Practical Management of Immune-Related Adverse Events from Immune Checkpoint Protein Antibodies for the Oncologist

2012 ◽  
pp. 174-177 ◽  
Author(s):  
Jeffrey S. Weber
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Early Recognition ◽  
Cell Cancer ◽  
Immune Checkpoint Blockade ◽  
Physician Education ◽  
Programmed Death 1 ◽  
Grade 3 ◽  
Immune Checkpoint Proteins

Overview: Monoclonal antibodies directed against immune checkpoint proteins, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) or programmed death-1 (PD-1), can boost endogenous immune responses directed against tumor cells. Recently, ipilimumab was approved by the U.S. Food and Drug Administration (FDA) for the treatment of metastatic melanoma, and the anti-PD-1 antibody BMS-936558 has shown promising results in patients with melanoma, non-small cell lung cancer, and renal cell cancer. During treatment with these antibodies, a unique set of toxicities occur called immune-related adverse events (irAEs). These irAEs may occur at any time during treatment and include colitis characterized by a mild to moderate but occasionally severe and persistent diarrhea. Hypophysitis, hepatitis, pancreatitis, iridocyclitis, lymphadenopathy, neuropathies, and nephritis have also been reported with ipilimumab, and a subset of those side effects has also been observed with BMS-936558. Patient and physician education as well as good patient–caretaker communication are keys to limiting the morbidity of irAEs. Early recognition of these irAEs and initiation of treatment are critical to reduce the risk of complications, since virtually all irAEs are reversible with the use of steroids and other immune suppressants. The onset of grade 3 to 4 irAEs correlated with treatment response in some ipilimumab studies. This article provides detailed description and recommendations for practicing oncologists to manage the common irAEs associated with antibodies against immune checkpoint blockade.

Immune-related adverse events associated with immune checkpoint inhibitors in patients with cancer

2020 ◽  
pp. 030089162095346
Author(s):  
Nilay Sengul Samanci ◽  
Duygu Ilke Cikman ◽  
Kerem Oruc ◽  
Sahin Bedir ◽  
Emir Çelik ◽  
...  
Keyword(s):  
Adverse Events ◽  
Health Care Providers ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Early Recognition ◽  
Care Providers ◽  
Patients With Cancer ◽  
Combination Treatments ◽  
Grade 3

Introduction: With the widespread use of immune checkpoint inhibitors (ICIs), we are facing challenges in the management of immune-related adverse events (irAEs). We aimed to characterize the spectrum of toxicity, management, and outcomes for irAEs. Methods: Patients who were treated with at least one ICI in clinical trials, expanded access programs, or routine clinical practice were included. Clinical and laboratory parameters were collected retrospectively to determine the incidence of irAEs, methods of management, and treatment outcomes. Results: A total of 255 patients were screened retrospectively. Of these, 71 (27.8%) patients developed irAEs. More than 2 different types of irAEs were detected in 16 (6.2%) out of 255 patients. A total of 3177 doses were given to 255 patients. In 93 (2.9%) of the 3177 doses, 1 episode of irAEs was experienced. A total of 22 out of 93 (23.7%) episodes were reported as grade 1, 49 (52.7%) as grade 2, 19 (20.4%) as grade 3, and 3 (3.2%) as grade 4. The most frequently seen irAEs were pneumonitis, hepatitis, and hypothyroidism. With regard to treatment, 39 out of 93 episodes (42%) of any grade irAEs occurred after anti–programmed cell death-1 therapy, 47 (50.5%) occurred following administration of anti–programmed death-ligand 1, and 7 (7.5%) occurred after combination treatments. Conclusion: With the increased use of immunotherapeutic agents, increased awareness and early recognition are required for effective management of irAEs. Our experience as a single institution might be of use for health care providers in oncology.

scholarly journals Acute kidney injury from immune checkpoint inhibitor use

2019 ◽  
Vol 12 (10) ◽  
pp. e231211 ◽  
Author(s):  
Lexis Gordon ◽  
Pouneh Dokouhaki ◽  
Kimberly Hagel ◽  
Bhanu Prasad
Keyword(s):  
Acute Kidney Injury ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Kidney Injury ◽  
Acute Interstitial Nephritis ◽  
Programmed Death ◽  
Programmed Death 1

Immune checkpoint inhibitors are novel oncological medications, current classes of which include monoclonal antibodies that target inhibitory receptors cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed death 1 protein (PD-1) and programmed death-ligand 1. While they are novel in their ability to treat cancer, they also have a unique spectrum of immune-related adverse events. Renal-related immune adverse events, though rare, are an increasingly recognised clinical entity. We present the case of a 67-year-old man with acute kidney injury (AKI) after the second cycle of combination anti-CTLA-4 and anti-PD-1 antibodies for metastatic cutaneous melanoma. He presented with vomiting and diarrhoea, and AKI secondary to dehydration was treated with aggressive rehydration. After failing to recover biochemically, a renal biopsy was performed, which demonstrated severe acute interstitial nephritis. The culprit medications were held and he was treated with steroids. With immunosuppression, creatinine improved to pretreatment values.

scholarly journals Molecular Interactions of Antibody Drugs Targeting PD-1, PD-L1, and CTLA-4 in Immuno-Oncology

Molecules ◽  
2019 ◽  
Vol 24 (6) ◽  
pp. 1190 ◽  
Author(s):  
Hyun Lee ◽  
Sang Lee ◽  
Yong-Seok Heo
Keyword(s):  
Molecular Interactions ◽  
Immune Checkpoint ◽  
Rational Design ◽  
Cytotoxic T Lymphocyte ◽  
Immune Surveillance ◽  
Structural Studies ◽  
Checkpoint Proteins ◽  
Wide Range ◽  
Programmed Death 1 ◽  
Immune Checkpoint Proteins

Cancer cells can evade immune surveillance through the molecular interactions of immune checkpoint proteins, including programmed death 1 (PD-1), PD-L1, and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). Since 2011, the FDA-approved antibody drugs ipilimumab (Yervoy®), nivolumab (Opdivo®), pembrolizumab (Keytruda®), cemiplimab (Libtayo®), atezolizumab (Tecentriq®), durvalumab (Imfinzi®), and avelumab (Bavencio®), which block the immune checkpoint proteins, have brought about a significant breakthrough in the treatment of a wide range of cancers, as they can induce durable therapeutic responses. In recent years, crystal structures of the antibodies against PD-1, PD-L1, and CTLA-4 have been reported. In this review, we describe the latest structural studies of these monoclonal antibodies and their interactions with the immune checkpoint proteins. A comprehensive analysis of the interactions of these immune checkpoint blockers can provide a better understanding of their therapeutic mechanisms of action. The accumulation of these structural studies would provide a basis that is essential for the rational design of next-generation therapies in immuno-oncology.

scholarly journals Endocrine-related adverse events following ipilimumab in patients with advanced melanoma: a comprehensive retrospective review from a single institution

2014 ◽  
Vol 21 (2) ◽  
pp. 371-381 ◽  
Author(s):  
Mabel Ryder ◽  
Margaret Callahan ◽  
Michael A Postow ◽  
Jedd Wolchok ◽  
James A Fagin
Keyword(s):  
Clinical Trials ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Hormone Replacement ◽  
Symptomatic Relief ◽  
Hormone Secretion ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Increased Risk

Novel immune checkpoint blockade with ipilimumab, an antibody blocking the cytotoxic T-lymphocyte antigen 4 (CTLA4), is revolutionizing cancer therapy. However, ipilimumab induces symptomatic, sometimes severe, endocrine immune-related adverse events (irAEs) that are inconsistently recognized and reported. The objective of this review was to comprehensively characterize the incidence, presentation, and management of endocrinopathies following ipilimumab therapy in a single center that is highly specialized in immune checkpoint blockade. We carried out a retrospective analysis of endocrine irAEs in melanoma patients receiving ipilimumab therapy in clinical trials between 2007 and 2013. A total of 256 patients were included in this analysis. We reviewed pituitary-, thyroid-, and adrenal-related hormone test results, as well as radiographic studies and the clinical histories of patients, to identify and characterize cases of hypophysitis, hypothyroidism, thyroiditis, and adrenal dysfunction. Following ipilimumab therapy, the overall incidence of hypophysitis was 8% and that of hypothyroidism/thyroiditis 6%. Primary adrenal dysfunction was rare. Therapy with a combination of ipilimumab and nivolumab, an anti-programmed cell death 1 (PDCD1, also called PD1) receptor antibody, was associated with a 22% incidence of either thyroiditis or hypothyroidism and a 9% incidence of hypophysitis. Symptomatic relief, in particular, for hypophysitis, was achieved in all patients with hormone replacement, although endogenous hormone secretion rarely recovered. In summary, we observed that CTLA4 blockade alone, and in particular in combination with PD1 blockade, is associated with an increased risk of symptomatic, sometimes severe, hypophysitis as well as thyroid dysfunction. Prompt initiation with hormone replacement reverses symptoms. Evaluation and reporting of endocrine irAEs in clinical trials should be done using standardized diagnostic criteria and terminology.

scholarly journals Matrix-binding checkpoint immunotherapies enhance antitumor efficacy and reduce adverse events

2017 ◽  
Vol 9 (415) ◽  
pp. eaan0401 ◽  
Author(s):  
Jun Ishihara ◽  
Kazuto Fukunaga ◽  
Ako Ishihara ◽  
Hans M. Larsson ◽  
Lambert Potin ◽  
...  
Keyword(s):  
Adverse Events ◽  
Tumor Growth ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Autoimmune Diabetes ◽  
Systemic Exposure ◽  
Immune Checkpoint Blockade ◽  
Genetically Engineered ◽  
Checkpoint Blockade ◽  
Affinity Peptide

Immune checkpoint blockade exhibits considerable antitumor activity, but previous studies have reported instances of severe treatment-related adverse events. We sought to explore local immune checkpoint blockade, with an antibody (Ab) form that would be retained intra- or peritumorally, limiting systemic exposure. To accomplish this, we conjugated the checkpoint blockade Abs to an extracellular matrix (ECM)–super-affinity peptide derived from placenta growth factor–2 (PlGF-2123–144). We show enhanced tissue retention and lower Ab concentrations in blood plasma after PlGF-2123–144 conjugation, reducing systemic side effects such as the risk of autoimmune diabetes. Peritumoral injections of PlGF-2123–144–anti-CTLA4 (cytotoxic T lymphocyte antigen 4) and PlGF-2123–144–anti–PD-L1 (programmed death ligand 1) Abs delayed tumor growth and prolonged survival compared to the unmodified Abs in genetically engineered murine tumor models of melanoma and breast cancer. The PlGF-2123–144–Abs increased tumor-infiltrating activated CD8+ and CD4+ T cells, resulting in a delay of distant tumor growth as well. This simple and translatable approach of engineered ECM-binding Abs may present a viable and safer approach in checkpoint blockade.

scholarly journals Immune checkpoint blockade in hematologic malignancies

Blood ◽  
2015 ◽  
Vol 125 (22) ◽  
pp. 3393-3400 ◽  
Author(s):  
Philippe Armand
Keyword(s):  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Hematologic Malignancies ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Natural Target ◽  
Tumor Types

Abstract Therapeutic blockade of immune checkpoint pathways, in particular cytotoxic T-lymphocyte associated protein 4 and programmed-death 1 (PD-1), has become a paradigm-shifting treatment in solid tumor oncology. Hematologic malignancies (HMs), many of which are known to have clinically exploitable immune sensitivity, are a natural target for this type of treatment. Several clinical trials of checkpoint blockade have been conducted in HM, with preliminary results suggesting the therapeutic usefulness of this approach across several tumor types. In particular, the results of PD-1 blockade in Hodgkin lymphoma (HL) are remarkable, and raise hope that it may alter the treatment landscape in this disease. However, numerous questions remain about the optimal role of checkpoint blockade both in HL and beyond. Those questions are the focus of this review, in the hope that, if we are at the dawn of a new day in HM immunotherapy, we may begin to envision its morning.

scholarly journals Immune Checkpoint Blockade in Gynecologic Cancers: State of Affairs

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3301
Author(s):  
Maureen L. Drakes ◽  
Cheryl M. Czerlanis ◽  
Patrick J. Stiff
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Gynecologic Cancer ◽  
Immune Checkpoint Blockade ◽  
Gynecologic Cancers ◽  
Programmed Death 1 ◽  
Cancer Types ◽  
State Of Affairs

This review provides an update on the current use of immune checkpoint inhibitors (ICI) in female gynecologic cancers, and it addresses the potential of these agents to provide therapy options for disease management and long-term remission in advanced disease patients, where surgery, chemotherapy, and/or radiation fail to meet this goal. The topic of immune checkpoint inhibitors (ICI) blocking cytotoxic T lymphocyte associated protein-4 (CTLA-4) and the programmed death-1 (PD-1) axis has come to the forefront of translational medicine over the last decade for several malignancies. The text will focus primarily on a discussion of ovarian cancer, which is the most frequent cause of death of gynecologic cancers; endometrial cancer, which is the most often diagnosed gynecologic cancer; and cervical cancer, which is the third most common female gynecologic malignancy, all of which unfavorably alter the lives of many women. We will address the critical factors that regulate the outcome of these cancer types to ICI therapy, the ongoing clinical trials in this area, as well as the adverse immune responses that impact the outcome of patients given ICI regimens.

Cutaneous adverse events associated with immune checkpoint blockade: A meta-analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14500-e14500
Author(s):  
Yiqun Han ◽  
Jiayu Wang ◽  
Binghe Xu
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Early Recognition ◽  
Meta Analysis ◽  
Combined Treatment ◽  
Immune Checkpoint Blockade ◽  
Cochrane Library ◽  
Predictive Values ◽  
Dermatological Toxicity

e14500 Background: Dermatological toxicity is the most common immune-related adverse events (irAEs) following immune checkpoint inhibitors (ICIs). A better understanding of this side effect enables early recognition, diagnosis, and management in clinical practice. Methods: We did a meta-analysis of literature published on ClinialTrials.gov, Pubmed, Embase, and Cochrane Library up to April 30, 2020. Randomized controlled trials (RCTs) which reported the cases of cutaneous irAEs following ICIs (anti-PD-1, anti-PD-L1, anti-CTLA-4) were included. We comprehensively assessed the differences in cutaneous irAEs among ICIs, the effect from dosage and combined treatment on the incidence, the correlations of cutaneous irAE with other organ-specific irAEs, and the predictive values for prognosis. This study was prospectively registered in the PROSPERO platform (ID: CRD42020182247). Results: A total of 687 publications were initially identified and 46 eligible RCTs involving 28569 patients were included. Compared with that in patients receiving anti-CLTA-4 antibody, the overall risk of dermatological irAEs tended to be lower in patients receiving anti-PD-1 antibody (RRrash, 0.60; 95%CrI, 0.36-0.99; RRpruritus, 0.51; 95%CrI, 0.22-1.10) and was lower in those receiving anti-PD-L1 antibody (RRrash, 0.63; 95%CrI, 0.43-0.90; RRpruritus, 0.37; 95%CrI, 0.20-0.67). In general, neither treatment in combination nor dosage were estimated to add additional risk to the incidence of cutaneous irAEs. Dermatological toxicity was positively associated with immune-related hepatitis (P = 0.006), neuropathy (P = 0.040) and gastrointestinal dysfunctions (P = 0.038). The cutaneous irAEs was not confirmed as a surrogate predictor for survival with ICIs monotherapy. Conclusions: This study indicates that cutaneous irAEs are dose-independent and agent-specific immune reactions with the highest risk observed in CTLA-4 blockade, and the occurrence is associated with hepatic, neurological, and gastrointestinal disorders. The exploration in the predictive value of cutaneous irAEs for response and survival outcomes will be warranted in the future.

Gastrointestinal and Hepatic Toxicities of Checkpoint Inhibitors: Algorithms for Management

2018 ◽  
pp. 13-19 ◽  
Author(s):  
Shilpa Grover ◽  
Osama E. Rahma ◽  
Nikroo Hashemi ◽  
Ramona M. Lim
Keyword(s):  
Adverse Effects ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Early Recognition ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Immune Checkpoints ◽  
Effective Management ◽  
Rule Out

Gastrointestinal toxicities are among the leading causes of immune-related adverse effects of checkpoint blockade. These adverse events can be severe enough to require interruption or withdrawal of immune checkpoint blockade therapy. Patients with immune-related adverse effects require early recognition with an evaluation to rule out alternative etiologies and effective management to minimize complications. This article reviews the gastrointestinal and hepatic toxicities of the antibodies that target immune checkpoints CTLA-4 and PD-1/PD-L1 and provides an approach to their diagnosis and management.

scholarly journals Cutaneous Adverse Events of Immune Checkpoint Inhibitors: A Literature Review

2021 ◽  
pp. e2021155
Author(s):  
Zoe Apalla ◽  
Chryssoula Papageorgiou ◽  
Aimilios Lallas ◽  
Florentina Delli ◽  
Christina Fotiadou ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Early Recognition ◽  
Skin Toxicity ◽  
Immune Checkpoint Blockade ◽  
Self Tolerance ◽  
Oncologic Patients ◽  
Dose Modifications

Immune checkpoint inhibitors (CPIs) are targeted molecules that modulate the immune system, assist with self-tolerance, and minimize collateral tissue damage when immune responses are activated. Although they are characterized by a favorable risk/benefit ratio, immune checkpoint blockade has been associated with a new subset of autoimmune-like toxicities, named immune-related adverse events (irAE). Dermatologic reactions are among the most prevalent irAE triggered by CPIs. In a majority of cases they are self-limiting and readily manageable. However, it is not uncommon that they result in severe skin involvement and impairment of patients’ quality of life. Awareness of the spectrum of cutaneous irAEs is mandatory for every clinician involved in the management of oncologic patients. The role of the dermatologists is essential because early recognition and appropriate management of skin toxicity may prevent dose modifications and discontinuation of CPIs. The latter is particularly relevant, considering that recent data suggest favorable oncologic response in patients developing irAEs.  

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