Immunotherapy. 2012;4(2):201-212. © 2012 Future Medicine Ltd.
Last year, we celebrated the 100th anniversary of the first successful studies of allergen immunotherapy (AIT) performed on patients with hayfever. Whereas the subcutaneous route is still a reference, tolerance induction via alternative routes has raised considerable interest over the last three decades. Importantly, sublingual immunotherapy (SLIT) is the only approach established as a valid noninvasive alternative to the subcutaneous route for immunotherapy (SCIT).
Tolerance Induction by Parenteral Routes of Administration
SCIT has been shown to be effective in decreasing both immediate and delayed symptoms, as well as the consumption of medication in patients with type I allergies to insect venom, HDM, grass and tree pollens, molds or animal dander In other words, allergy “shots” as we know them do work! The application of SCIT is limited by several drawbacks, including the need for repeated injections over several years, and the risk of anaphylaxis, which is rare but potentially life-threatening.
Clinical Trials With Intralymphatic Allergen-specific Immunotherapy
Intralymphatic administration consists of the direct injection of the allergen into the lymph nodes. Yikes, this sounds painful and technically difficult. But wait….It was initially tested to enhance protective immunity against viruses and tumors using vaccines based on proteins, peptides, naked DNA or tumor cells. As a potential alternative to SCIT, intralymphatic allergen-specific immunotherapy (ILIT) is now being investigated in humans in order to shorten the immunization scheme with low doses of allergen extracts (with a 100–1000-fold reduction when compared with SCIT), while maintaining efficacy. Studies in clinical trials have provided interesting results since ILIT with a reduced number of allergen shots and doses demonstrates some efficacy (i.e., better tolerance to allergen challenge)
For instance, a comparative clinical trial conducted in 165 grass pollen-allergic patients has shown that ILIT is comparable to SCIT in terms of its efficacy, even when very low doses of allergens are used. In this study, patients were randomized to receive either SCIT with pollen extracts for over 3 years (with cumulative allergen doses corresponding to 4 million standardized quality units) or ILIT consisting of three intralymphatic injections for over 2 months (with corresponding cumulative allergen doses of 3000 standardized quality units). In this setting, ILIT improved hayfever symptoms, reduced skin prick test reactivity while enhancing patient quality-of-life and compliance. In terms of safety, ILIT exhibited only mild side effects in the form of local pain or inflammation. Could this be because the dose required is so much smaller than traditional SCIT?
Overall, ILIT has provided promising clinical results and, as such, represents an attractive new approach, potentially reducing treatment duration from years to weeks. However, additional developments are necessary, including the need to assess efficacy and to optimize treatment dose in large Phase III studies. In addition, the use of complex medical equipment associated with the training of skilled personnel may also hinder its broad use in humans. Would you let a nurse stick your lymph node like this?
Clinical Trials With Epicutaneous Allergen-specific Immunotherapy
Epicutaneous (skin application) allergen-specific immunotherapy (EPIT) is growing in interest, as it represents a safe, noninvasive and patient friendly treatment for IgE-mediated allergic diseases linked with either respiratory or food allergens. More than 50 years ago, pioneer studies demonstrated clinical efficacy following EPIT in grass pollen-allergic patients. However, the use of skin scarification (and you think a tatoo is bad!) was quite burdensome precluding its broad use in humans. Currently, novel approaches have been developed to increase the safety and efficacy of EPIT. In particular, a recent study by Senti et al. reports the results from a Phase I/II study documenting the safety and efficacy of EPIT in patients allergic to grass pollen allergens (i.e., Phleum pratense extract). Allergic symptoms were reduced in nasal provocation tests, even if the efficacy was not significantly higher in the active group when compared with the placebo. No serious adverse events were recorded except for local eczematous reactions, probably due to the tape-stripping of the skin before EPIT, which may induce the release of proinflammatory cytokines (i.e., IL-1, IL-6, IL-8 or TNF-α) by keratinocytes.
A new epicutaneous delivery systems (i.e., Viaskin®, DBV technology, Bagneux, France) is currently been tested in humans. It consists of a condensation chamber that allows the release of soluble allergens while hydrating layers of the epidermis. The evaluation of this delivery system in children allergic to cow’s milk in a pilot EPIT study confirmed that the treatment was well tolerated. However, neither clinical efficacy nor immunological changes (i.e., a decrease in cow’s milk-specific IgEs) were documented in this study.
Taken together, those studies suggest that the EPIT approach is safe and well tolerated, and paves the way for further investigations into its efficacy for the treatment of respiratory or food allergies in large cohorts of patients. Further developments should take into account the allergen dose, as well as the number and duration of allergen administrations.
Clinical Trials With Intranasal Allergen-specific Immunotherapy
Local nasal immunotherapy (LNIT) consists of spraying allergen extracts into the nasal cavity. It was first investigated at the end of the 1970s, with encouraging clinical data ( Table 2 ). LNIT is performed by the administration of natural biological or chemically-modified (allergoid, preventing IgE reactivity) allergen extracts in a soluble form. It demonstrates a significant reduction in both symptoms and medication needed in patients allergic to ragweed and grass pollens.[28–31] Adverse effects are mainly limited to the site of administration.[30,32] Subsequent intranasal vaccines based on allergen extracts in macronized powder forms (e.g., Parietaria, birch and grass) or on allergen-coated strips (e.g., mites) enhance clinical efficacy, while decreasing local adverse effects in allergic patients.[32–38] Long-lasting effects of LNIT induced by a 4-year treatment are noticed on nasal symptoms.[39,40] Recently, LNIT with rBet v 1 reduced nasal flow in birch pollen-allergic patients. Interestingly, the use of hypoallergenic rBet v 1 fragments had no effect on symptom scores, suggesting that the presence of IgE epitopes is mandatory in allergen-specific tolerance induction.
Altogether, LNIT appears to be of interest in the treatment of allergic rhinitis patients, since it is safe and efficient. However, better compliance is needed due to frequent nasal reactions. Also, it remains difficult to control the exact dose of allergen administered when using this route. DBPC Phase III studies are required to further document its safety and efficacy prior to a wide use in humans.
Clinical Trials With Oral Allergen-specific Immunotherapy
The use of oral allergen-specific immunotherapy (OIT) started 30 years ago, in patients with pollen-induced allergic rhinitis ( Table 2 ).[42–50] Although well tolerated, OIT with grass pollen extracts (low and high doses) as an aqueous solution, a powder or enterosoluble forms, is clinically and immunologically ineffective in adults.[42–45] Alternatively, OIT with high doses of aqueous extracts (i.e., Dermatophagoides pteronyssinus or Artemisia)[49,51] or using encapsulated allergens (i.e., birch or ragweed)[46–48,50] is shown to be safe and efficient in both adults and children.
Today, OIT is mainly applied as a treatment for adults and children with food allergies, including cow’s milk, egg, peanuts, tree nuts, wheat, soy, fish and shellfish allergies. Most children with cow’s milk and egg allergies generally outgrow their disease in the first 6 years of life, whereas peanut, tree nut, fish or shellfish allergies are permanent and the reactions are often more severe. Owing to the risk of adverse effects, OIT requires the administration of small amounts of allergen (from micrograms to milligrams) by the oral route in order to re-establish a long-lasting tolerance to dietary proteins. To monitor OIT efficacy, a food challenge is usually performed at the end of the study protocol. Many studies performed in children with allergies to egg or cow’s milk[54–57] showed clinical efficacy results, as well as a good safety profile. Also, long-lasting effects were observed for up to 4–5 years after the end of treatment. Nevertheless, some difficulties are faced in evaluating OIT efficacy in those studies since they often rely upon small cohorts of patients and have to take into account spontaneous recovery rates. Overcoming such limitations, a recent study that included children with a severe and lifelong allergy to cow’s milk (i.e., cow’s milk specific IgEs >85 kU/l) revealed a significant improvement in tolerated food allergen intake. Specifically, 36% of children became fully tolerant and 54% were able to drink limited amounts of cow’s milk. Interestingly, the control group maintained on a cow’s milk-free diet failed the food challenge after 1 year. In addition, Skripak et al. performed the first DBPC study of OIT that confirmed the safety and efficacy of OIT in cow’s milk allergy. Specifically, patients in the active group exhibited a significant increase in their tolerization threshold when compared with the placebo group, with a median cumulative dose of 5140 and 40 mg of allergen tolerated, respectively. Those observations were extended to peanut OIT, as demonstrated in a DBPC study providing evidence for a successful oral food challenge in the active group associated with reduced skin prick tests.
Altogether, OIT has shown encouraging clinical data, especially in patients with food allergies. However, many questions remain unaddressed, such as the risks linked with OIT compared with eviction, dose incrementation and patient selection, as well as low allergen/protein bioavailability to the gut due to gastric enzymatic degradation. Further studies with large patients groups are necessary in order to address these concerns and firmly establish the clinical efficacy of OIT in humans.
Clinical Trials With Sublingual Allergen-specific Immunotherapy
Allergen-specific SLIT was introduced in 1970 for respiratory allergies and shown to improve symptoms in allergic patients, although the optimal dose, the efficacy and associated mechanisms were not well documented until the early 2000s ( Table 2 ).[61–68] Today, many DBPC studies, as well as meta-analyses, have shown that SLIT is effective in decreasing both immediate- and late-phase symptoms, as well as the need for medication, in adult and pediatric patients with allergic rhinoconjunctivitis to either pollens (from common grasses, ragweed, Parietaria, birch, olive and Cupressus), HDM or cat dander.[63,69–76] SLIT consists into the administration of high doses of natural-allergen extracts (pollens, mites or animal dander) as drops or tablets under the tongue, prior to swallowing. Generally, SLIT is administered once-daily for a period of time (e.g., 1–3 years). An excellent safety profile is recorded in SLIT studies, with more than 2 billion doses administered to either adults or children.[63,69,77,78] Only moderate adverse events occur locally at the start of the treatment, including oral pruritus, throat irritation or tongue swelling, but severe systemic reactions are extremely rare.
To date, the pertinence of SLIT for tolerance induction in humans has been confirmed by multiple DBPC studies conducted in large cohorts of patients allergic to grass pollen.[3,5–10,79] Also, long-term clinical benefits of SLIT have been documented following a 3-year treatment with two different grass allergy immunotherapy tablets in adults with rhinitis, demonstrating clinical improvements sustained for at least 2 years after stopping the treatment (i.e., a ‘disease-modifying’ effect of SLIT).
Those observations are not restricted to grass pollen allergy. HDM sublingual tablets (with both D. pteronyssinus and Dermatophagoides farinae mite species) tested in 509 adult patients in a pivotal Phase IIb/III clinical trial, also induced a significant decrease in rhinitis symptoms, while demonstrating an excellent safety profile after only 1 year of treatment, with sustained clinical benefit during the second treatment-free year [Bergmann KC et al., Unpublished Data]. The efficacy and safety of SLIT using HDM extracts as a solution were also demonstrated in adult patients suffering from mild to moderate asthma in a Phase III, DBPC study (conducted in 484 adults), thus strengthening the pertinence of SLIT to promote allergen-specific tolerance in humans suffering from rhinitis to mild–moderate asthma [Bergmann KC et al., Unpublished Data]. Beyond respiratory diseases, encouraging preliminary data suggests that SLIT (and also SCIT) with HDM allergens may provide benefit to patients with atopic dermatitis, based upon severity symptom score (scoring atopic dermatitis) as well as the use of symptomatic medications.[80–82]
Collectively, these data compiled in a recent review show that SLIT efficacy is comparable to SCIT. However, one of the advantages of SLIT is that it is safer than SCIT, with a significantly lower risk of inducing systemic reactions. Noticeably, the use of SLIT is recommended in position papers by the World Allergy Organization (WAO) and by the Allergic Rhinitis and its Impact on Asthma (ARIA) group.[2,84]