SQ house dust mite (HDM) SLIT-tablet provides clinical improvement in HDM-induced allergic rhinitis

House dust mite (HDM) allergy represents a highly prevalent inhalant allergy, and exposure to HDM allergens results in allergic rhinitis with persistent symptoms that may not be adequately controlled with available allergy pharmacotherapy. Allergy immunotherapy constitutes a complementary treatment option targeting the underlying immunological mechanisms of allergic disease and represents the only treatment with a potential for disease modification and long-term efficacy. As traditional allergy immunotherapy delivered by subcutaneous injection of specific HDM allergens involves a time-consuming treatment regimen and a risk of systemic adverse reactions, sublingually administered allergy immunotherapy (SLIT) has been investigated as a more convenient treatment option with similar levels of efficacy and an improved safety profile that allows for at-home daily administration.

In this Drug Profile, we provide a review of the clinical data behind the SQ HDM SLIT-tablet, which was recently approved for the treatment of HDM-induced allergic rhinitis by regulatory authorities in Europe and Japan.     

300 IR HDM tablet: a sublingual immunotherapy tablet for the treatment of house dust mite-associated allergic rhinitis

Introduction: The once-daily 300 index of reactivity (IR) house dust mite (HDM) tablet (Actair®; Stallergenes Greer, Antony, France/Shionogi & Co. Ltd., Osaka, Japan) is the first sublingual immunotherapy (SLIT) tablet to be approved for the treatment of HDM-induced allergic rhinitis.

Areas covered: This drug profile reviews the current body of evidence on the efficacy, safety and tolerability of the 300 IR HDM tablet, its pharmacodynamics, and its role in clinical practice.

Expert commentary: Data from its clinical development program demonstrate favorable efficacy and safety in adults and adolescents with HDM-induced allergic rhinitis, irrespective of mono- or polysensitization status, or the presence of comorbid mild asthma. The 300 IR HDM tablet is effective from as early as 2 months after treatment initiation, providing allergic symptom control and a reduction in the need for symptomatic medication, while improving health-related quality of life. Clinical efficacy is maintained for 1 year after treatment is stopped.     

Biomarkers of immunotherapy response in patients with allergic rhinitis

Introduction: Allergen immunotherapy represents the only disease-modifying therapy available for immunoglobulin E-mediated diseases such as allergic rhinitis and asthma. Allergen immunotherapy induces allergen tolerance by interfering with the immune-pathogenic mechanisms of the allergic response and is potentially able to provide long-term relief of symptoms of allergic rhinitis and asthma and alter the natural course of allergic diseases.

Areas covered: Since allergen immunotherapy (AIT) is actually considered an individualized treatment on patient’s clinical and immunological profile, the identification of specific biomarkers, which may guide diagnosis, management, and predict response to AIT treatment in allergic rhinitis (AR) patients, is essential and is currently an active field of research.

Expert commentary: The identification and validation of biomarkers of successful AIT for AR is an urgent need to definitively establish the role of AIT as a therapeutic tool of personalized medicine.     

Allergen immunotherapy in allergic rhinitis: current use and future trends

Introduction: Type-1 allergies are among the most chronic common diseases of humans. Allergen immunotherapy (AIT) is the only causative and disease-modifying treatment option besides allergen avoidance. Severe systemic adverse allergic reactions may be induced by every AIT treatment. Different approaches have been used to provide safer AIT preparations to lower or even totally overcome this risk.

Areas covered: A structured literature recherche in Medline and Pubmed under inclusion of national and international guidelines and Cochrane meta-analyses has been performed aiming at reviewing clinical use of such approaches in AIT.

New allergen preparations may include allergoids, recombinant allergens (recA) and modified recombinant allergens (recA) in subcutaneous as well as in mucosal immunotherapies (application e.g. using bronchial, nasal, oral and sublingual application) with sublingual being the established mucosal application route and new ways of application like intralymphatic and epicutaneous immunotherapy.

Expert commentary: Immune-modifying agents like Virus-like particles and CpG-motifs, adjuvants like MPL and aluminum hydroxide are evaluated and found to increase and direct the immunological response toward immunological tolerance.

New forms of allergen extracts can improve safety and efficacy of AIT and may change our way of performing allergen immunotherapy in the future.     

New opportunities for allergen immunotherapy using synthetic peptide immuno-regulatory epitopes (SPIREs)

Introduction: Allergen immunotherapy (AIT) reduces allergic rhinoconjunctivitis (ARC) symptoms, but long-term efficacy requires treatment for 3–5 years. Synthetic peptide immuno-regulatory epitopes, a new class of AIT, are allergen peptides with a shorter, more convenient treatment regimen that could potentially have benefits on adherence and outcomes.

Areas covered: Phase 2 trials of therapies derived from cat, house dust mite, grass, and ragweed allergen peptides demonstrated significant reduction in ARC symptoms after short-course treatment; improvement was sustained for 18–24 months posttreatment. We conducted a PubMed literature search for clinical publications using the search terms AIT; allergen peptides; ARC; cat, grass, house dust mite, and ragweed allergy; SCIT; SLIT; and synthetic peptides.

Expert commentary: Long-term disease modification is a realistic goal of AIT. The inconvenience of conventional AIT regimens negatively impacts long-term persistence and, thus, efficacy. In comparison, SPIREs have a more convenient treatment regimen that could potentially have benefits on adherence and outcomes.     

Cancer vaccines in colon and rectal cancer over the last decade: lessons learned and future directions

Introduction: Great advances have been made in screening for and treatment of colorectal cancer (CRC), but recurrence rates remain high and additional therapies are needed. There is great excitement around the field of immunotherapy and many attempts have been made to bring immunotherapy to CRC through a cancer vaccine.

Areas covered: This is a detailed review of the last decade’s significant CRC vaccine trials.

Expert commentary: Monotherapy with a CRC vaccine is likely best suited for adjuvant therapy in disease free patients. Vaccine therapy elicits crucial tumor infiltrating lymphocytes, which are lacking in microsatellite-stable tumors, and therefore may be better suited for these patients. The combination of CRC vaccines with checkpoint inhibitors may unlock the potential of immunotherapy for a much broader range of patients. Future studies should focus on vaccine monotherapy in correctly selected patients and combination therapy in more advanced disease.     

Allergic rhinitis management: what’s next?

Introduction: Allergic rhinitis (AR) is characterized by the presence of congestion, postnasal drainage, sneezing and rhinorrhea. AR contributes to reduced productivity and significant morbidity worldwide.

Areas covered: We review data emphasizing that the most effective therapy to alter the course of AR is allergen-specific immunotherapy, either subcutaneous or sublingual. However, significant advancements in developing alternative forms of therapies have opened the door for potential novel avenues of treating patients with AR. We discuss novel therapies currently under investigation or recently approved, which may provide a more effective and safer treatment option.

Expert commentary: Novel therapies for this common disorder which causes significant impaired quality of life are under investigation and will hopefully lead to better therapeutic options.     

Real-life clinical practice and management of polysensitized patients with respiratory allergies: a large,global survey of clinicians prescribing allergen immunotherapy

Background: The allermix survey was conducted to gain insights into the most frequently diagnosed allergies worldwide, the use of allergen immunotherapy (AIT) in clinical practice, and to identify current clinical approaches for the management of polyallergic patients.

Methods: The survey was conducted in 19 countries worldwide during 2016. Clinicians currently prescribing AIT completed an online questionnaire, designed to gather data on their daily clinical practice, most commonly diagnosed and treated allergies among their patients, awareness and adherence to recommendations and guidelines on AIT, the AIT format(s) that they choose to prescribe, and management of polyallergic patients.

Results: Respondents (N = 1029) considered a clinical demonstration of safety and effectiveness, and quality and standardization of allergen extract, as key factors influencing their choice of which AIT formulation to prescribe. 98% of respondents reported managing polyallergic patients; 58% were treated with single-allergen AIT and 42% with multiple-allergen AIT. 74% of respondents were aware of latest AIT practice guidelines, while 67% had an awareness of recent recommendations for pharmaceutical manufacturers.

Conclusion: These findings highlight the need for high-quality AIT products that are supported by robust efficacy and safety data, and address the treatment habits of allergy specialists in their real-life clinical practice.     

Comparison of allergenic extracts from different origins: the value of the FDA’s bioequivalent allergy unit (BAU)

Introduction: Allergy immunotherapy (AIT) is the only disease-modifying intervention for the treatment of allergic diseases. The clinical effectiveness of AIT is clearly dose-dependent, so it is important that clinicians can assess and compare the potency of the various products available. However, this is not possible in practice, because manufacturers use different methods to determine potency. Therefore, a clear need exists for adoption of a ‘gold-standard’ measure of allergenicity. The bioequivalent allergy unit (BAU) is thus far the only allergen unit approved by a regulatory agency (the US Food and Drug Administration), with European regulatory authorities yet to adopt a common unit.

Areas covered: Using PubMed, we performed a review of the literature on measures of allergen extract potency, use of the BAU, and BAU assessment for grass pollen tablets.

Expert commentary: There is an obvious benefit to allergists and patients for having a single, comparable unit across products, and we strongly support the adoption of a single, ‘gold-standard’ unit of measurement for all products. Use of the BAU allows a clear comparison of the potency of allergen products from different manufacturers, and enables better understanding of the potential reasons for any differences in administration and dosing protocols between these products.     

Immunotherapy of cancers comes of age

Introduction: Cancer immunotherapy has evolved and is aimed at generating the efficacious therapeutic modality to enhance the specificity and power of the immune system to combat tumors.

Areas covered: Current efforts in cancer immunotherapy fall into three main approaches. One approach is through the blockade of immune checkpoints, another approach is through adoptive cellular therapy, and the last approach is through vaccination. The goal of this review is to summarize the current understanding and status of cancer immunotherapy in these three categories.

Expert commentary: We foresee the development of therapeutic protocols combining these approaches with each other or conventional therapies to achieve the most appropriate guideline for management of cancer.     

A general strategy for de novo immunotherapy design: the active treatment of food allergy

Introduction: IgE-mediated food allergy (FA) has been emerging as a public health priority. It is a potentially life-threatening condition with negative impact on the quality of life of patients and their family and its prevalence is increasing in westernized countries in the recent two decades. The current standard approach to FA consists of the strict avoidance of the triggering food. However, an elimination diet may be difficult and frustrating, above all for those foods (e.g. milk and egg) that are pivotal in the common diet. Oral immunotherapy (OIT) may increase the amount of food that the patient can intake without reaction and reduce the risk of potential life-threatening allergic reactions. It is currently considered the most promising treatment for FA. However, many gaps are still unsolved.

Areas covered: The aim of this review is to shed light on the current evidence and the main needs in OIT in order to stimulate the development of longitudinal, prospective, and well-designed studies with the final goal of a ‘precision medicine.’

Expert commentary: Clinical trials for OIT conducted so far are extremely heterogeneous. The aim in the near future is to identify the most suitable candidates to OIT and algorithms for treatments tailored on well-characterized subpopulations of patients.     

Venom immunotherapy in patients with allergic reactions to insect stings

Introduction: Allergy to Hymenoptera (Apis mellifera, Vespula species, Polistes species, Vespa crabro) venom can be safely and effectively treated by venom immunotherapy (VIT), which in the 40 years since its introduction has been able to prevent reactions to stings, and to treatment as well, though systemic reactions, occasionally severe, are possible.

Areas covered: We reviewed the recent literature on VIT by searching in PubMed for the terms ‘venom immunotherapy’ and ‘Hymenoptera venom immunotherapy’ to highlight the current status of VIT and the likely development in the coming years.

Expert commentary: VIT, provided the correct choice of the venom and adequate venom preparations and maintenance doses are used, is a treatment of great value in preventing systemic reactions to Hymenoptera stings. A 5-year duration ensures a prolonged tolerance to stings following VIT discontinuation, unless patients suffer from mastocytosis. In fact, due to reports of fatal reactions after stopping VIT, patients with mastocytosis, or with very severe reactions to stings, need an indefinite duration of treatment.     

High numbers of myeloid derived suppressor cells in peripheral blood and ascitic fluid of cirrhotic and HCC patients

Background: Hepatocellular carcinoma (HCC) is the 3rd most common cause of cancer-related death worldwide. It has evolved different immune escape mechanisms, which might include emergence of lymphoid and myeloid regulatory cells.

Aim of this work: To determine the numbers of Myeloid-derived suppressor cells (MDSCs) in peripheral blood and ascitic fluid in cirrhosis and HCC and their relation to IFN-γ and α-fetoprotein (α-FP).

Patients and methods: Sixty individuals were enrolled in this study; forty cirrhotic patients with ascites; twenty without HCC (Group I), and twenty with HCC (group II) as well as twenty healthy individuals as a control group (group III). The phenotype and numbers of MDSCs were analyzed in peripheral blood of all the individuals and ascitic fluid of the patients using flow cytometry. Intracellular IFN-γ and serum alfa-fetoprotein were measured.

Results: Significant increases in the relative and the mean number of peripheral blood MDSCs were found in the cirrhosis and HCC groups than in the control group, with the HCC group showing the highest number. MDSC count was negatively correlated with IFN-γ levels, while α-FP was positively correlated with MDSC% in the HCC group. MDSC count was low in ascitic fluid of both HCC and cirrhosis groups with no significant difference between the 2 groups.

Conclusion: A high frequency of MDSCs was detected in the peripheral blood of cirrhotic and HCC patients, indicating presence of immunosuppressive arms. These cells could be targeted to develop a new effective immunotherapy or an adjuvant to current therapies.     

Harpagoside-induced anaphylactic reaction in an IgE-independent manner both in vitro and in vivo

Background: Harpagoside (HAR) is an active component of Scrophularia ningpoensis (SN), which has anti-inflammatory and anti-immune effects. SN is used widely in China to treat various diseases. Recently, SN has been used as a traditional Chinese medicine injection and used clinically. However, allergic responses to these injections are frequently reported.

Aim: We examined whether the main component of SN, HAR, is associated with the allergic reaction to SN.

Methods: This study assessed the effects of HAR in mice and mast cell activation to characterize its anaphylactic effects and underlying mechanisms. Mice hindpaw swelling, serum allergy factor detection, enzyme-linked immunosorbent assays, and degranulation assays were performed to measure allergic mediators both in vivo and in vitro.

Results: The present study indicated that HAR induced paw swelling, interleukin-6, inositol triphosphate, tumor necrosis factor-α, and histamine increases in mice. Our in vitro data also showed that HAR induced β-hexosaminidase, inositol triphosphate, and interleukin-6 release, leading to mast cell degranulation. In contrast, neither C48/80 nor HAR induced local anaphylaxis in STOCK Kit^W-sh/HNihrJaeBsmJNju mice.

Conclusions: HAR is a potential sensitization compound in SN, and these results provide information for the safe clinical use of SN.     

Therapy implications of the role of interleukin-2 in cancer

Introduction: Despite its apparent failure in cancer therapy, IL-2 still remains fundamental in the activation of antitumor immunity.

Areas covered: The aim of this review is the reinterpretation of the role of IL-2 in anticancer immunity, according to knowledge gained of the cytokine network, by highlighting its importance in inducing T helper-1 (TH1) cell proliferation, natural killer (NK) actHivation and IL-12 secretion. However, its main negative effect is the stimulation of regulatory T cells (Tregs), which in contrast suppresses anticancer immunity.

Expert commentary: Cardiovascular toxicity, which was the main clinical problem at the beginning of IL-2 therapy at high intravenous doses, has almost been completely solved by subcutaneous low-dose IL-2 injection. In order to enhance the anticancer efficacy of IL-2, several strategies have been explored, including chemotherapy and interferon, but up until now no regimen has appeared to be clearly better than IL-2 alone. However, considering the role of immune checkpoints (PD-1 and CTLA-4) in Tregs stimulation, the most effective immunotherapy in the future could be concomitant IL-2 administration, to enhance lymphocyte count, and checkpoint inhibitors, such as anti-PD1 or anti-CTLA-4 monoclonal antibodies, or IL-12, which is also able to counteract IL-2-induced Treg cell generation. Therefore, the time for IL-2 immunotherapy in cancer treatment has finally arrived.     

Blockade of CCR5-mediated myeloid derived suppressor cell accumulation enhances anti-PD1 efficacy in gastric cancer

Purpose: Myeloid derived suppressor cells (MDSC) play an important role in tumor immune evasion and its level significantly increased in patients with gastric cancer. Studies confirmed the associations between MDSC and various cytokines in the peripheral blood. However, little is known about the mechanism drawing MDSC into tumor parenchyma. This study was to analyze the correlation between MDSC subsets and CCR5 level in gastric cancer.

Materials and methods: G-MDSC and M-MDSC from the peripheral blood and tumor parenchyma were analyzed by flow cytometry. CCR5 ligand CCL5 was detected by ELISA. CCR5 was detected by real-time PCR, western blot and flow cytometry. Furthermore, the therapeutic effects of CCR5 blockade was assessed by the tumor model.

Results: CCR5 ligand, gene and protein expression of CCR5, and surface expression of CCR5 significantly increased in blood and tumor of tumor-bearing mice, suggesting MDSC may be attracted into the parenchyma by CCL5/CCR5. Anti-CCR5 treatment decreased G-MDSC and M-MDSC in the periphery and tumor. In addition, combination treatment enhanced CD4+ and CD8+ T cell infiltration and decreased the tumor burden of tumor-bearing mice.

Conclusions: This study elucidated a possible association between MDSC subsets and CCR5, in addition to provide a new potential target to enhance the efficacy of immunotherapy in patients with gastric cancer.     

Clinical use of adjuvants in allergen-immunotherapy

Introduction: Allergen-specific Immunotherapy (AIT) is the only available treatment aimed to tackle the underlying causes of allergy. The active components of subcutaneous vaccines traditionally consist of natural or modified allergen extracts which can be combined with adjuvant platforms. In recent years new targets have been further developed in an attempt to raise the safety and efficacy profile of AIT.

Areas covered: In this review, we discuss the desirable attributes of adjuvants and delivery systems from empiricism to rational design, for current and future clinical applications in AIT.

Expert commentary: The introduction of novel adjuvants, in combination with active targets, has been demonstrated to reduce symptoms of AIT, increase clinical efficacy of allergy treatment and reduce the number of doses. The evolution of vaccine development for AIT is entering a phase of scientific progress that challenges dogmas. Over the past century the traditional concept of immunotherapy, entailing long-course administration of native extract preparations and first generation adjuvants, has seen evolution in the past decade from proof-of-concept to clinical development pipelines encompassing the advent of second generation adjuvants and delivery systems forming essential components of modern AIT development.     

Allergen immunotherapy in atopic dermatitis

Introduction: Atopic dermatitis (AD) is a chronic relapsing skin disease, characterized by flare-up due to the exposure to allergens in patients sensitized to them. Currently, therapy of AD is mainly based on symptomatic treatment and avoidance of irritating/allergenic factors, house dust mites being particularly important. Allergen immunotherapy (AIT) is suggested to be the only etiologic treatment, to modify the natural history of the disease.

Areas covered: The aim of this review is investigating the putative role of AIT in AD through the evaluation of the most recent scientific literature. Several studies have been conducted since 1970, with promising results in improving the clinical outcome of AD, but they often lack the necessary scientific rigorousness. Moreover, heterogeneity of the studies makes it very difficult to compare and to analyze data in a systematic review or meta-analysis.

Expert commentary: As a result of the above-mentioned limitations, the treatment of AD with causative aeroallergen can nowadays be suggested only as an add-on therapy in selected patients who are non-responsive to the traditional therapy.     

New biologics for allergic diseases

Introduction: Allergic conditions such as asthma and atopic dermatitis have a high prevalence but represent a heterogeneous group of diseases despite similar clinical presentation and underlying pathophysiology. A better understanding of the phenotypes and endotypes of these diseases has driven rapid development of biologic medications targeting many steps of the inflammatory pathways.

Areas covered: There are 2 major inflammatory pathways that drive allergic diseases: Type-2 (Th-2) inflammation and non-type 2 inflammation. All of the biologic medications currently approved for use, and most of the biologic medications under development for allergic diseases have focused on the Th-2 inflammatory pathway. Biologic targets along this pathway include Anti-Immunoglobulin E (IgE), Anti-Interleukin 5 (IL-5), Anti-IL 4, and Anti-IL 13. Although the most study has been done in the realm of severe asthma, biologic targets for other allergic diseases including atopic dermatitis, chronic rhinosinusitis with nasal polyposis, chronic idiopathic urticaria, eosinophilic esophagitis, and eosinophilic granulomatosis with polyangiitis are also discussed.

Expert commentary: Novel biologic therapies have emerged over the last several years that have revolutionized the management of patients with refractory allergic disease.