Moderne Aspekte der Immuntherapie mit Checkpoint-Inhibitoren bei Melanom

2020 ◽  
Vol 8 (3) ◽  
pp. 92-101
Author(s):  
Vera Petrova ◽  
Ihor Arkhypov ◽  
Rebekka Weber ◽  
Christopher  Groth ◽  
Peter Altevogt ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Microenvironment ◽  
Programmed Cell Death ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Zielgerichtete Therapien ◽  
Cell Death Protein

Das Melanom gehört zu den am stärksten immunogenen Tumoren. Dennoch ist es in der Lage, sich einer antitumoralen Immunantwort zu entziehen, indem es Toleranzmechanismen, einschließlich negativer Immuncheckpoint-Moleküle, nutzt. Die am umfassendsten untersuchten Immuncheckpoints sind CTLA-4 (cytotoxic T lymphocyte-associated protein-4) und PD-1 (programmed cell death protein 1). Immuncheckpoint-Inhibitoren (ICI), die in den vergangenen 10 Jahren häufig zur Behandlung von Melanomen eingesetzt wurden, können antitumorale Immunreaktionen auslösen und eine Rückbildung des Melanoms bewirken. Patienten, die auf die ICI-Behandlung ansprachen, erreichten eine langanhaltende Remission oder einen Zustand der Krankheitskontrolle. Eine große Gruppe von Patienten sprach dagegen nicht auf diese Therapie an, was darauf hindeutet, dass es zu einer Entwicklung von Resistenzmechanismen kommt, darunter intrinsische Eigenschaften des Tumors, Funktionsstörungen der Effektorzellen und die Entstehung eines immunsuppressiven Tumormikromilieus (tumor microenvironment, TME). In der vorliegenden Übersichtsarbeit werden die Erfolge der ICI-Therapie bei Melanom, die Gründe für ein Therapieversagen und vielversprechende Ansätze zur Überwindung der Resistenz erörtert. Letztere umfassen die Kombination verschiedener ICI, Strategien zur Neutralisierung des immunsuppressiven Tumormikromilieus und die Kombination von ICI mit anderen antitumoralen Therapien wie Bestrahlung, onkolytische Viren oder zielgerichtete Therapien. Darüber hinaus werden neue therapeutische Ansätze, die gegen andere Immuncheckpoint-Moleküle gerichtet sind, ebenfalls besprochen.

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 Anti-PD-1 Therapy-Associated Perforating Colitis

2018 ◽  
Vol 2018 ◽  
pp. 1-3 ◽  
Author(s):  
Romulo Celli ◽  
Harriet M. Kluger ◽  
Xuchen Zhang
Keyword(s):  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
Adverse Effects ◽  
T Lymphocyte ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Colonic Perforation ◽  
Advanced Malignancies ◽  
Cell Death Protein

Inhibition of immune checkpoint T cell regulatory molecules by using programmed cell death protein 1 (PD-1), or its ligand (PDL-1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) has been increasingly used to treat advanced malignancies. The immune-related adverse effects associated with these treatments such as diarrhea, colitis, and CTLA-4 treatment-associated perforating colitis have been reported. However, anti-PD-1/PD-L1-associated perforating colitis has rarely been reported. We report a case of colonic perforation in a patient recently treated with pembrolizumab, a PD-1 inhibitor for metastatic melanoma. Awareness of anti-PD-1/PD-L1-associated colitis and perforation will facilitate a timely diagnosis and management as they are increasingly used in oncology.

scholarly journals Immune checkpoints: Cytotoxic T-lymphocyte antigen 4 and programmed cell death protein 1 in breast cancer surgery

2015 ◽  
Vol 10 (2) ◽  
pp. 1079-1086 ◽  
Author(s):  
AGNIESZKA KOLACINSKA ◽  
BARBARA CEBULA-OBRZUT ◽  
LUKASZ PAKULA ◽  
JUSTYNA CHALUBINSKA-FENDLER ◽  
ALINA MORAWIEC-SZTANDERA ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Programmed Cell Death ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Cancer Surgery ◽  
Breast Cancer Surgery ◽  
Immune Checkpoints ◽  
Lymphocyte Antigen ◽  
Cell Death Protein

scholarly journals The Tumor Microenvironment in SCC: Mechanisms and Therapeutic Opportunities

2021 ◽  
Vol 9 ◽  
Author(s):  
Nádia Ghinelli Amôr ◽  
Paulo Sérgio da Silva Santos ◽  
Ana Paula Campanelli
Keyword(s):  
Cell Death ◽  
Monoclonal Antibodies ◽  
Tumor Microenvironment ◽  
Programmed Cell Death ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Molecules

Squamous cell carcinoma (SCC) is the second most common skin cancer worldwide and, despite the relatively easy visualization of the tumor in the clinic, a sizeable number of SCC patients are diagnosed at advanced stages with local invasion and distant metastatic lesions. In the last decade, immunotherapy has emerged as the fourth pillar in cancer therapy via the targeting of immune checkpoint molecules such as programmed cell-death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). FDA-approved monoclonal antibodies directed against these immune targets have provide survival benefit in a growing list of cancer types. Currently, there are two immunotherapy drugs available for cutaneous SCC: cemiplimab and pembrolizumab; both monoclonal antibodies (mAb) that block PD-1 thereby promoting T-cell activation and/or function. However, the success rate of these checkpoint inhibitors currently remains around 50%, which means that half of the patients with advanced SCC experience no benefit from this treatment. This review will highlight the mechanisms by which the immune checkpoint molecules regulate the tumor microenvironment (TME), as well as the ongoing clinical trials that are employing single or combinatory therapeutic approaches for SCC immunotherapy. We also discuss the regulation of additional pathways that might promote superior therapeutic efficacy, and consequently provide increased survival for those patients that do not benefit from the current checkpoint inhibitor therapies.

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.

Erianin regulates programmed cell death ligand 1 expression and enhances cytotoxic T lymphocyte activity

2020 ◽  
pp. 113598
Author(s):  
Ao Yang ◽  
Ming Yue Li ◽  
Zhi Hong Zhang ◽  
Jing Ying Wang ◽  
Yue Xing ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Lymphocyte Activity

scholarly journals Der Einsatz von Immuncheckpoint-Inhibitoren im onkologischen Alltag

2020 ◽  
Vol 79 (8) ◽  
pp. 809-817 ◽  
Author(s):  
Julian Schardt
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Mismatch Repair ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Programmed Cell Death 1

Zusammenfassung Hintergrund Die Einführung von Immuncheckpoint-Inhibitoren (ICI) hat die Behandlungskonzepte der Onkologie für eine Vielzahl von unterschiedlichen Krebsarten maßgeblich verändert. Dabei werden in der klinischen Routine v. a. humanisierte Antikörper gegen Immuncheckpoints wie „cytotoxic T‑lymphocyte associated protein 4“ (CTLA-4) oder „programmed cell death 1/programmed cell death ligand 1“ (PD1/PD-L1) eingesetzt. Fragestellung Übersicht zur Therapielandschaft mit Immuncheckpoint-Inhibitoren bei mehrheitlich soliden Tumoren in der Onkologie. Material und Methoden Darstellung und Diskussion aktueller Studienresultate, Einbezug aktueller Behandlungsempfehlungen und Zulassungsindikationen. Ergebnisse Sieben verschiedene Immuncheckpoint-Inhibitoren werden in der Onkologie therapeutisch eingesetzt: ein Anti-CTLA-4-Antikörper, 3 Anti-PD1-Antikörper und 3 Anti-PD-L1-Antiköper. FDA-Zulassung auf dem US-Markt für 17 verschiedene Tumorentitäten und einer agnostischen Indikation (Tumoren mit defizienter Mismatch-repair-Maschinerie/hohe Mikrosatelliteninstabilität). Langzeitremissionen sind in ca. zwei Drittel der Patienten mit Tumoransprechen möglich. Schlussfolgerungen Nutzen der Immuncheckpoint-Inhibitoren nur für einen Teil der behandelten Patienten. Primäre und sekundäre Resistenzmechanismen erst in Anfängen verstanden. Kombinationstherapien der Immuncheckpoint-Inhibitoren mit z. B. Chemotherapie, neuen Immuncheckpoint-Inhibitoren (z. B. Anti-LAG3-Antikörper) oder gezielten Therapien (z. B. CDK4/6, PARP-Inhibitoren) zur Verbesserung der Wirksamkeit werden in klinischen Studien untersucht. Verlässliche, prädiktive Marker sind dringend erforderlich.

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