Emerging evidence on the role of the antitumor activity of the immune system has generated great interest in immunotherapy even for tumors that were historically considered as nonimmunogenic. ...Immunotherapy is emerging as a major modality in non-small cell lung cancer (NSCLC) treatment focusing on vaccine approaches to elicit specific immune responses and development of inhibitors of the molecular mediators of cancer-induced immunosuppression (immune checkpoints) to boost antitumor immune responses. Amplification of the host response against evolving tumors through vaccination is being investigated in ongoing clinical trials with tumor cell vaccines; however, the clinical efficacy of these agents has been limited. Blocking inhibitory pathways such as the CTL antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) checkpoint pathways with mAbs has generated antitumor immune responses that are transforming cancer therapeutics. PD-1 and programmed cell death ligand 1 (PD-L1) antibodies have shown durable responses in NSCLC, with a favorable safety profile and manageable side effects. The activity of immune checkpoint inhibitors is currently been assessed in treatment-naïve patients with PD-L1-positive advanced NSCLC. Combinatorial approaches with other immune checkpoint inhibitors, chemotherapy, or targeted agents are being explored in ongoing clinical trials, and may improve outcome in NSCLC.
Antibodies are among the most frequently used tools in basic science research and in clinical assays, but there are no universally accepted guidelines or standardized methods for determining the ...validity of these reagents. Furthermore, for commercially available antibodies, it is clear that what is on the label does not necessarily correspond to what is in the tube. To validate an antibody, it must be shown to be specific, selective, and reproducible in the context for which it is to be used. In this review, we highlight the common pitfalls when working with antibodies, common practices for validating antibodies, and levels of commercial antibody validation for seven vendors. Finally, we share our algorithm for antibody validation for immunohistochemistry and quantitative immunofluorescence.
Summary
Peanut nut and tree nut allergy are characterised by IgE mediated reactions to nut proteins. Nut allergy is a global disease. Limited epidemiological data suggest varying prevalence in ...different geographical areas. Primary nut allergy affects over 2% of children and 0.5% of adults in the UK. Infants with severe eczema and/or egg allergy have a higher risk of peanut allergy. Primary nut allergy presents most commonly in the first five years of life, often after the first known ingestion with typical rapid onset IgE‐mediated symptoms. The clinical diagnosis of primary nut allergy can be made by the combination of a typical clinical presentation and evidence of nut specifc IgE shown by a positive skin prick test (SPT) or specific IgE (sIgE) test. Pollen food syndrome is a distinct disorder, usually mild, with oral/pharyngeal symptoms, in the context of hay fever or pollen sensitisation, which can be triggered by nuts. It can usually be distinguish clinically from primary nut allergy. The magnitude of a SPT or sIgE relates to the probability of clinical allergy, but does not relate to clinical severity. SPT of ≥ 8 mm or sIgE ≥ 15 KU/L to peanut is highly predictive of clinical allergy. Cut off values are not available for tree nuts. Test results must be interpreted in the context of the clinical history. Diagnostic food challenges are usually not necessary but may be used to confirm or refute a conflicting history and test result. As nut allergy is likely to be a long‐lived disease, nut avoidance advice is the cornerstone of management. Patients should be provided with a comprehensive management plan including avoidance advice, patient specific emergency medication and an emergency treatment plan and training in administration of emergency medication. Regular re‐training is required.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Peanut allergy is common, potentially severe and rarely resolves causing impaired quality of life. No disease-modifying treatment exists and there is therefore a need to develop a therapeutic ...intervention. The aim of this study was to investigate whether peanut oral immunotherapy (OIT) can induce clinical tolerance to peanut protein. Four peanut-allergic children underwent OIT. Preintervention oral challenges were performed to confirm clinical allergy and define the amount of protein required to cause a reaction (dose thresholds). OIT was then administered as daily doses of peanut flour increasing from 5 to 800 mg of protein with 2-weekly dose increases. After 6 further weeks of treatment, the oral challenge was repeated to define change in dose threshold and subjects continued daily treatment. Preintervention challenges confirmed peanut allergy and revealed dose thresholds of 5-50 mg (1/40-1/4 of a whole peanut); one subject had anaphylaxis during challenge and required adrenaline injection. All subjects tolerated immunotherapy updosing to 800 mg protein and i.m. adrenaline was not required. Each subject tolerated at least 10 whole peanuts (approximately 2.38 g protein) in postintervention challenges, an increase in dose threshold of at least 48-, 49-, 55- and 478-fold for the four subjects. We demonstrated a substantial increase in dose threshold after OIT in all subjects, including the subject with proven anaphylaxis. OIT was well tolerated and conferred protection against at least 10 peanuts, more than is likely to be encountered during accidental ingestion.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Summary
Background
Peanut allergy is severe and rarely resolves.
Objective
To test the efficacy and safety of a new oral immunotherapy (OIT) protocol for peanut allergy.
Method
Twenty‐two ...peanut‐allergic children underwent oral challenge. OIT was administered by gradual updosing with 2‐weekly increments (8–38 weeks) to 800 mg of protein (5 peanuts/day) followed by 30‐week maintenance. Oral challenge was repeated after 6 and 30 weeks maintenance.
Results
Twenty‐two children (median 11 years) had positive challenges (threshold 1–110 mg). Nineteen of 22 (86%) tolerated updosing and maintenance at 800 mg protein/day. One of 22 dropped out; 2/22 tolerated updosing and maintenance at 200–400 mg protein. Reactions, mostly mild, occurred in 86% during immunotherapy, adrenaline was not required. Eight of 8 with pre‐immunotherapy peanut IgE<27.3 kU/L required no dose adjustment compared with 5/13 with pre‐immunotherapy peanut IgE27.3 kU/L. Twelve of 22 (54%) required a transient dose reduction because of reactions possibly related to extrinsic factors: tiredness, infection and exercise. After 6 weeks, 12/22 (54%) had no reaction to a 2.6 g protein challenge. After 30 weeks, 14/22 (64%) tolerated 6.6 g protein. The median tolerated peanut dose increased 1000‐fold following immunotherapy, from 6 to 6459 mg of protein.
Conclusions and Clinical Relevance
We used a novel protocol using gradual updosing, and higher maintenance dose resulting in a better outcome compared with rush protocols. There was a 1000‐fold increase in the amount of peanut tolerated with a good safety profile. No serious adverse events occurred. Most subjects tolerated five peanuts and all were protected against amounts likely during accidental ingestion. New information is provided on ‘extrinsic factors’, updosing method and factors associated with success (trial registration http://ClinicalTrials.gov– ID number NCT01259804).
Cite this as: K. Anagnostou, A. Clark, Y. King, S. Islam, J. Deighton and P. Ewan, Clinical & Experimental Allergy, 2011 (41) 1273–1281.
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7.
What do we mean by oral tolerance? Anagnostou, K.; Clark, A.
Clinical & experimental allergy/Clinical and experimental allergy,
06/2016, Volume:
46, Issue:
6
Journal Article
Peer reviewed
Open access
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Background
Egg allergy is common and although resolution to uncooked egg has been demonstrated, there is lack of evidence to guide reintroduction of well‐cooked egg.
Objectives
To examine the ...rate of resolution to well‐cooked, compared with uncooked egg in children, and safety of egg challenges.
Method
A longitudinal study of egg‐allergic children from 2004 to 2010, who underwent challenge with well‐cooked and if negative, uncooked egg. Participants underwent repeat annual challenges and egg‐specific IgE measurement.
Results
One hundred and eighty‐one open egg challenges were performed in 95 children whose median age of allergy onset was 12 months. Fifty‐three of 95 (56%) had at least one annual repeat challenge. Pre‐study historical reactions occurred to baked egg in five (5%), lightly cooked in 58 (61%) and uncooked in nine (9%); respiratory reactions occurred in 11 (12%) and seven (7%) had anaphylaxis; adrenaline was used during five reactions. There were 77 well‐cooked and 104 uncooked egg challenges. Tolerance was gained twice as rapidly to well‐cooked than uncooked egg (median 5.6 vs. 10.3 years; P<0.0001) and continued to 13 years; hazard ratio 2.23 (95% confidence interval 1.6–3.9). Nearly 1/3 had resolved allergy to well‐cooked egg at 3 years and 2/3 at 6 years. Of 28/77 (37%) positive well‐cooked egg challenges, 65% had cutaneous symptoms, 68% gastrointestinal and 39% rhinitis, with no other respiratory reactions. Adrenaline was not required.
Conclusions and Clinical Relevance
Resolution of egg allergy takes place over many years, with children outgrowing allergy to well‐cooked egg approximately twice as quickly as they outgrow allergy to uncooked egg. There were no severe reactions to well‐cooked egg challenge, and adrenaline was not required. Our data support initiation of home reintroduction of well‐cooked egg from 2 to 3 years of age in children with previous mild reactions and no asthma. Resolution continues to occur in older children, so that despite an earlier positive challenge, attempts at reintroduction should be continued.
Cite this as: A. Clark, S. Islam, Y. King, J. Deighton, S. Szun, K. Anagnostou and P. Ewan, Clinical & Experimental Allergy, 2011 (41) 706–712.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Thyroid transcription factor 1 (TTF1) is a transcription factor that regulates the expression of multiple genes involved in lung development. It is preferentially expressed in adenocarcinomas of the ...lung and has been investigated as a potential prognostic parameter in patients with lung cancer, with conflicting results. We quantitatively assessed TTF1 protein expression in two large and independent data sets to investigate the impact of TTF1 nuclear expression on patient survival.
Automated quantitative analysis, a fluorescent-based method for analysis of in situ protein expression, was used to assess a series of cell lines to find the threshold of detection of TTF1 expression. Then two independent cohorts (176 and 237 cases, respectively) were measured by the same technique, and TTF1 expression was correlated with survival.
Tumors expressed TTF1 in 45% and 58% of the cases in each cohort. TTF1 was consistently expressed in adenocarcinomas (n = 61 and 73; Spearman rho = 0.313 and 0.4 for the first and second set, respectively; P < .0001) independent of their differentiation and stage. Survival analysis showed that patients with stage I adenocarcinoma with TTF1 expression had a longer median overall survival than those without expression (n = 43, 44.3 v 26.2 months, P = .05 for the first cohort; n = 87; 49.7 v 38.5 months, P = .03 for the second cohort) Multivariate analysis revealed an independent lower risk of death for patients with stage I adenocarcinoma with TTF1-expressing tumors (hazard ratio = 0.479, 95% CI, 0.235 to 0.977; P = .043).
TTF1 expression defines a subgroup of patients with a favorable outcome and may be useful for prognostic stratification of patients with stage I lung adenocarcinoma.
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