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1.
The Effect of Birch Pollen Immunotherapy on Apple and rMal d 1 Challenges in Adults with Apple Allergy.
van der Valk, JPM, Nagl, B, van Wljk, RG, Bohle, B, de Jong, NW
Nutrients. 2020;(2)
Abstract
BACKGROUND A proportion of patients allergic to birch pollen are also allergic to pit fruit. The objective of this study was to investigate the effect of immunotherapy with birch pollen on birch-pollen-related apple allergy. METHOD Patients with birch pollen immunotherapy underwent a skin-prick test with birch pollen, apple and rMal d 1, global assessments and nasal challenges with birch pollen, open food challenge with apple and a double-blind, placebo-controlled test with rMal d 1 at the start of and during the immunotherapy. Measurements of specific IgE in response to Bet v 1 and rMal d 1 and IgG4 in response to Bet v 1 and rMal d 1 took place. RESULTS Six of eight patients demonstrated an improvement of nasal challenge test results and all patients improved on global assessment during the immunotherapy. The median oral dose of apple required to elicit a reaction increased but was not statistically significant. The patients showed a decrease in skin-prick test values in response to birch pollen (1.05 to 0.36), apple (0.78 to 0.25) and rMal d 1 (0.51 to 0.10) with p-values of 0.04, 0.03 and 0.06, respectively and a decrease of specific IgE in response to Bet v 1 (10.66 kU/L to 5.19 kU/L) and rMal d 1 (0.99 to 0.61 kU/L) with p-values of 0.01 and 0.05, respectively. Only the median specific IgG4 value to Bet v 1 increased from 0.05 to 1.85 mg/L (p-value of 0.02) and not to IgG4 rMal d 1 (0.07 to 0.08 kU/L). CONCLUSION The beneficial effects of immunotherapy for birch pollen were accompanied by a limited effect on apple allergy.
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2.
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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3.
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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Activating Antibodies to The Calcium-sensing Receptor in Immunotherapy-induced Hypoparathyroidism.
Lupi, I, Brancatella, A, Cetani, F, Latrofa, F, Kemp, EH, Marcocci, C
The Journal of clinical endocrinology and metabolism. 2020;(5)
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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Immunotherapy to improve pregnancy outcome in women with abnormal natural killer cell levels/activity and recurrent miscarriage or implantation failure: A systematic review and meta-analysis.
Woon, EV, Day, A, Bracewell-Milnes, T, Male, V, Johnson, M
Journal of reproductive immunology. 2020;:103189
Abstract
There is a trend towards offering immunotherapy to women with unexplained reproductive failure based on abnormal Natural Killer (NK) cell levels. Previous systematic reviews evaluating immunotherapy usage have not focused on women with abnormal level of NK cells. To address the gap in literature, this systematic review aims to evaluate the efficacy of immunotherapy to improve pregnancy outcome in women with recurrent miscarriage (RM) or implantation failure (RIF) specifically selected based on abnormal levels and/or activity of NK cells. Six databases were searched for peer-reviewed studies following PRISMA guidelines. Risk of bias assessment was conducted using RoB2 for randomized controlled trials (RCT) and ROBINS-I for non-RCT. Of 1025 studies identified, seven studies on intravenous immunoglobulin (IVIG) (four), prednisolone (one), etanercept (one) and intralipid (one) were included. Meta-analysis of the non-RCT IVIG studies (557 participants; 312 intervention, 245 controls) showed livebirth in favour of intervention (RR 2.57; 95 % CI = 1.79-3.69; p < 0.05), however there were significant heterogeneity (I2 = 62 %) and moderate to severe risk of bias in these studies. Individual RCTs reported improved livebirth outcome in etanercept, intralipid and prednisolone and this was significant in the former two (p < 0.05). In conclusion, there may be some benefit of immunotherapy, but paucity of high quality evidence means that it is not possible to support the use of immunotherapy even when selected based on abnormal NK cell level/activity. Further research with application of scientifically validated immunological biomarkers in well-planned large scale RCTs will determine whether immunotherapy is beneficial in this subpopulation of women.
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7.
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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8.
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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i-Move, a personalised exercise intervention for patients with advanced melanoma receiving immunotherapy: a randomised feasibility trial protocol.
Hyatt, A, Gough, K, Murnane, A, Au-Yeung, G, Dawson, T, Pearson, E, Dhillon, H, Sandhu, S, Williams, N, Paton, E, et al
BMJ open. 2020;(2):e036059
Abstract
INTRODUCTION There is increasing evidence demonstrating the benefits of exercise in counteracting cancer treatment-related fatigue. Immunotherapy is an established treatment for advanced melanoma, and is associated with fatigue in a third of patients. The safety and efficacy of exercise in counteracting treatment-related fatigue in patients with advanced melanoma receiving immunotherapy are yet to be determined. This study aims to assess the safety, adherence to and acceptability of a mixed-methods parallel-group, pilot randomised controlled trial of a personalised, 12-week semi-supervised exercise programme prescribed by an exercise physiologist (iMove) in 30 patients with stage IV melanoma scheduled to commence immunotherapy: single agent ipilimumab, nivolumab or pembrolizumab, or combination ipilimumab and nivolumab. The trial will be used to provide preliminary evidence of the potential efficacy of exercise for managing fatigue. METHODS AND ANALYSIS Thirty participants will be recruited from a specialist cancer centre between May and September, 2019. Participants will be randomised 1:1 to receive iMove, or usual care (an information booklet about exercise for people with cancer). Feasibility data comprise: eligibility; recruitment and retention rates; adherence to and acceptability of exercise consultations, personalised exercise programme and study measures; and exercise-related adverse events. Patient-reported outcome measures assess potential impact of the exercise intervention on: fatigue, role functioning, symptoms and quality of life. Follow-up will comprise five time points over 24 weeks. Physical assessments measure physical fitness and functioning. ETHICS AND DISSEMINATION This study was reviewed and approved by the Peter MacCallum Cancer Centre Human Research Ethics Committee (HREC/48927/PMCC-2019). The findings from this trial will be disseminated via conference presentations and publications in peer-reviewed journals, and by engagement with clinicians, media, government and consumers. In particular, we will promote the outcomes of this work among the oncology community should this pilot indicate benefit for patients. TRIAL REGISTRATION NUMBER ACTRN12619000952145; Pre-results.
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10.
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.