From clinical trials to clinical use of checkpoint inhibitors for patients with metastatic urothelial cancer

Immunotherapy ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 67-77
Author(s):  
Rosa Tambaro ◽  
Marilena Di Napoli ◽  
Carmela Pisano ◽  
Sabrina Chiara Cecere ◽  
Laura Attademo ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Urothelial Cancer ◽  
Unmet Needs ◽  
Checkpoint Inhibitors ◽  
Slight Improvement ◽  
Metastatic Urothelial Cancer ◽  
Advanced Urothelial Cancer ◽  
Improvement In Survival ◽  
Cell Death Protein

Monoclonal antibodies targeting the checkpoint inhibitors (CPIs), programmed cell death protein-1 or programmed cell death ligand-1, are changing the landscape of urothelial carcinoma therapeutics. Overall, clinical studies in metastatic or advanced urothelial cancer showed that CPIs provided a slight improvement in survival and a relevant advantage in safety, compared with chemotherapy. After reviewing published and ongoing trials, the authors discuss expected answers to unmet needs, with a special attention to the research of biological markers for patients with urothelial cancer eligible for treatment with CPIs in this article.

scholarly journals Clinical Applications of Immunotherapy Combination Methods and New Opportunities for the Future

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Ece Esin
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Checkpoint Inhibitors ◽  
Innate Immune ◽  
Small Subset ◽  
New Class ◽  
Combination Strategies ◽  
Combination Methods ◽  
Immune Editing ◽  
Cell Death Protein

In the last decade, we have gained a deeper understanding of innate immune system. The mechanism of the continuous guarding of progressive mutations happening in a single cell was discovered and the production and the recognition of tumor associated antigens by the T-cells and elimination of numerous tumors by immune-editing were further understood. The new discoveries on immune mechanisms and its relation with carcinogenesis have led to development of a new class of drugs called immunotherapeutics. T lymphocyte-associated antigen 4, programmed cell death protein 1, and programmed cell death protein ligand 1 are the classes drugs based on immunologic manipulation and are collectively known as the “checkpoint inhibitors.” Checkpoint inhibitors have shown remarkable antitumor efficacy in a broad spectrum of malignancies; however, the strongest and most durable immune responses do not last long and the more durable responses only occur in a small subset of patients. One of the solutions which have been put forth to overcome these challenges is combination strategies. Among the dual use of methods, a backbone with either PD-1 or PD-L1 antagonist drugs alongside with certain cytotoxic chemotherapies, radiation, targeted drugs, and novel checkpoint stimulators is the most promising approach and will be on stage in forthcoming years.

scholarly journals Evolving Treatment of Advanced Urothelial Cancer

2017 ◽  
Vol 13 (5) ◽  
pp. 309-315 ◽  
Author(s):  
Srikala S. Sridhar
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Metastatic Disease ◽  
Urothelial Cancer ◽  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Standard Of Care ◽  
The United States ◽  
Poor Performance Status ◽  
Cancer Of The Bladder

Urothelial cancer of the bladder is a smoking-related cancer and the fifth most common cancer in the United States. At presentation, up to 25% of patients will have muscle-invasive disease and, despite cystectomy or bladder-sparing trimodality approaches, will develop metastatic disease. Cisplatin-based combination chemotherapy regimens remain the standard of care in first-line metastatic disease. Although response rates to these regimens are high, they are rarely durable, and median overall survival is only 12 to 15 months. Treatment options following progression on cisplatin-based regimens or for patients unfit for cisplatin due to poor performance status, impaired renal function, or comorbidities have been quite limited. However, there is now a new class of drugs known as immune checkpoint inhibitors, which target the programmed cell death 1/programmed cell death-ligand 1 axis and promote antitumor immunity, that are showing both efficacy and tolerability. These drugs have now been approved for use in both cisplatin-treated and most recently cisplatin-unfit patients. Clinical trials are currently ongoing to determine how best to use these drugs and whether they should be used alone or in combination with other treatments. This review will discuss the current standard of care in the management of urothelial cancer and highlight recent trials of immunotherapy in this disease.

scholarly journals Immune Thrombocytopenia Induced by Immune Checkpoint Inhibitrs in Lung Cancer: Case Report and Literature Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Wang Xie ◽  
NaNa Hu ◽  
LeJie Cao
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Immune Checkpoint ◽  
Clinical Presentation ◽  
Checkpoint Inhibitors ◽  
Immune Dysregulation ◽  
Cancer Case ◽  
Severe Thrombocytopenia ◽  
Cell Death Protein

Immune checkpoint inhibitors (ICIs), including antibodies targeting programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1), are being extensively used on advanced human malignancies therapy. The treatment with ICIs have acquired durable tumor inhibition and changed the treatment landscape in lung cancer. Immune-related adverse events including pneumonitis and thyroiditis have been well described, but less frequent events, such as ICIs-induced thrombocytopenia, are now emerging and may sometimes be severe or fatal. Since early detection and prompt intervention are crucial to prevent fatal consequences, it is of outmost importance that medical staff is aware of these potential toxicities and learn to recognize and treat them adequately. This review focuses on the epidemiology, clinical presentation, mechanisms, and clinical management of ICIs-induced thrombocytopenia in patients with lung cancer. We also present a patient with advanced lung adenocarcinoma who received the PD-L1 inhibitor atezolizumab and eventually developed severe thrombocytopenia. The case indirectly suggests that cytokine changes might contribute to immune dysregulation in ICIs-induced thrombocytopenia.

scholarly journals Failure of Immunotherapy—The Molecular and Immunological Origin of Immunotherapy Resistance in Lung Cancer

2021 ◽  
Vol 22 (16) ◽  
pp. 9030
Author(s):  
Justyna Błach ◽  
Kamila Wojas-Krawczyk ◽  
Marcin Nicoś ◽  
Paweł Krawczyk
Keyword(s):  
Lung Cancer ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Current Knowledge ◽  
Checkpoint Inhibitors ◽  
Treatment Resistance ◽  
Immune Checkpoints ◽  
Cytotoxic T Cell ◽  
Number Of Patients ◽  
Cell Death Protein

Immune checkpoint inhibitors (ICIs) have a huge impact on clinical treatment results in non-small cell lung cancer (NSCLC). Blocking antibodies targeting programmed cell death protein 1 (PD-1), programmed cell death protein ligand 1 (PD-L1) or CTLA-4 (cytotoxic T cell antigen 4) have been developed and approved for the treatment of NSCLC patients. However, a large number of patients develop resistance to this type of treatment. Primary and secondary immunotherapy resistance are distinguished. No solid biomarkers are available that are appropriate to predict the unique sensitivity to immunotherapy. Knowledge of predictive markers involved in treatment resistance is fundamental for planning of new treatment combinations. Scientists focused research on the use of immunotherapy as an essential treatment in combination with other therapy strategies, which could increase cancer immunogenicity by generating tumor cells death and new antigen release as well as by targeting other immune checkpoints and tumor microenvironment. In the present review, we summarize the current knowledge of molecular bases underlying immunotherapy resistance and discuss the capabilities and the reason of different therapeutic combinations.

Autoimmune complications of immunotherapy: pathophysiology and management

BMJ ◽  
2020 ◽  
pp. m736 ◽  
Author(s):  
Karmela K Chan ◽  
Anne R Bass
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Case Fatality ◽  
High Grade ◽  
Almost All ◽  
Inhibitory Molecules ◽  
Patients Experience ◽  
Cell Death Protein

Abstract Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target inhibitory molecules, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), or its ligand, programmed cell death protein ligand 1 (PD-L1), and lead to immune activation in the tumor micro-environment. ICIs can induce durable treatment responses in patients with advanced cancers, but they are commonly associated with immune related adverse events (irAEs) such as rash, colitis, hepatitis, pneumonitis, and endocrine and musculoskeletal disorders. Almost all patients experience some form of irAE, but high grade irAEs occur in approximately half of those on combination therapy (eg, anti-CTLA-4 plus anti-PD-1), and up to one quarter receiving ICI monotherapy. Fatal irAEs occur in approximately 1.2% of patients on CTLA-4 blockade and 0.4% of patients receiving PD-1 or PD-L1 blockade, and case fatality rates are highest for myocarditis and myositis. IrAEs typically occur in the first three months after ICI initiation, but can occur as early as one day after the first dose to years after ICI initiation. The mainstay of treatment is with corticosteroids, but tumor necrosis factor inhibitors are commonly used for refractory irAEs. Although ICIs are generally discontinued when high grade irAEs occur, ICI discontinuation alone is rarely adequate to resolve irAEs. Consensus guidelines have been published to help guide management, but will likely be modified as our understanding of irAEs grows.

scholarly journals Anti-Cancer Activity of PAK4/NAMPT Inhibitor and Programmed Cell Death Protein-1 Antibody in Kidney Cancer

Kidney360 ◽  
2020 ◽  
Vol 1 (5) ◽  
pp. 376-388
Author(s):  
Josephine F. Trott ◽  
Omran Abu Aboud ◽  
Bridget McLaughlin ◽  
Katie L. Anderson ◽  
Jaime F. Modiano ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Kidney Cancer ◽  
Renal Cell ◽  
Checkpoint Inhibitors ◽  
The United States ◽  
Nicotinamide Phosphoribosyltransferase ◽  
Programmed Cell Death 1 ◽  
Anti Cancer ◽  
Cell Death Protein

BackgroundKidney cancer (or renal cell carcinoma, RCC) is the sixth most common malignancy in the United States and is increasing in incidence. Despite new therapies, including targeted therapies and immunotherapies, most RCCs are resistant to treatment. Thus, several laboratories have been evaluating new approaches to therapy, both with single agents as well as combinations. Although we have previously shown efficacy of the dual PAK4/nicotinamide phosphoribosyltransferase (NAMPT) inhibitor KPT-9274, and the immune checkpoint inhibitors (CPI) have shown utility in the clinic, there has been no evaluation of this combination either clinically or in an immunocompetent animal model of kidney cancer.MethodsIn this study, we use the renal cell adenocarcinoma (RENCA) model of spontaneous murine kidney cancer. Male BALB/cJ mice were injected subcutaneously with RENCA cells and, after tumors were palpable, they were treated with KPT-9274 and/or anti–programmed cell death 1 (PDCD1; PD1) antibody for 21 days. Tumors were measured and then removed at animal euthanasia for subsequent studies.ResultsWe demonstrate a significant decrease in allograft growth with the combination treatment of KPT-9274 and anti-PD1 antibody without significant weight loss by the animals. This is associated with decreased (MOUSE) Naprt expression, indicating dependence of these tumors on NAMPT in parallel to what we have observed in human RCC. Histology of the tumors showed substantial necrosis regardless of treatment condition, and flow cytometry of antibody-stained tumor cells revealed that the enhanced therapeutic effect of KPT-9274 and anti-PD1 antibody was not driven by infiltration of T cells into tumors.ConclusionsThis study highlights the potential of the RENCA model for evaluating immunologic responses to KPT-9274 and checkpoint inhibitor (CPI) and suggests that therapy with this combination could improve efficacy in RCC beyond what is achievable with CPI alone.

Immune checkpoint inhibitor-induced gastrointestinal and hepatic injury: pathologists’ perspective

2018 ◽  
Vol 71 (8) ◽  
pp. 665-671 ◽  
Author(s):  
Dipti M Karamchandani ◽  
Runjan Chetty
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Survival Rates ◽  
Immune Mediated ◽  
Self Tolerance ◽  
Novel Drugs ◽  
Cell Death Protein

Immune checkpoint inhibitors (CPIs) are a relatively new class of ‘miracle’ dugs that have revolutionised the treatment and prognosis of some advanced-stage malignancies, and have increased the survival rates significantly. This class of drugs includes cytotoxic T lymphocyte antigen-4 inhibitors such as ipilimumab; programmed cell death protein-1 inhibitors such as nivolumab, pembrolizumab and avelumab; and programmed cell death protein ligand-1 inhibitors such as atezolizumab. These drugs stimulate the immune system by blocking the coinhibitory receptors on the T cells and lead to antitumoural response. However, a flip side of these novel drugs is immune-related adverse events (irAEs), secondary to immune-mediated process due to disrupted self-tolerance. The irAEs in the gastrointestinal (GI) tract/liver may result in diarrhoea, colitis or hepatitis. An accurate diagnosis of CPI-induced colitis and/or hepatitis is essential for optimal patient management. As we anticipate greater use of these drugs in the future given the significant clinical response, pathologists need to be aware of the spectrum of histological findings that may be encountered in GI and/or liver biopsies received from these patients, as well as differentiate them from its histopathological mimics. This present review discusses the clinical features, detailed histopathological features, management and the differential diagnosis of the luminal GI and hepatic irAEs that may be encountered secondary to CPI therapy.

scholarly journals Immune checkpoint dysfunction in large and medium vessel vasculitis

2017 ◽  
Vol 312 (5) ◽  
pp. H1052-H1059 ◽  
Author(s):  
Ryu Watanabe ◽  
Hui Zhang ◽  
Gerald Berry ◽  
Jörg J. Goronzy ◽  
Cornelia M. Weyand
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
Immune Checkpoint ◽  
Intimal Hyperplasia ◽  
Cd4 T Cells ◽  
Vessel Wall ◽  
Checkpoint Inhibitors ◽  
Cell Death Protein

Giant cell arteritis (GCA) is a granulomatous vasculitis of the aorta and its medium-sized branch vessels. CD4 T cells, macrophages, and dendritic cells (DCs) build granulomatous infiltrates that injure the vessel wall and elicit a maladaptive response to injury. Pathological consequences include fragmentation of elastic membranes, destruction of the medial layer, microvascular neoangiogenesis, massive outgrowth of myofibroblasts, and lumen-occlusive intimal hyperplasia. Antigens have been suspected to drive the local activation of vasculitogenic CD4 T cells, but recent data have suggested a more generalized defect in the threshold setting of such T cells, rendering them hyperreactive. Under physiological conditions, immune checkpoints provide negative signals to curb T cell activation and prevent inflammation-associated tissue destruction. This protective mechanism is disrupted in GCA. Vessel wall DCs fail to express the immunoinhibitory ligand programmed cell death ligand-1, leaving lesional T cells unchecked. Consequently, programmed cell death protein-1-positive CD4 T cells can enter the immunoprivileged vessel wall, where they produce a broad spectrum of inflammatory cytokines (interferon-γ, IL-17, and IL-21) and have a direct role in driving intimal hyperplasia and intramural neoangiogenesis. The deficiency of the programmed cell death protein-1 immune checkpoint in GCA, promoting unopposed T cell immunity, contrasts with checkpoint hyperactivity in cancer patients in whom excessive programmed cell death ligand-1 expression paralyzes the function of antitumor T cells. Excessive checkpoint activity is the principle underlying cancer-immune evasion and is therapeutically targeted by immunotherapy with checkpoint inhibitors. Such checkpoint inhibitors, which unleash anticancer T cells and induce immune-related toxicity, may lead to drug-induced vasculitis.

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.

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.

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