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20th August 2021
Allergic rhinitis is characterised by several symptoms including sneezing, itching, nasal congestion and rhinorrhoea. It can be categorised as either seasonal allergic rhinitis, in which symptoms are evoked in response to season triggers such as pollen or perennial allergic rhinitis, where symptoms are continually present. Seasonal allergic rhinitis is a global health problem and has been reported to affect 15 to 25% of adults and children. Moreover, while localised symptoms are problematic for patients, the condition also has a more generalised effect upon sufferers leading to fatigue, mood changes and reduced cognitive function which can affect work and overall quality of life. Treatment involves the use of oral and intranasal antihistamines as well as intranasal corticosteroids. However, when such treatments fail to provide symptomatic relief, subcutaneous or sublingual allergen immunotherapy can be used with subcutaneous therapy appearing to be more effective. In fact, a recent review found that the benefits of allergen immunotherapy were sustained for at least 2 – 3 years after cessation of treatment.
The role of interleukins (IL) in the pathophysiology of seasonal allergic rhinitis is uncertain although some evidence observed a trend towards higher levels of both IL-4 and IL-13. The monoclonal antibody dupilumab targets the IL-4 and IL-13 receptor and been recently shown to improve asthma and perennial allergic rhinitis symptoms. This led a team from the Department of Medicine and Paediatrics, David Geffen School of Medicine, California, US, to examine whether addition of dupilumab to subcutaneous immunotherapy would provide an additional benefit to patients with seasonal allergic rhinitis. They undertook a phase 2a, randomised trial with four arms, comparing subcutaneous immunotherapy (SCIT) either alone or combined with dupilumab verses placebo in patients with seasonal allergic rhinitis. The study involved a 12-week screening period, a 16-week treatment phase and an 8-week post-treatment follow-up in adult patients (aged 18 years and over but less than 55 years) with seasonal grass pollen allergy. The four treatment arms were: SCIT + placebo; SCIT + dupilumab 300mg every 2 weeks; Dupilumab alone; SCIT alone. The primary outcome as the percentage change from pre-baseline in the area under the curve for peak total nasal symptom score (TNSS), a composite of rhinorrhoea, nasal congestion, nasal itching, and sneezing and measured 0 – 1 hour following a nasal allergen challenge.
A total of 103 patients were enrolled and randomised to one of the four arms. The mean age of participants assigned to SCIT and dupilumab was 33 years (30.8% male) and the mean age across the study ranged from 33 to 40.3 years. At week 17 and following a nasal allergen challenge, there was no difference between SCIT and SCIT + dupilumab (least squares mean – 56.76% vs 52.03%). Similarly, there was no significant difference in the absolute change in TNSS scores. There was however, a slight, but significant improvement in the peak TNSS scores when dupilumab was added to SCIT (p = 0.026), suggesting that addition of the drug may help improve SCIT tolerability. The authors concluded that there was no benefit from adding dupilumab to SCIT in terms of reducing the response to an allergen challenge.
Corren J et al. Short-term subcutaneous allergy immunotherapy and dupilumab are well tolerated in allergic rhinitis: a randomised trial. J Asthma Allergy 2021
18th August 2021
The treatment of cancer has traditionally involved surgery, chemotherapy or radiotherapy although in recent years, there has been increased interest in immunotherapy which makes use of the patient’s immune system to fight cancer. One form of immunotherapy is Chimeric Antigen Receptor (CAR) T-cell therapy which involves genetic modification of a patient’s T cells to express a specific tumour antigen. After modification, these modified T cells are infused back into a patient, attacking and destroying chemotherapy-resistant cancer. However, a major limitation to the use of CAR-T cells is that the tumour antigen can also be expressed by normal, healthy tissue and the modified T cells are unable to differentiate between malignant and benign cells. It is therefore not always easy to identify a specific antigen that is preferentially expressed on tumour cells. This led a team from the Department of Bioengineering, University of California, US, to create inducible cells that were engineered to express the surface protein but only in response to short-pulsed, focused ultrasound stimulation.
The team subcutaneously injected the specific CAR-T cells at the site of a tumour in mice, followed by three 5-minute pulses of focused ultrasound at 43 degrees centigrade. This resulted in a significant reduction in tumour size. To ensure that it was specifically the combination of the CAR-T cells and focused ultrasound that were shrinking the tumour, the team used two control groups of mice with tumours. In one group, the pulsed ultrasound was used in the absence of the specific CAR-T cells injected and this had no impact on tumour growth. The second group of mice also received the ultrasound but this time, but this time in the presence of naïve T cells, as opposed to the CAR-T cells and again, there was no effect on tumour growth. Finally, the researchers examined whether localised, pulsed ultrasound was effective using mice with both a local and distal tumour. Injection of standard CAR-T cells reduced the size of both the local and distal tumour. However, after injection of the CAR-T cells and directing the ultrasound only at the local tumour, there was a dramatic reduction in size of the local, but not distal tumour.
Discussing their findings, the authors noted the use of the targeted pulsed ultrasound was a potentially effective approach to the treatment of localised tumours. They added the local administration of the CAR-T cells has already been tested in animals and patients and a further advantage of their technique was the potential for a reduction in off-target activity, i.e., where the CAR-T cells affected healthy tissue.
While this novel approach appeared to be effective, further work is required to ensure that the method represents a much safer form of cell therapy.
Wu Y et al. Control of the activity of CAR-T cells within tumours via focused ultrasound. Nat Biomed Eng 2021
28th June 2021
The European Alliance of Associations for Rheumatology (EULAR) is the organisation that represents the people with arthritis/rheumatism, health professions in rheumatology and scientific societies of rheumatology of all the European nations. With immune mechanisms clearly involved in the evolution of more severe COVID-19, there is a potentially important role for immunotherapy in those infected with the virus. As a result, EULAR convened a task force to develop overarching principles (OPs) and points to consider (PtC) on the pathophysiology of COVID-19 from a rheumatological perspective through a systematic review of the available evidence. The task force included 24 members from 8 different countries and comprised rheumatologists, translational immunologists, haematologists, paediatric rheumatologists and a patient representative. Based on the evidence from the literature, a series of statements were prepared and circulated to members, discussed and voted on. Initially EULAR sought at least 75% agreement on statement wording from members but where this did not occur, refinements were made and the revised statement re-circulated and the accepted level of acceptance was set at 67% for this second round.
The task force defined two overarching principles. The first was that the phenotype of COVID-19 infection is heterogenous and ranged from asymptomatic to lethal disease as a result of multi-organ failure. The second highlighted the need for different treatment approaches to manage an infection and that these were required at different stages of the disease.
The task force also approved 14 PtC, with a view to offering guidance on the management COVID-19 with immunotherapy. Six of the PtC covered aspects of the pathophysiology of COVID-19 with the remainder discussing the use of immunotherapy. For example, it was recognised that while cellular and humoral immune responses to COVID-19 were highly variable in patients, there was insufficient evidence to associate these differing responses directly with patient outcomes. The first PtC for immunotherapy noted the absence of evidence supporting a role for this treatment modality among non-hospitalised patients, or for the value of initiating such treatment. In contrast, given the evidence on oral corticosteroids, there was a recommendation to use these drugs (in particular dexamethasone and which has the strongest evidence), in patients receiving supplemental oxygen, non-invasive or mechanical ventilation. While the evidence base continued to change rapidly, another PtC was that it was still inappropriate to offer a formal recommendation for the routine use of tocilizumab in hospitalised COVID-19 patients requiring either supplemental oxygen, non-invasive or mechanical ventilation. The final PtC was that there was a lack of evidence to recommend the use of immunomodulators including convalescent plasma, interferon kappa, interferon beta, lenzilumab, cyclosporin or canakinumab.
An important caveat with the EULAR document is that it is not intended to undermine or override local regulations or guidelines produced by bodies such as the World Health Organization. Rather the purpose is to provide recommendations of good practice to help clinicians analyse their own therapeutic strategy and inspire change were appropriate. The authors concluded that given how knowledge around COVID-19 changes quickly, these PtCs will be updated as and when appropriate.
Aluno A et al. EULAR points to consider on pathophysiology and use of immunomodulatory therapies in COVID-19. Ann Rheum Dis 2021; 80(6): 698-706