Subacute CNS Demyelination after Treatment with Immune Checkpoint Inhibitors

2021 ◽  
pp. 10.1212/CPJ.0000000000001069
Author(s):  
Elizabeth Tan ◽  
Heather Shaw ◽  
Paul Nathan ◽  
Subhadip Ghosh-Ray ◽  
Diego Ottaviani
Keyword(s):  
Immune Responses ◽  
T Lymphocyte ◽  
Immune Checkpoint Inhibitors ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Tumour Immunity ◽  
Solid Malignancies ◽  
Cns Demyelination ◽  
Cell Death Protein

Immune checkpoints are molecules on the surface of leucocytes which modulate the amplitude of immune responses. Monoclonal antibodies blocking these molecules are known as immune checkpoints inhibitors (ICIs) and have been shown to unleash anti- tumour immunity and mediate durable cancer regressions. ICIs include ipilimumab which blocks the cytotoxic T-lymphocyte antigen-4 (CTLA-4), nivolumab and pembrolizumab which are both against the programmed cell death protein 1 (PD-1)1. The clinical use of these ICIs has led to significantly improved survival in patients with a variety of solid malignancies including melanoma.

scholarly journals Treating tumors with immune checkpoint inhibitors: Rationale and limitations

2017 ◽  
Vol 1 (1) ◽  
pp. 2 ◽  
Author(s):  
Judith Anna Seidel ◽  
Atsushi Otsuka ◽  
Kenji Kabashima
Keyword(s):  
Immune Responses ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Programmed Cell Death 1 ◽  
Human Use ◽  
Blocking Antibodies ◽  
Medical Advances

Immune checkpoints are essential for preventing immunopathology but can also obstruct anti-tumor immune responses. Recent medical advances in blocking these mechanisms have therefore opened promising avenues in the treatment of cancer.  Various blocking antibodies targeting the immune checkpoints programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are now approved for human use. This review summarizes the properties of PD-1 and CTLA-4 in physiological and tumor settings, and examines the treatment efficacy, side effects and biomarkers of their inhibitors. Future avenues in the application and development of immune checkpoint inhibitors for the treatment of cancer are also explored.

Activating Antibodies to The Calcium-sensing Receptor in Immunotherapy-induced Hypoparathyroidism

2020 ◽  
Vol 105 (5) ◽  
pp. 1581-1588 ◽  
Author(s):  
Isabella Lupi ◽  
Alessandro Brancatella ◽  
Filomena Cetani ◽  
Francesco Latrofa ◽  
E Helen Kemp ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
T Lymphocyte ◽  
Immune Checkpoint Inhibitors ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Cell Death Protein

Abstract Context Immune checkpoint inhibitors (ICIs), such as programmed cell death protein-1 (PD-1), programmed cell death protein-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibodies, are approved for the treatment of some types of advanced cancer. Their main treatment-related side-effects are immune-related adverse events (irAEs), especially thyroid dysfunction and hypophysitis. Hypoparathyroidism, on the contrary, is an extremely rare irAE. Objectives The aim of the study was to investigate the etiology of autoimmune hypoparathyroidism in a lung cancer patient treated with pembrolizumab, an anti-PD-1. Methods Calcium-sensing receptor (CaSR) autoantibodies, their functional activity, immunoglobulin (Ig) subclasses and epitopes involved in the pathogenesis of autoimmune hypoparathyroidism were tested. Results The patient developed hypocalcemia after 15 cycles of pembrolizumab. Calcium levels normalized with oral calcium carbonate and calcitriol and no remission of hypocalcemia was demonstrated during a 9-month follow-up. The patient was found to be positive for CaSR-stimulating antibodies, of IgG1 and IgG3 subclasses, that were able to recognize functional epitopes on the receptor, thus causing hypocalcemia. Conclusion The finding confirms that ICI therapy can trigger, among other endocrinopathies, hypoparathyroidism, which can be caused by pathogenic autoantibodies.

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 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.

Synergies of Targeting Angiogenesis and Immune Checkpoints in Cancer: From Mechanism to Clinical Applications

2020 ◽  
Vol 20 (7) ◽  
pp. 768-776 ◽  
Author(s):  
Shi Zhou ◽  
Haijun Zhang
Keyword(s):  
Web Of Science ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Angiogenesis Inhibitors ◽  
Immune Checkpoints ◽  
Antiangiogenic Agents ◽  
Recent Developments ◽  
Antiangiogenic Drugs ◽  
Tumor Types ◽  
Cell Death Protein

Background: Angiogenesis marks key progress in the growth, recurrence, and metastasis of various cancers. Antiangiogenic drugs can improve the blood supply and oxygen content of tumors and enhance the effects of chemotherapy and radiotherapy by normalizing tumor blood vessels and microenvironment. The further recent developments of Immune Checkpoint Inhibitors (ICIs) provide significant progress in cancer immunotherapy. The study focused on programmed cell death protein 1 (PD-1) and Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) blockade, reflecting on the evidence of durable responses among various tumor types. The aim of this review was to sum up present evidence and clarify the rationale behind supporting the benefits of combining antiangiogenic drugs with immunotherapy for cancer treatment as well as list the ongoing clinical trials that are being conducted. Methods: Using PubMed and Web of Science, published articles have been searched and comprehensively reviewed. Results: Antiangiogenic agents can trigger antitumor and immunity, and they can also be induced by the immune system. Combining antiangiogenic drugs with immunotherapy may be effective for the treatment of human cancers. Conclusion: It is evidenced that combining angiogenesis inhibitors with immunotherapy has a synergistic effect thus improving the curative effect of both agents.

scholarly journals B7 Family Members in Lymphoma: Promising Novel Targets for Tumor Immunotherapy?

2021 ◽  
Vol 11 ◽  
Author(s):  
Wei Zhang ◽  
Yu Qiu ◽  
Xiaoli Xie ◽  
Yao Fu ◽  
Lijuan Wang ◽  
...  
Keyword(s):  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nk Cell ◽  
Checkpoint Inhibitors ◽  
Vital Role ◽  
Immune Checkpoints ◽  
Programmed Death ◽  
B7 Family ◽  
Cell Death Protein

T cells play a vital role in the immune responses against tumors. Costimulatory or coinhibitory molecules regulate T cell activation. Immune checkpoint inhibitors, such as programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) have shown remarkable benefits in patients with various tumor, but few patients have displayed significant immune responses against tumors after PD-1/PD-L1 immunotherapy and many have been completely unresponsive. Thus, researchers must explore novel immune checkpoints that trigger durable antitumor responses and improve clinical outcomes. In this regard, other B7 family checkpoint molecules have been identified, namely PD-L2, B7-H2, B7-H3, B7-H4 and B7-H6. The aim of the present article was to address the expression, clinical significance and roles of B7 family molecules in lymphoma, as well as in T and NK cell-mediated tumor immunity. B7 family checkpoints may offer novel and immunotherapeutic strategies for patients with lymphoma.

scholarly journals Overview and management of toxicities of immune checkpoint-blocking drugs

2016 ◽  
Vol 7 (1) ◽  
pp. 28-37 ◽  
Author(s):  
Panagiota Economopoulou ◽  
Amanda Psyrri
Keyword(s):  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Cancer Management ◽  
New Methods ◽  
Organ Specific ◽  
Clinical Benefits ◽  
Immune Oncology ◽  
Cell Death Protein

Abstract Immunotherapy is considered to be the most important breakthrough in cancer management in the past few years. This success was based on the scientific understanding of immune mechanisms due to improvement in preclinical science and the introduction of new methods of investigation. Immune checkpoint inhibitors (ICIs) are among the most promising drugs in the field of immune-oncology; they represent monoclonal antibodies that modulate the effects of immune checkpoints, such as cytotoxic T lymphocyte Antigen 4 (CTLA-4) and Programmed Cell Death protein 1 (PD-1), which are co-inhibitory signals responsible for immune suppression. Despite clinical benefits, ICIs are immune activating agents that are associated with a number of important side effects (immune-related adverse events-irAEs), attributed to organ-specific inflammation. Herein, we review the toxicities of ICIs, highlighting the importance of early identification and management.

scholarly journals Anti–PD-L1 Treatment Induced Central Diabetes Insipidus

2017 ◽  
Vol 103 (2) ◽  
pp. 365-369 ◽  
Author(s):  
Chen Zhao ◽  
Sri Harsha Tella ◽  
Jaydira Del Rivero ◽  
Anuhya Kommalapati ◽  
Ifechukwude Ebenuwa ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Diabetes Insipidus ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Central Diabetes Insipidus ◽  
Early Screening ◽  
Cell Death Protein

Abstract Context Immune checkpoint inhibitors, including anti–programmed cell death protein 1 (PD-1), anti–programmed cell death protein ligand 1 (PD-L1), and anti–cytotoxic T-lymphocyte antigen 4 (anti-CTLA4) monoclonal antibodies, have been widely used in cancer treatment. They are known to cause immune-related adverse events (irAEs), which resemble autoimmune diseases. Anterior pituitary hypophysitis with secondary hypopituitarism is a frequently reported irAE, especially in patients receiving anti–CTLA4 treatment. In contrast, posterior pituitary involvement, such as central diabetes insipidus (DI), is relatively rare and is unreported in patients undergoing PD-1/PD-L1 blockade. Case Description We describe a case of a 73-year-old man with Merkel cell carcinoma who received the anti–PD-L1 monoclonal antibody avelumab and achieved partial response. The patient developed nocturia, polydipsia, and polyuria 3 months after starting avelumab. Further laboratory testing revealed central DI. Avelumab was held and he received desmopressin for the management of central DI. Within 6 weeks after discontinuation of avelumab, the patient’s symptoms resolved and he was eventually taken off desmopressin. The patient remained off avelumab and there were no signs or symptoms of DI 2 months after the discontinuation of desmopressin. Conclusion To our knowledge, this is the first report of central DI associated with anti–PD-L1 immunotherapy. The patient’s endocrinopathy was successfully managed by holding treatment with the immune checkpoint inhibitor. This case highlights the importance of early screening and appropriate management of hormonal irAEs in subjects undergoing treatment with immune checkpoint inhibitors to minimize morbidity and mortality.

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