from a treatment with ICIs. ICIs are monoclonal antibodies that block inhibitory ligand–receptor interactions, essential for both immunological homeostasis and self-tolerance, in order to enhance the activity of a patient’s immune system to fight cancer. In 2011, ipilimumab (Yervoy®), an inhibitor of the T-lymphocyte-associated antigen-4 (CTLA-4), was the first ICI to gain approval from the United States Food and Drug Administration (FDA). In the following years, other ICIs have also become clinically available, namely inhibitors of programmed cell death protein-1 (PD-1; nivolumab, pembrolizumab, cemiplimab, dostarlimab) and its ligand, programmed cell death ligand-1 (PD-L1; atezolizumab, avelumab, durvalumab). In 2022, a second CTLA-4 also gained the FDAs approval, in combination with durvalumab, i.e., tremelimumab. As opposed to the conventional anti-cancer therapies, characterized by acute onset emetic and myelosuppressive effects, ICIs exhibit a favorable side effect profile. Nevertheless, their increased use over the last few years has led to the discovery of a distinct set of adverse effects, i.e., immune-related adverse events (irAEs). irAEs have gained significant interest over the past decade. Although initially research focused on fatal and severe adverse events, the increasing use of ICIs in the treatment of both the advanced and early stages of various malignancies has resulted in a substantial increase in the incidence of both acute and chronic irAEs. Approximately 50% of the patients who receive ICI treatment will experience some kind of irAE. This Special Issue will focus on a wide range of irAEs affecting different organs during ICI treatment.

Prof. Dr. Christof Vulsteke
Guest Editor

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Keywords

  • checkpoint inhibitors
  • cancer
  • cardiovascular
  • immune-related adverse events
  • cardiotoxicity

Published Papers (6 papers)

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Research

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11 pages, 863 KiB  
Article
Cutaneous Adverse Events of Systemic Melanoma Treatments: A Retrospective Single-Center Analysis
by Lukas Kraehenbuehl, Stephanie Schneider, Laura Pawlik, Joanna Mangana, Phil Cheng, Reinhard Dummer and Barbara Meier-Schiesser
Pharmaceuticals 2023, 16(7), 935; https://doi.org/10.3390/ph16070935 - 27 Jun 2023
Viewed by 929
Abstract
Recent progress in the treatment of advanced melanoma has led to the improved survival of affected patients. However, novel treatments also lead to considerable and distinct skin toxicity. To further characterize cutaneous adverse events (AE) of systemic treatments, we conducted a single-center retrospective [...] Read more.
Recent progress in the treatment of advanced melanoma has led to the improved survival of affected patients. However, novel treatments also lead to considerable and distinct skin toxicity. To further characterize cutaneous adverse events (AE) of systemic treatments, we conducted a single-center retrospective study of biopsy-proven cutaneous adverse events of melanoma treatment over a period of 10 years at the University Hospital of Zurich, Switzerland. In 102 identified patients, 135 individual skin AEs developed. Immune checkpoint blockade (ICB) was causal for 81 skin AEs, and 54 were related to targeted therapies (TT). Recorded types of skin AEs included lichenoid, maculopapular, acneiform, urticarial, panniculitis, folliculitis, psoriasiform, granulomatous, eczematous, and others. The incidence of skin AEs was higher with TT (18.54%) than with ICB (9.64%, p = 0.0029). Most AEs were low-grade, although 19.21% of AEs were common terminology criteria for adverse events (CTCAE) Grades 3 or 4. A large spectrum of skin AEs was documented during treatment of advanced melanoma, and distinct phenotypes were observed, depending on treatment classes. AEs occurred earlier during treatment with TT than with ICB, and distinct types of skin AEs were associated with respective treatment classes. This study comprehensively describes skin AEs occurring during systemic treatment for melanoma at a single center. Full article
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Review

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21 pages, 307 KiB  
Review
Immune Checkpoint Inhibitors and Lupus Erythematosus
by Hans Vitzthum von Eckstaedt, Arohi Singh, Pankti Reid and Kimberly Trotter
Pharmaceuticals 2024, 17(2), 252; https://doi.org/10.3390/ph17020252 - 15 Feb 2024
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Abstract
Immune checkpoint inhibitors (ICIs) are the standard of care for a growing number of malignancies. Unfortunately, they are associated with a broad range of unique toxicities that mimic the presentations of primary autoimmune conditions. These adverse events are termed immune-related adverse events (irAEs), [...] Read more.
Immune checkpoint inhibitors (ICIs) are the standard of care for a growing number of malignancies. Unfortunately, they are associated with a broad range of unique toxicities that mimic the presentations of primary autoimmune conditions. These adverse events are termed immune-related adverse events (irAEs), of which ICI-lupus erythematosus (ICI-LE) constitutes a small percentage. Our review aims to describe the available literature on ICI-LE and ICI treatment for patients with pre-existing lupus. Most diagnoses of ICI-LE had findings of only cutaneous lupus; four diagnoses of ICI-LE had systemic lupus manifestations. Over 90% (27 of 29) of cases received anti-PD-1/PDL-1 monotherapy, 1 received combination therapy, and 1 received only anti-CTLA-4 treatment. About three-fourths (22 of 29 or 76%) of patients with ICI-lupus were managed with topical steroids, 13 (45%) received hydroxychloroquine, and 10 (34%) required oral corticosteroids. In our case series, none of the patients with pre-existing lupus receiving ICI therapy for cancer had a flare of their lupus, but few had de novo irAE manifestations, all of which were characterized as low-grade. The review of the literature yielded seven ICI-LE flares from a total of 27 patients with pre-existing lupus who received ICI. Most flares were manageable without need for ICI cessation. Full article
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21 pages, 422 KiB  
Review
Safety of Immunomodulatory Systemic Therapies Used in the Management of Immune-Related Cutaneous Adverse Events
by Stephanie L. Gu, Sandy Nath and Alina Markova
Pharmaceuticals 2023, 16(11), 1610; https://doi.org/10.3390/ph16111610 - 15 Nov 2023
Viewed by 1044
Abstract
Immune-related cutaneous adverse events (ircAEs) commonly occur in patients on treatment with immune checkpoint inhibitors and can significantly reduce patient quality of life. These are often treated with immunomodulatory agents, including glucocorticoids, immunosuppressants, and biologics. While often effective at managing symptoms, these therapies [...] Read more.
Immune-related cutaneous adverse events (ircAEs) commonly occur in patients on treatment with immune checkpoint inhibitors and can significantly reduce patient quality of life. These are often treated with immunomodulatory agents, including glucocorticoids, immunosuppressants, and biologics. While often effective at managing symptoms, these therapies can cause several adverse events which may limit their use. In addition, immunomodulatory agents should be used with particular caution in patients receiving immunotherapy, as the efficacy of the oncologic regimen may potentially be undermined. In this review, we summarize the safety of systemic therapies that are used in the management of ircAEs, with a particular focus on the resultant risk of secondary tumor progression in patients with active cancer. Full article

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10 pages, 1122 KiB  
Brief Report
IL12/23 Blockade with Ustekinumab as a Treatment for Immune-Related Cutaneous Adverse Events
by Stephanie L. Gu, Tara Maier, Andrea P. Moy, Stephen Dusza, David M. Faleck, Neil J. Shah and Mario E. Lacouture
Pharmaceuticals 2023, 16(11), 1548; https://doi.org/10.3390/ph16111548 - 02 Nov 2023
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Abstract
Background: Immune-related cutaneous adverse events (ircAEs) are frequent and may reduce quality of life and consistent dosing. IL12/23 has been implicated in psoriasis, which is reminiscent of the psoriasiform/lichenoid ircAE phenotype. We report the use of ustekinumab as a therapeutic option. Methods [...] Read more.
Background: Immune-related cutaneous adverse events (ircAEs) are frequent and may reduce quality of life and consistent dosing. IL12/23 has been implicated in psoriasis, which is reminiscent of the psoriasiform/lichenoid ircAE phenotype. We report the use of ustekinumab as a therapeutic option. Methods: Patients at Memorial Sloan Kettering Cancer Center, New York, who received immune checkpoint inhibitors and were treated with ustekinumab or had the keywords “ustekinumab” or “Stelara” in their clinical notes between 1 March 2017 and 1 December 2022 were retrospectively identified via a database query. Documentation from initial and follow-up visits was manually reviewed, and response to ustekinumab was categorized into complete cutaneous response (CcR, decrease to CTCAE grade 0), partial cutaneous response (PcR, any decrease in CTCAE grade exclusive of decrease to grade 0), and no cutaneous response (NcR, no change in CTCAE grade or worsening). Labs including complete blood count (CBC), cytokine panels, and IgE were obtained in a subset of patients as standard of care. Skin biopsies were reviewed by a dermatopathologist. Results: Fourteen patients with psoriasiform (85.7%), maculopapular (7.1%), and pyoderma gangrenosum (7.1%) ircAEs were identified. Ten (71.4%) receiving ustekinumab had a positive response to treatment. Among these 10 responders, 4 (40%) demonstrated partial cutaneous response and 6 (60%) demonstrated complete cutaneous resolution. Six patients (42.9%) experienced interruptions to their checkpoint inhibitor treatment as a result of intolerable ircAEs, and following ircAE management with ustekinumab, two (33.3%) were successfully rechallenged with their checkpoint inhibitors. On histopathology, patients primarily had findings of interface or psoriasiform dermatitis. No patients reported an adverse event related to ustekinumab. Conclusions: Ustekinumab showed a benefit in a subset of patients with psoriasiform/lichenoid ircAEs. No safety signals were identified. However, further prospective randomized controlled trials are needed to confirm our findings. Full article
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12 pages, 991 KiB  
Opinion
Usefulness of Longitudinal Strain to Assess Cancer Therapy-Related Cardiac Dysfunction and Immune Checkpoint Inhibitor-Induced Myocarditis
by Yudai Tamura and Yuichi Tamura
Pharmaceuticals 2023, 16(9), 1297; https://doi.org/10.3390/ph16091297 - 14 Sep 2023
Cited by 2 | Viewed by 1269
Abstract
Longitudinal strain (LS) measured by echocardiography has been reported to be useful not only for the diagnosis and risk stratification of various cardiac diseases, but also in cardio-oncology. Most previous studies have been conducted on patients undergoing treatment with anthracyclines and human epidermal [...] Read more.
Longitudinal strain (LS) measured by echocardiography has been reported to be useful not only for the diagnosis and risk stratification of various cardiac diseases, but also in cardio-oncology. Most previous studies have been conducted on patients undergoing treatment with anthracyclines and human epidermal growth factor receptor 2-targeted therapies. Existing guidelines recommend that global LS (GLS) should be measured before and after the administration of cancer drugs. This recommendation is based on many reports showing that a decline in GLS is indicative of early or mild cancer therapy-related cardiac dysfunction. The main purpose of this article is to provide insight into the importance of LS in patients undergoing cancer treatment and highlight the role of LS evaluation in patients undergoing immune checkpoint inhibitor (ICI) treatment, which is being used with increasing frequency. Among cancer drug therapies, immune checkpoint inhibitors (ICIs) have an important place in cancer treatment and are used for the treatment of many types of cancer. Although the efficacy of ICIs in cancer treatment has been reported, immune-related adverse events (irAEs) have also been reported. Among these irAEs, cardiovascular complications, although rare, are recognized as important adverse events that may result in ICI treatment discontinuation. Myocarditis is one severe adverse event associated with ICIs, and it is important to standardize diagnostic and therapeutic approaches to it. Several studies have reported a relationship between LS and cardiac complications associated with ICIs which may contribute to the early diagnosis of ICI-induced cardiac complications. Full article
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14 pages, 585 KiB  
Protocol
Extensive CArdioVAscular Characterization and Follow-Up of Patients Receiving Immune Checkpoint Inhibitors: A Prospective Multicenter Study
by Danielle Delombaerde, Johan De Sutter, Lieselot Croes, Delphine Vervloet, Veronique Moerman, Nico Van de Veire, Anne-Marie Willems, Kristien Wouters, Marc Peeters, Hans Prenen and Christof Vulsteke
Pharmaceuticals 2023, 16(4), 625; https://doi.org/10.3390/ph16040625 - 20 Apr 2023
Cited by 1 | Viewed by 1726
Abstract
Background: The increasing use of immune checkpoint inhibitors (ICIs) in the treatment of both advanced and early stages of various malignancies has resulted in a substantial increase in the incidence of cardiovascular (CV) immune-related adverse events (irAEs). The current follow-up guidelines are based [...] Read more.
Background: The increasing use of immune checkpoint inhibitors (ICIs) in the treatment of both advanced and early stages of various malignancies has resulted in a substantial increase in the incidence of cardiovascular (CV) immune-related adverse events (irAEs). The current follow-up guidelines are based on anecdotal evidence and expert opinions, due to a lack of solid data and prospective studies. As many questions remain unanswered, cardiac monitoring, in patients receiving ICIs, is not always implemented by oncologists. Hence, an urgent need to investigate the possible short- and long-term CV effects of ICIs, as ICI approval is continuing to expand to the (neo)adjuvant setting. Methods: We have initiated a prospective, multicenter study, i.e., the CAVACI trial, in which a minimum of 276 patients with a solid tumor, eligible for ICI treatment, will be enrolled. The study consists of routine investigations of blood parameters (troponin and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, in particular) and a thorough CV follow-up (electrocardiograms, transthoracic echocardiograms, and coronary calcium scoring) at fixed time points for a total period of two years. The primary endpoint is the cumulative incidence of troponin elevation in the first three months of ICI treatment, compared to baseline levels. Furthermore, secondary endpoints include incidence above the upper limit of normal of both troponin and NT-proBNP levels, evolution in troponin and NT-proBNP levels, the incidence of CV abnormalities/major adverse cardiac events, evaluation of associations between patient characteristics/biochemical parameters and CV events, transthoracic echocardiography parameters, electrocardiography parameters, and progression of coronary atherosclerosis. Recruitment of patients started in January 2022. Enrolment is ongoing in AZ Maria Middelares, Antwerp University Hospital, AZ Sint-Vincentius Deinze, and AZ Sint-Elisabeth Zottegem. Trial registration: ClinicalTrials.gov Identifier: NCT05699915, registered 26 January 2023. Full article
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