Immunotherapy in Special and Rare Situations: A Brief Review

ABSTRACT Immunotherapy has established itself as an important component of the treatment armamentarium against various solid as well as hematologic cancers. Immune checkpoint inhibitors (ICI) provide for a very well-tolerated and efficacious treatment option that has improved survival in several cancers. The approved ICIs mainly consist of antibodies targeting cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) or its ligand, programmed cell death ligand 1 (PD-L1). However, most clinical trials of ICI have excluded patients from high-risk populations, such as those with autoimmune diseases, patients on chronic steroid intake for various reasons or preexisting HIV infections. The older adults are also an underrepresented section of the population enrolled into such trials, most probably due to the higher prevalence of comorbidities and frailty affecting their Eastern Co-Operative Oncology Group performance status, and thus the eligibility for clinical trial enrollment. This paper aimed to briefly review the available evidence and thus guide the decision-making process for use of ICI in such rare and special situations.

Autoimmune complications of immunotherapy: pathophysiology and management

BMJ ◽

10.1136/bmj.m736 ◽

2020 ◽

pp. m736 ◽

Cited By ~ 8

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 ◽

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.

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

Journal of Clinical Pathology ◽

10.1136/jclinpath-2018-205143 ◽

2018 ◽

Vol 71 (8) ◽

pp. 665-671 ◽

Cited By ~ 49

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 ◽

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.

Anti–PD-L1 Treatment Induced Central Diabetes Insipidus

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2017-01905 ◽

2017 ◽

Vol 103 (2) ◽

pp. 365-369 ◽

Cited By ~ 33

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 ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Central Diabetes Insipidus ◽

Early Screening ◽

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

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgaa092 ◽

2020 ◽

Vol 105 (5) ◽

pp. 1581-1588 ◽

Cited By ~ 2

Author(s):

Isabella Lupi ◽

Alessandro Brancatella ◽

Filomena Cetani ◽

Francesco Latrofa ◽

E Helen Kemp ◽

...

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

T Lymphocyte ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Calcium Sensing Receptor ◽

Calcium Sensing ◽

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.

Toxicidade Cutânea dos Inibidores de Checkpoint Imunológico: Uma Revisão Narrativa

Acta Médica Portuguesa ◽

10.20344/amp.12424 ◽

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 ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

Cutaneous Toxicity ◽

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.

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

BioMed Research International ◽

10.1155/2017/1623679 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 1

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 ◽

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.

Management of Hematologic Adverse Events Associated With Immune Checkpoint Inhibitors

Journal of the Advanced Practitioner in Oncology ◽

10.6004/jadpro.2021.12.4.4 ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Barbara Barnes Rogers, CRNP, MN, AOCN, ANP-BC ◽

Carolyn Zawislak, MPAS, PA-C ◽

Victoria Wong, PA-C

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Adverse Events ◽

Immune Checkpoint ◽

Blood Cells ◽

Cytotoxic T Lymphocyte ◽

Checkpoint Inhibitors ◽

White Blood Cells ◽

Activated T Cells

Immune checkpoint inhibitors target suppressor receptors, including cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1). The activated T cells are not antigen specific; therefore, the blockade of the immune checkpoint may result in the development of autoimmune adverse events. The most common immune-related adverse events (irAEs) are rash, colitis, and endocrinopathies. However, irAEs that affect the hematologic system are rare and can affect red blood cells (e.g., autoimmune hemolytic anemia), white blood cells, and platelets (e.g., immune thrombocytopenia). Usually one cell line is affected; however, in some cases, multiple cell lines can be affected. Other changes in the hematologic system can also be affected (e.g., cryoglobulinemia, cytokine release syndrome). Due to the rarity and lack of recognition of these AEs, the timing, spectrum of events, and clinical presentation are poorly understood. Management of hematologic irAEs usually involves the use of steroids; however, other agents (e.g., IVIG, cyclosporine, rituximab) or procedures (e.g., plasma exchange, transfusions) can also be used.

Evolving Treatment of Advanced Urothelial Cancer

Journal of Oncology Practice ◽

10.1200/jop.2017.022137 ◽

2017 ◽

Vol 13 (5) ◽

pp. 309-315 ◽

Cited By ~ 13

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.

The Tumor Microenvironment in SCC: Mechanisms and Therapeutic Opportunities

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.636544 ◽

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.

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

Frontiers in Immunology ◽

10.3389/fimmu.2021.790051 ◽

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 ◽

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.