Epicutaneous immunotherapy may transform allergy treatment

July 19, 2017

As an allergy sufferer myself, I tend to pore over the journals and literature to learn what new exciting technologies may be on the horizon. When I came across epicutaneous immunotherapy (EPIT), my mind went in a multitude of different directions about the endless possibilities for both systemic and ocular allergy management.

 

As an allergy sufferer myself, I tend to pore over the journals and literature to learn what new exciting technologies may be on the horizon. My understanding and grasp of content can have limitations. Nevertheless, that does not hinder my thirst to take a deep dive into these new technologies. When I came across epicutaneous immunotherapy (EPIT), my mind went in a multitude of different directions about the endless possibilities for both systemic and ocular allergy management.

Previous treatments

Before breaking down new technology, it is always a good idea to take a step back and look at the previous methodology.

Previously from Dr. Cooper: How to combat vernal keratoconjunctivitis

Prior to EPIT, allergen-specific immunotherapy (SIT), subcutaneous immunotherapy (SCIT), and sublingual immunotherapy (SLIT) responses are mediated by a level of immune deviation of Th2 to Th1 by increasing the number of regulatory T cells.1–3 With less immune reactivity and tolerance to an allergen, the literature suggests this translates to less IgE and IgG4 concentration.3–6

These delivery systems can be effective, but they do have drawbacks. SCIT or “allergy shots,” developed over a century ago by Leonard Moon, features two disadvantages: it is time consuming with a need for 30 to 70 medical visits, and it causes localized and systemic side effects due to exposure to the bloodstream.7–10

Related: How to improve diagnosis and treatment of allergy

Sublingual therapy has ameliorated some of these concerns through targeted allergen therapy into the dendritic cells of the nasal mucosa by a multi-layered epithelium.11,12 Normally, allowing an allergen to diffuse in the deeper layers including the mast cells would stimulate local oral side effects; however, by avoiding direct penetration into the blood vasculature by injection these effects can be diminished or eliminated.11,12

 

EPIT was shown to be successful in 1921 by by placing the allergen onto scarified skin, resulting in decreased allergy symptoms in patients allergic to horses. A rebirth began when French company DBV-Technologies went back to the engineering table to facilitate a novel process called “electrospray” to deliver a thin layer of specific proteins via intact skin on a patch.14 Currently, the FDA has given DBV’s product Viaskin a fast-track designation for peanuts and milk.15,16

Related: An allergist talks allergy

How EPIT works

EPIT is similar to SLIT in that the allergen is delivered initially to a non-vascularized tissue, but it differs by decreasing the allergen-specific Th2 response with a sharper decrease of IL-4, IL-5, IL-10, and IL-13, a trend of increasing TGF-𝛽, and a potential dramatic decrease of eosinophils along with IgE expression.17

Keratinocytes can additionally be activated by physical irritation such as abrading, adhesive tape stripping, or adding adjuvants by hyperhydration against the skin. Subsequent epithelial damage increases keratinocyte expression of additional molecules such as IL-1α, IL-6 and TNF-α, skewing the immune response toward a Th1-type response.18 Of importance is that such instigation of keratinocytes can create a pro-inflammatory environment with enhanced activation of Langerhans cells.

Viaskin has the potential not only to reduce side effects by minimizing allergen penetration to the vasculature but also to shorten treatment duration by increasing immunogenicity of the administered allergen formulation. Furthermore, the electrospray process that set the electrically charged proteins on the patch in dry form becomes rehydrated when the patch’s condensation chamber allows the antigen to disseminate into the upper layers of the epidermis, namely the stratum corneum.19

Murine and human models illustrates that while the technology is far from perfect, it is a step in the appropriate direction for treating children to adolescents suffering from peanut and milk allergies.20,21

Related: Connecting allergy and osmolarity

Viaskin Peanut’s Efficacy and Safety (VIPES) and Open Label Follow-Up Study (OLFUS-VIPES) Phase IIB studies show that the efficacy improved from 50 to 70 percent in the first year with an augmentation of these results at 80 percent over a two-year period.22,23 After 24 months, a median 40 percent decrease from the VIPES baseline value in peanut-specific IgE was observed, while the high median levels in IgG4 were maintained at an 800 percent increase from the VIPES baseline, demonstrating the potential for longitudinal success in managing the condition.23

 

Looking ahead

The EPIT delivery platform has the potential to transform the delivery of childhood vaccinations and allergy shots, but the obvious question is how does this technology relate to eye care?

The gut reaction most of us have would be to say contact lenses or the Helios ring (Allergan) as a repository for the allergen’s dispersion. The broader picture is enhanced molecular profiling to engage which allergen(s) need to be targeted for treatment.

Modifying gene expression in a more exacting fashion across all ages could potentially lead to less tachyphylaxis with a side benefit of improving safety and decreased healthcare consumption costs.

Related: Differentiating ocular allergy

 

References

1. Bohle B, Kinaciyan T, Gerstmayr M, Radakovics A, Jahn-Schmid B, Ebner C. Sublingual immunotherapy induces IL-10-producing T regulatory cells, allergen-specific T-cell tolerance, and immune deviation. J Allergy Clin Immunol. 2007 Sep;120(3):707–13.

2. Jutel M, Akdis M, Budak F, Aebischer-Casaulta C, Wrzyszcz M, Blaser K, Akdis CA. IL-10 and TGF-beta cooperate in the regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy. Eur J Immunol. 2003 May;33(5):1205–14.

3. Scadding GW, Shamji MH, Jacobson MR, Lee DI, Wilson D, Lima MT, Pitkin L, Pilette C, Nouri-Aria K, Durham SR. Sublingual grass pollen immunotherapy is associated with increases in sublingual Foxp3-expressing cells and elevated allergen-specific immunoglobulin G4, immunoglobulin A and serum inhibitory activity for immunoglobulin E-facilitated allergen binding to B cells. Clin Exp Allergy. 2010 Apr;40(4):598–606.

4. Shamji MH, Durham SR. Mechanisms of immunotherapy to aeroallergens. Clin Exp Allergy. 2011 Sep;41(9):1235–46.

5. Ebner C, Siemann U, Bohle B, Willheim M, Wiedermann U, Schenk S, Klotz F, Ebner H, Kraft D, Scheiner O. Immunological changes during specific immunotherapy of grass pollen allergy: reduced lymphoproliferative responses to allergen and shift from TH2 to TH1 in T-cell clones specific for Phl p 1, a major grass pollen allergen. Clin Exp Allergy. 1997 Sep;27(9):1007–15.

6. O'Brien RM, Byron KA, Varigos GA, Thomas WR. House dust mite immunotherapy results in a decrease in Der p 2-specific IFN-gamma and IL-4 expression by circulating T lymphocytes. Clin Exp Allergy. 1997;27(1):46–51.

7. Noon L. Prophylactic inoculation against hay fever. Ann Allergy. 1960 Mar;18:287-291.

8. Cox L, Calderon MA. Subcutaneous specific immunotherapy for seasonal allergic rhinitis: a review of treatment practices in the US and Europe. Curr Med Res Opin. 2010 Dec;26(12):2723–2733.

9. Cox L, Nelson H, Lockey R, Calabria C, Chacko T, Finegold I, Nelson M, Weber R, Bernstein DI, Blessing-Moore J, Khan DA, Lang DM, Nicklas RA, Oppenheimer J, Portnoy JM, Randolph C, Schuller DE, Spector SL, Tilles S, Wallace D. Allergen immunotherapy: a practice parameter third update. J Allergy Clin Immunol. 2011 Jan;127(1 Suppl):S1–S55.

10. Bousquet J, Lockey R, Malling HJ. Allergen immunotherapy: therapeutic vaccines for allergic diseases. A WHO position paper. J Allergy Clin Immunol. 1998 Oct;102(4 Pt 1):558–562.

11. Cox LS, Larenas Linnemann D, Nolte H, Weldon D, Finegold I, Nelson HS. Sublingual immunotherapy: a comprehensive review. J Allergy Clin Immunol. 2006 May;117(5):1021–1035.

12. Canonica GW, Bousquet J, Casale T, Lockey RF, Baena-Cagnani CE, Pawankar R, Potter PC, Bousquet PJ, Cox LS, Durham SR, Nelson HS, Passalacqua G, Ryan DP, Brozek JL, Compalati E, Dahl R, Delgado L, van Wijk RG, Gower RG, Ledford DK, Filho NR, Valovirta EJ, Yusuf OM, Zuberbier T, Akhanda W, Almarales RC, Ansotegui I, Bonifazi F, Ceuppens J, Chivato T, Dimova D, Dumitrascu D, Fontana L, Katelaris CH, Kaulsay R, Kuna P, Larenas-Linnemann D, Manoussakis M, Nekam K, Nunes C, O'Hehir R, Olaguibel JM, Onder NB, Park JW, Priftanji A, Puy R, Sarmiento L, Scadding G, Schmid-Grendelmeier P, Seberova E, Sepiashvili R, Solé D, Togias A, Tomino C, Toskala E, Van Beever H, Vieths S. Sub-lingual immunotherapy: World Allergy Organization Position Paper 2009. Allergy. 2009;64(Suppl 91):1–59.

13. Vallery-Radot P, Hangenau J. Asthme d’origine équine. Essai de désensibilisation par des cutiréactions répétées. Bull Soc Méd Hôp Paris. 1921;45:1251–1260.

14. DBV Technologies. Electrospray Technology. Available at: https://www.dbv-technologies.com/en/viaskin-technology/electrospray. Accessed 6/28/17.

15. DBV Technologies. DBV Technologies Receives FDA Fast Track Designation for Viaskin Milk for the Treatment of Cow’s Milk Protein Allergy. 2016 Sept. Available at: https://www.dbv-technologies.com/en/investor-relations/regulated-information/3627,FDA-Fast-Track-Designation-for-Viaskin-Milk. Accessed 6/28/17.

16. DBV Technologies. DBV Technologies Receives FDA Breakthrough Therapy Designation for Viaskin Peanut for the Treatment of Peanut Allergy in Children. 2015 Apr. Available at: https://www.dbv-technologies.com/ressources/_pdf/2/1875,PR-Viaskin-Peanut-Breakthrough-desi.pdf. Accessed 6/28/17.

17. Swamy M, Jamora C, Havran W, Hayday A. Epithelial decision makers: in search of the ‘epimmunome’. Nat Immunol. 2010 Aug;11(8):656–665.

18. von Moos S, Johansen P, Waeckerle-Men Y, Mohanan D, Senti G, Häffner A, Kündig TM. The contact sensitizer diphenylcyclopropenone has adjuvant properties in mice and potential application in epicutaneous immunotherapy. Allergy. 2012 May;67(5):638–646.

19. DBV Technologies. Viaskin patch. Available at: https://www.dbv-technologies.com/en/viaskin-technology/viaskin-patch. Accessed 6/28/17.

20. Senti G, vonMoos S, Tay F, Graf N, Johansen P, Kündig TM. Determinants of efficacy and safety in epicutaneous allergen immunotherapy: summary of three clinical trials. Allergy. 2015; 70: 707–710.

21. Mondoulet, L, Dioszeghy, V, Ligouis, M, Dhelft V, Dupont C, Benhamou PH. Epicutaneous immunotherapy on intact skin using a new delivery system in a murine model of allergy. Clinical & Experimental Allergy. 2010; 40: 659–667.

22. DBV Technologies. DBV Technologies Announces Primary Endpoint Met in VIPES, Viaskin Peanut’s Phase llb Clinical Trial in Peanut Allergy. 2014 Sept. Available at: https://www.dbv-technologies.com/en/investor-relations/regulated-information/1521,phase-IIb-clinical-trial-vipes. Accessed 6/28/17.

23. DBV Technologies. Follow-Up Study of Viaskin Peanut Shows Significant Increase in Peanut Consumption and Treatment Benefit in Peanut Allergic Children. 2015 Oct. Available at: https://media.dbv-technologies.com/d286/ressources/_pdf/2/2325-PR-DBV-OLFUS-Results.pdf. Accessed 6/28/17.

Read more from Dr. Cooper here