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Time to dissect the autoimmune etiology of cancer antibody immunotherapy.
Dougan, M, Pietropaolo, M
The Journal of clinical investigation. 2020;(1):51-61
Abstract
Immunotherapy has transformed the treatment landscape for a wide range of human cancers. Immune checkpoint inhibitors (ICIs), monoclonal antibodies that block the immune-regulatory "checkpoint" receptors CTLA-4, PD-1, or its ligand PD-L1, can produce durable responses in some patients. However, coupled with their success, these treatments commonly evoke a wide range of immune-related adverse events (irAEs) that can affect any organ system and can be treatment-limiting and life-threatening, such as diabetic ketoacidosis, which appears to be more frequent than initially described. The majority of irAEs from checkpoint blockade involve either barrier tissues (e.g., gastrointestinal mucosa or skin) or endocrine organs, although any organ system can be affected. Often, irAEs resemble spontaneous autoimmune diseases, such as inflammatory bowel disease, autoimmune thyroid disease, type 1 diabetes mellitus (T1D), and autoimmune pancreatitis. Yet whether similar molecular or pathologic mechanisms underlie these apparent autoimmune adverse events and classical autoimmune diseases is presently unknown. Interestingly, evidence links HLA alleles associated with high risk for autoimmune disease with ICI-induced T1D and colitis. Understanding the genetic risks and immunologic mechanisms driving ICI-mediated inflammatory toxicities may not only identify therapeutic targets useful for managing irAEs, but may also provide new insights into the pathoetiology and treatment of autoimmune diseases.
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Technical review on the management of eosinophilic esophagitis: a report from the AGA institute and the joint task force on allergy-immunology practice parameters.
Rank, MA, Sharaf, RN, Furuta, GT, Aceves, SS, Greenhawt, M, Spergel, JM, Falck-Ytter, YT, Dellon, ES, , , , , et al
Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 2020;(5):424-440.e17
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Abstract
Eosinophilic esophagitis (EoE) is a chronic inflammatory condition of the esophagus. Many new studies have been reported recently that describe EoE management. An expert panel was convened by the American Gastroenterological Association Institute and the Joint Task Force on Allergy-Immunology Practice Parameters to provide a technical review to be used as the basis for an updated clinical guideline. This technical review was developed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. Eighteen focused EoE management questions were considered, with 15 answered using the GRADE framework and 3 with a narrative summary. There is moderate certainty in the evidence that topical glucocorticosteroids effectively reduce esophageal eosinophil counts to <15 per high-power field over a short-term treatment period of 4-12 weeks, but very low certainty about the effects of using topical glucocorticosteroids as maintenance therapy. Multiple dietary strategies may be effective in reducing esophageal eosinophil counts to <15 per high-power field over a short-term treatment period, with moderate certainty for elemental diets, low certainty for empiric 2-, 4-, and 6-food elimination diets, and very low certainty that allergy-based testing dietary eliminations have a higher failure rate compared to empiric diet elimination. There is very low certainty for the effect of proton pump inhibitors in patients with esophageal eosinophilia. Although esophageal dilation appears to be relatively safe, there is no evidence that it reduces esophageal eosinophil counts. There is very low certainty in the effects of multiple other medical treatments for EoE: anti-interleukin-5 therapy, anti-interleukin-13 therapy, anti-IgE therapy, montelukast, cromolyn, and anti-TNF therapy.
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Central nervous system injury from novel cancer immunotherapies.
Winter, SF, Vaios, EJ, Dietrich, J
Current opinion in neurology. 2020;(6):723-735
Abstract
PURPOSE OF REVIEW Neurotoxicity from antineoplastic treatment remains a challenge in oncology. Cancer treatment-induced central nervous system (CNS) injury can be therapy-limiting, severely disabling, and even fatal. While emerging cancer immunotherapies have revolutionized oncology during the past decade, their immunomodulatory properties can cause immune-related adverse effects (IRAE) across organ systems, including the nervous system. Central neurologic IRAEs from chimeric antigen receptor T cells (CAR-T) and immune checkpoint inhibitors (ICPI) are challenging complications of such therapies.We aim to provide clinicians with a comprehensive review of the relevant forms of CAR-T and ICPI-associated CNS toxicity, focusing on clinical features of such complications, diagnostic workup, predictive biomarkers, and management considerations in affected patients. RECENT FINDINGS Unique forms of CAR-T and ICPI-related CNS toxicity have been characterized in the recent literature. CAR-T-related neurotoxicity is common and clinically well delineated. ICPI-related CNS toxicity is relatively rare but includes a heterogenous spectrum of severe and diagnostically challenging conditions. While putative risk factors, neurotoxicity biomarkers, imaging correlates and treatment strategies have been put forward, development of tailored diagnostic and management consensus guidelines awaits further clinical investigation. SUMMARY As CAR-T and ICPI become more widely adopted, early recognition, documentation, and management of immunotherapy-related CNS toxicity are of paramount importance in the clinical setting.
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New Insights Into Immunological Therapy for Retinal Disorders.
Takeda, A, Yanai, R, Murakami, Y, Arima, M, Sonoda, KH
Frontiers in immunology. 2020;:1431
Abstract
In the twentieth century, a conspicuous lack of effective treatment strategies existed for managing several retinal disorders, including age-related macular degeneration; diabetic retinopathy (DR); retinopathy of prematurity (ROP); retinitis pigmentosa (RP); uveitis, including Behçet's disease; and vitreoretinal lymphoma (VRL). However, in the first decade of this century, advances in biomedicine have provided new treatment strategies in the field of ophthalmology, particularly biologics that target vascular endothelial growth factor or tumor necrosis factor (TNF)-α. Furthermore, clinical trials on gene therapy specifically for patients with autosomal recessive or X-linked RP have commenced. The overall survival rates of patients with VRL have improved, owing to earlier diagnoses and better treatment strategies. However, some unresolved problems remain such as primary or secondary non-response to biologics or chemotherapy, and the lack of adequate strategies for treating most RP patients. In this review, we provide an overview of the immunological mechanisms of the eye under normal conditions and in several retinal disorders, including uveitis, DR, ROP, RP, and VRL. In addition, we discuss recent studies that describe the inflammatory responses that occur during the course of these retinal disorders to provide new insights into their diagnosis and treatment.
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Radiotherapy in women with epithelial ovarian cancer: historical role, current advances, and indications.
Flores-Balcázar, CH, Urías-Arce, DM
Chinese clinical oncology. 2020;(4):49
Abstract
Epithelial ovarian cancer (OC) is known to be a neoplasm responsive to radiotherapy (RT). Nevertheless, the role of RT in the management of this disease represent a topic of controversy, and the indications for its use are not fully established. Initial studies suggested that the addition of RT in the form of intraperitoneal (IP) radioisotopes was useful. Indications for this treatment were peritoneal cytology with tumor cells, peritoneal implants, and capsule rupture. The instillation of radioisotopes was contraindicated when macroscopic residual disease was present. Pelvic RT was used after surgery in patients with an absence of gross residual disease. Early studies established the inadequacy of this technique and the need for treating the whole abdomen. Whole abdominal irradiation (WAI) was a therapeutic tool used in the prechemotherapy era to eradicate large amounts of microscopic peritoneal disease. Ideal candidates for WAI were stage I patients with grade 2 or 3 tumors; stage II patients with grade 1 or 2 tumors and residual disease, and stage III, grade 1 patients with <2 cm residual disease. The disadvantages of WAI were the dose-limiting toxicities, which were predominantly acute hematologic and late gastrointestinal. The era of aggressive debulking and platinum agents made WAI fall out of favor as a treatment of OC. Selective approaches with highly conformal radiotherapy (CRT) have been used in case of limited recurrent or unresectable disease with the potential for long-term disease control. Currently, the role of RT in OC applies for patients with recurrent oligometastatic or oligoprogressive disease and in the palliative setting for symptom control. We performed a nonsystematic review and included data from both retrospective and prospective studies focusing on the use of RT for OC and its biological rationale. Furthermore, ongoing trials on this issue are reported.
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Hepatobiliary Adverse Events.
Abu-Sbeih, H, Wang, Y
Advances in experimental medicine and biology. 2020;:271-276
Abstract
Immune checkpoint inhibitors (ICIs) are increasingly used for multiple cancer types. Hepatotoxicity is a reported adverse event of ICI treatment. It can present as asymptomatic elevation of aspartate transaminase and alanine transaminase or symptomatic hepatitis with fever, malaise, and even death in rare cases. The diagnosis of ICI-induced hepatitis is made after exclusion of other etiologies based on medical history, laboratory evaluation, and imaging and histological findings. Treatment of ICI-induced hepatitis consists of ICI discontinuation and immunosuppression in severe cases. Pancreatic injury as asymptomatic lipase elevation or acute pancreatitis-like disease with abdominal pain and evidence on imaging has been documented as a toxicity of ICI therapy. Appropriate treatment of pancreatitis still needs further investigation. Few cases, reports, and series documented cholecystitis and cholangitis as possible adverse events related to ICI therapy as well.
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7.
Tumor hypermetabolism confers resistance to immunotherapy.
Liu, A, Curran, MA
Seminars in cancer biology. 2020;:155-163
Abstract
Advances in our understanding of tumor immune biology and development of cancer immunotherapies have led to improved outcomes for patients that suffer from aggressive cancers such as metastatic melanoma. Despite these advances, a significant proportion of patients still fail to benefit, and as a result, attention has shifted to understanding how cancer cells escape immune destruction. Of particular interest is the metabolic landscape of the tumor microenvironment, as recent studies have demonstrated how both competition for essential nutrients and depletion of specific amino acids can promote T cell dysfunction. Here, we will discuss the major energetic pathways engaged by both T cells and cancer cells, metabolic substrates present in the tumor microenvironment, and emerging therapeutic strategies that seek to improve T cell metabolic fitness and bolster the antitumor immune response.
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[Immune check point inhibitor-associated renal toxicity].
Izzedine, H, Gueutin, V
Nephrologie & therapeutique. 2020;(1):19-26
Abstract
Immune checkpoint inhibition had a major clinical success in clinical oncology and impacted the treatment paradigm in many cancers. Immune related adverse events are well-described toxicities that are closely associated with CPI therapies and can involve any organ in the body. Renal toxicity is multifocal. In addition to the predominant tubulointerstitial involvement, immunotherapy can lead to a variety of glomerular damage and electrolyte disorders. Suggested mechanisms include direct renal interstitium lymphocyte infiltration, renal immune complex deposition, microangiopathic endothelial disease, or cytokine release leading to podocytopathy. Immunotherapy in the renal transplant patient raises the question of the rejection occurrence. Current recommendations for diagnosis and management of renal effects are not optimal because of the limited data available and understanding of their pathophysiology.
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9.
T cell metabolism: new insights in systemic lupus erythematosus pathogenesis and therapy.
Sharabi, A, Tsokos, GC
Nature reviews. Rheumatology. 2020;(2):100-112
Abstract
T cell subsets are critically involved in the development of systemic autoimmunity and organ inflammation in systemic lupus erythematosus (SLE). Each T cell subset function (such as effector, helper, memory or regulatory function) is dictated by distinct metabolic pathways requiring the availability of specific nutrients and intracellular enzymes. The activity of these enzymes or nutrient transporters influences the differentiation and function of T cells in autoimmune responses. Data are increasingly emerging on how metabolic processes control the function of various T cell subsets and how these metabolic processes are altered in SLE. Specifically, aberrant glycolysis, glutaminolysis, fatty acid and glycosphingolipid metabolism, mitochondrial hyperpolarization, oxidative stress and mTOR signalling underwrite the known function of T cell subsets in patients with SLE. A number of medications that are used in the care of patients with SLE affect cell metabolism, and the development of novel therapeutic approaches to control the activity of metabolic enzymes in T cell subsets represents a promising endeavour in the search for effective treatment of systemic autoimmune diseases.
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Immunotherapy and potential molecular targets for the treatment of pituitary adenomas resistant to standard therapy: a critical review of potential therapeutic targets and current developments.
Maghathe, T, Miller, WK, Mugge, L, Mansour, TR, Schroeder, J
Journal of neurosurgical sciences. 2020;(1):71-83
Abstract
INTRODUCTION Pituitary adenomas (PAs) are primary central nervous system (CNS) tumors, accounting for as much as 25% of intracranial neoplasms. Although existing remedies show success in treating most PAs, treatment of invasive and non-functioning PAs, in addition to functioning PAs unresponsive to standard therapy, remains challenging. With the continually increasing understanding of biochemical pathways involved in tumorigenesis, immunotherapy stands as a promising alternative therapy for pituitary tumors that are resistant to standard therapy. EVIDENCE ACQUISITION A literature search was conducted of the PubMed database for immunotherapies of PAs. The search yielded a total of 2621 articles, 26 of which were included in our discussion. EVIDENCE SYNTHESIS Several pathologically expressed molecules could potentially serve as promising targets of current or future immunotherapies for PAs. Programmed death ligand-1, matrix metalloproteinases, EpCAM (Trop1) and Trop2, cancer-testis antigen MAGE-A3, epidermal growth factor receptor (EGFR), folate receptor alpha, vascular endothelial growth factor, and galectin-3 have all been implicated as crucial factors involved with tumor survival and invasion. Inhibition of these pathways may prove efficacious in the management of invasive and treatment-resistant PAs. CONCLUSIONS Rapid advancements in tumor immunology may increase the probability of successful treatment of PAs by exploitation of the normal immune response or by targeting novel proteins. Current research on many of the targets reviewed in this article are successfully being utilized to manage various neoplastic disease including CNS tumors. These therapies may eventually play a key role in the treatment of PAs that do not respond to standard therapy.