Current Trends in Allergy Immunotherapy

Pharm-Olam is an allergy focused CRO and have worked on over 35 allergy clinical trials. In this article, we explore the area of Allergy Immunotherapy, or AIT, and discuss the different types of AIT and current trends seen in this modality of treatment.

What is Allergy Immunotherapy?

Allergy Immunotherapy, or AIT, is a modern, beneficial and cost-effective treatment approach for many people who suffer from allergic conditions. AIT via the subcutaneous and sublingual routes is highly effective in IgE-mediated disease in patients with a limited spectrum (1 or 2) of allergies. Allergen immunotherapy has been shown to be effective in the treatment of stinging-insect hypersensitivity, allergic rhinitis or conjunctivitis due to the seasonal pollinosis. From a long-term perspective, AIT is considered to be significantly more cost effective in allergic rhinitis and allergic asthma than pharmacotherapy-based treatments. Allergy Immunotherapy is also helpful for those patients who do not respond well to standard drug therapy.

However, AIT is not one type of treatment; it is a therapeutic area. The term may be used to refer to several types of allergy immunotherapy.

Allergen Immunotherapy (AIT)

Traditional allergen immunotherapy (AIT) is sometimes called allergy vaccines. They involve the administration of gradually increasing quantities of specific allergens to patients with IgE-mediated conditions until a dose is reached that is effective in reducing disease severity from natural exposure.

Subcutaneous Injection Immunotherapy (SCIT)

Subcutaneous injection immunotherapy (SCIT) uses high-dose standardized vaccines. In general, these treatments contain 5-20 mcg of the major allergen. SCIT are delivered in monthly maintenance injections. Unlike antiallergic medication, allergen immunotherapy has the potential of altering the allergic disease course after three to five years of therapy.

Sub-lingual Allergy Immunotherapy (SLIT)

Sub-lingual allergy immunotherapy (SLIT) treatment engages special, tolerance-promoting immune cells in sublingual space, also called oral Langerhans cells. There are two forms of SLIT treatment available – liquid antigen (drops) and tablets. The SLIT tablets currently available each contain only a single dose of one environmental allergen. This can be inconvenient and expensive for those with multiple allergies. Additionally, many environmental allergens are not available in tablet form. For example, no food allergens are available in tablet form. The liquid antigen form – sometimes called “SLIT allergy drops” – is much more flexible. This option can treat for one or multiple allergens at once, can be adjusted to an extremely large spectrum of doses to fit specific needs over time and increase its safety, and can be used for both environmental and food allergens.

Allergy Immunotherapy Goals

Allergen immunotherapy is meant to develop a marked increase in “blocking” IgG antibodies and to facilitate the blunting of seasonal increases in allergen specific IgE concentrations. There is inhibition of the recruitment and activation of effector cells including mast cells, eosinophils, and basophils in the allergic respiratory mucosa of the nose and bronchi. Both sublingual and subcutaneous immunotherapy have been shown to inhibit seasonal activation of blood basophils and innate lymphoid cells (ILC2s) during the pollen season.

The long-term goals of allergy immunotherapy can be summarized as the following:

Considerations in Allergy Immunotherapy

Allergen immunotherapy has a good safety profile, but the potential for an adverse reaction is always present. Although severe, potentially life-threatening systemic reactions during AIT are possible, these events are very rare when safety protocols are followed. Most adverse events are mild to moderate and can be treated well.

In AIT, the presence of asthma and /or polysensitization does not compromise the efficacy in subjects with whom it is possible to select for immunotherapy a ‘dominant’ allergen that is responsible for symptoms. Evidence supports the view that allergy immunotherapy may prevent progression of rhinitis to asthma in children – but the therapeutic strategy is not appropriate in all cases. Allergen immunotherapy is not very effective in the treatment of atopic dermatitis, urticaria, or headaches and might be dangerous if used for antibiotic allergies. Food allergy is still under investigation and discussion.

Dose-dependent adverse local reactions occur frequently in the mouth and throat in SLIT. Because of this, SCIT injections and the initiation of SLIT should only be performed by a physician experienced in this type of treatment and who is able to administer emergency treatment in the case of an allergic reaction.

Systemic reactions have been described in SLIT, but they are seen far less often than with SCIT. In terms of anaphylaxis and other severe systemic reactions, SLIT has a better safety profile than SCIT. The risk and effects of adverse systemic reactions in the setting of AIT can be effectively reduced by training of personnel, adhering to safety standards and prompt use of emergency measures, including early administration of epinephrine.

Individual formulations enable the prescription of rare allergen sources (pollen from ash, mugwort or ambrosia, mold Alternaria, animal allergens) for specific immunotherapy. Mixing these allergens with TAV allergens is not permitted.

Clinical Success in Allergy Immunotherapy

Strong evidence of the efficacy of SCIT in pollen allergy-induced allergic rhino conjunctivitis in adulthood is well-documented in numerous trials. Its success in childhood and adolescence is also evidenced in a few trials. For example, efficacy in using AIT to mitigate a house dust mite allergy is documented by a number of controlled trials in adults and few controlled trials in children. Only a few controlled trials, independent of age, are available for mold allergy (in particular Alternaria). With regard to animal dander allergies (primarily to cat allergens), only small studies, some with methodological deficiencies are available. So far, only a moderate and inconsistent therapeutic effect in atopic dermatitis has been observed in the quite heterogeneous studies conducted to date.

The efficacy of SLIT in grass pollen-induced allergic rhino conjunctivitis is extensively documented in adults and children, whilst its efficacy in tree pollen allergy has only been shown in adults. Compared with allergic rhino conjunctivitis, there are only few studies on the efficacy of SLIT in allergic asthma. In this context, newer studies show an efficacy for SLIT on asthma symptoms in the subgroup of grass pollen-allergic children, adolescents, and adults with asthma and efficacy in primary house dust mite allergy-induced asthma in adolescents aged from 14 years and in adults.

Aspects of secondary prevention, in particular the reduction of new sensitizations and reduced asthma risk, are important rationales for choosing to initiate treatment early in childhood and adolescence. Research has shown that both SCIT and SLIT can modify the course of allergic disease by reducing the risk of new allergic sensitizations and inhibiting the development of clinical asthma in children treated for allergic rhinitis. However, products for SCIT or SLIT cannot be compared at present due to their heterogeneous composition, nor can allergen concentrations given by different manufacturers be compared meaningfully due to the varying methods used to measure their active ingredients.

Non-modified allergens are used for SCIT in the form of aqueous or physically absorbed (depot) extracts, as well as chemically-modified allergens (allergoids) as depot extracts. Allergen extracts for SLIT are used in the form of aqueous solutions or tablets. The clinical efficacy of AIT is measured using various scores as primary and secondary study endpoints.

The Future of Allergy Immunotherapy Research

Allergy Immunotherapy is a promising area of research. Its ability to treat and prevent the development of certain allergies is exciting and unparalleled in terms of treatment options. However, this area of medicine is still in its infancy. Further studies are necessary to establish clinical efficacy for the different allergens. Going forward, it is important that AIT is measured using the same scores for primary and secondary study endpoints.

Sources

1. Frew AJ¹.J Allergy Clin Immunol. 2010 Feb;125(2 Suppl 2):S306-13. doi: 10.1016/j.jaci.2009.10.064.
2. Pfaar O¹, Bachert C², Bufe A³, Buhl R⁴, Ebner C⁵, Eng P⁶, Friedrichs F⁷, Fuchs T⁸, Hamelmann E⁹, Hartwig-Bade D¹⁰, Hering T¹¹, Huttegger I¹², Jung K¹³, Klimek L¹⁴, Kopp MV¹⁵, Merk H¹⁶, Rabe U¹⁷, Saloga J¹⁸, Schmid-Grendelmeier P¹⁹, Schuster A²⁰, Schwerk N²¹, Sitter H²², Umpfenbach U²³, Wedi B²⁴, Wöhrl S²⁵, Worm M²⁶, Kleine-Tebbe J27, Kaul S²⁸, Schwalfenberg A²⁹. Guideline on allergen-specific immunotherapy in IgE-mediated allergic diseases: S2k Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the Society for Pediatric Allergy and Environmental Medicine (GPA), the Medical Association of German Allergologists (AeDA), the Austrian Society for Allergy and Immunology (ÖGAI), the Swiss Society for Allergy and Immunology (SGAI), the German Society of Dermatology (DDG), the German Society of Oto- Rhino-Laryngology, Head and Neck Surgery (DGHNO-KHC), the German Society of Pediatrics and Adolescent Medicine (DGKJ), the Society for Pediatric Pneumology (GPP), the German Respiratory Society (DGP), the German Association of ENT Surgeons (BV-HNO), the Professional Federation of Paediatricians and Youth Doctors (BVKJ), the Federal Association of Pulmonologists (BDP) and the German Dermatologists Association (BVDD). Allergo J Int. 2014;23(8):282-319. https://www.ncbi.nlm.nih.gov/pubmed/26120539
3. JENNIFER L. HUGGINS, M.D., and R. JOHN LOONEY, M.D., University of Rochester School of Medicine and Dentistry, Rochester, New York. Am Fam Physician. 2004 Aug 15;70(4):689-696. https://www.aafp.org/afp/2004/0815/p689.html
4. G. Walter Canonica, Stephen R. Durham. Allergen Immunotherapy for allergic rhinitis and asthma: A Synopsis. https://www.worldallergy.org/education-and-programs/education/allergic-disease-resource-center/professionals/allergen-immunotherapy-a-synopsis