epicutaneous immunotherapy

Epicutaneous immunotherapy

Boonthorn

4 december 2009

outline

Specific immunotherapy and meta-analysis

Immunological mechanism of SIT Epicutaneous immunotherapy in animal

model Epicutaneous immunotherapy in human

Meta-analysis Data Sources:

Electronic databases searched up to April 30, 2008, for meta-analyses of randomized, placebo-controlled trials assessing specific IT in respiratory allergy. We looked for studies that evaluated effects on symptom scores and use of rescue medication

Results: 7 of 13 meta-analyses met the inclusion criteria 5 evaluating sublingual IT and 2 evaluating subcutaneous IT 7 meta-analyses reported reduction in symptom and medication

scores Sublingual IT meta-analysis not find significant size effect,

probably because of the inclusion criteria.Enrico C. et al.,Ann Allergy Asthma Immunol. 2009;102:22–28

Specific immunotherapy: current meta-analysis (Sc IT)

Source Patients Characteristics Outcomes

Abramson et al

2003

1,064 adults and

children

Meta-analysis of RCT of asthma

Double-blind, single-blind, and open studies

75 studies for outcomes (36 with HDM, 20 pollen, 10 animal dander, 2 Cladosporium mould allergy, 1 latex, and 6

multiple allergens)

significant improvements in asthma symptom scores

Calderon et al,

2007

1,063 adults Meta-analysis of randomized DBPC studies of

rhinitis

15 studies for outcomes (a variety of allergens

were administered: ragweed, mixed grass,

timothy, Parietaria, birch, orchard, cedar,

Bermuda grass, Juniperus ashei, and Cocos

Symptom scores ,Medication scores were reduced in the immunotherapy

Enrico C. et al.,Ann Allergy Asthma Immunol. 2009;102:22–28

Meta-analysis ( SL IT )Source Patients Characteristics Outcomes

Calamita et al

2006

303 adults and children

Meta-analysis of randomized placebo-controlled,open and blinded studies of asthma

9 studies (5 with pollen and 4 with mites)

no significant reduction in asthma symptoms

Penagos et al

2008

441 children Meta-analysis of randomized DBPC studies of asthma 9 studies for the outcomes (6 with mites and 3 with pollens)

Overall, there was a significant reduction in symptoms

Olaguibel et al

2005

256 children Meta-analysis of randomized DBPC clinical trials of

respiratory asthma or allergic rhinitis

7 studies for the outcomes

Decreased symptom and medication score

Penagos et al

2006

484 children Meta-analysis of randomized DBPC studies of AR

10 studies for the outcomes (6 with pollens and 4 with HDM )

There were significant reductions in

symptom scores Wilson et al

2005

959 adults and

children

Meta-analysis of randomized DBPC studies of AR

22 studies for the outcomes (6 with HDM, 5 grass pollen, 5 Parietaria, 2 olive, and 1 ambrosia, cat, and cupressaceous

Overall there were significant reductions in symptoms


Efficacy of specific immunotherapy (SIT). Summary of meta-analysis results expressed as effect size on symptoms. (SM

D, standardized mean difference )


Immunological mechanism

Nat Rev Immunol 2006;6:761-71

Mechanisms of allergic reactions


Effects of allergen-specific immunotherapy on clinical and experimental immune parameters


Proposed role of regulatory T cells and cytokines in allergen-specific immunotherapy


Epicutaneous immunotherapy in animal model

Epicutaneous is as efficient as subcutaneous desensitization in a mouse model of allergy

Method48 BALB/c mice were Sc sensitized,nasally

boosted to pollen or ovalbuminDesensitized during 8,16 wks by EC or ScCompared sensitized,nontreated and naïvePlethysmography ( index of

bronchochonstriction)Serum specific Ab ( IgE,IgG1,IgG2a )

JACI .2008;121:793


Result (index of provocation, % of control)

nontreated EC Sc

8wk 16wk 8wk 16wk 8wk 16wk

pollen 174% 139% 67%P<0.001

76%P<0.01

90%P<0.05

57%P<0.01

ovalbumin 291% 171% 79%P<0.01

112%P<0.01

154%P<0.05

86%P<0.05

JACI .2008;121:793


Result desensitization ( for pollen )

Specific IgG2a increase 2.3 times (EC,P<0,05) Increase 1.9 times ( Sc,p<0.05 )

For ovalbumin 10 times both SC,EC ( p<0.05 )

NT and control unchange

Conclusion In animal model ,EPIT seem as efficient as subcutaneous route

JACI .2008;121:793

EPIT for HDM allergy using VIASKINR

technology : a preclinical study

Method4 Group BALB/c mice(C,n=10),(NT,n=9),(EP,n=9),

(Sc,n=9) IT once a week,8weeks (EP 48hrs. HDM extract ,

Sc)Monitor

IgE,IgG1,IgG2a Penh ( measure bronchial hyper-reactivity) BAL cell

JACI .2008;123:S177



Results Sc EP NT P value

sIgG2aDer.f/Der p

baseline 0.009/0.075 0.097/0.061 <0.01

After IT 2.009/0.726 2.463/0.468

BAL ( Eo,L) baseline 4.1*104 1.0*105 1.9*105 <0.001

After IT 3.3*104 6.9*104 2.9*105

JACI .2008;123:S177



Result sIgE and sIgG1 not vary BAL neutrophil and macrophage not vary Penh lower in treated group ( 158% of C in

EP,141%in Sc,185% in NT,p<0.05)

Conclusion In HDM sensitized mice,EPIT seems as efficient as

SCIT

JACI .2008;123:S177

EPIT:proof of concept with various Ag in sensitized mouse Methods

Sensitized mice (sc) to Ova (n=18),pollen(n=18),HDM (n=24)

Oral to peanut (n=18)Allocated into 3 group (EP,Sc,NT)and controlMonitor sIgE,sIgG1,sIgG2aPlethysmography after provocation (Penh)

EPIT:proof of concept with various Ag in sensitized mouse results

IgG2a pollen OVA HDM peanuts P value

EP (μg/ml)

0.97 0.39 2.5 18 <0.05

NT(μg/ml)

0.42 0.15 0.5 5.5

Doi:10.1016/j.clim.2009.03.254No significant diff. between EP and sc

EPIT:proof of concept with various Ag in sensitized mouse resultsPenh value pollen OVA HDM peanuts

EP 7.2 4.8 7.6 4.6

NT 12.8 9.7 9.6 7.1

Doi:10.1016/j.clim.2009.03.254

Penh value not significant diff. in EP , sc and controlConclusion : in sensitized mice ,with 4 tested allergens, EPIT as efficient as SCIT

Repeated applications of Peanut protein extracts during EPIT induce a change of cytokine response from Th2 to mixed Th2/Th1 in sensitized mice

MethodsBABL/c mice sensitized by PPEEPIT perform during 8wks by 24 or 48

hrs.,application of PPE on VIASKINR

Skin was harvested after D42,91 for cytokine measurement and histology

Doi:10.1016/j.clim.2009.03.251


Results Increase IgG2a,decrease IgG1/IgG2a ratioThickening of epidermis,langerhan cell network

perturbation ,migration of dendritic epidermal T cell,massive recruitement of CD11b+ inflammatory cell

After 24 hrs. Th2 cytokine (IL-1β,IL-4) increase compared control at

D42,91

Doi:10.1016/j.clim.2009.03.251


Results Treg ,Th1 cytokines,TNFα not diff. from control at D42,but

significant increase at D91

During 48 hrs, D42 , Th2 cytokine decrease dramatically D91, cytokine response was attenuated

Conclusion In animal model , EPIT with VIASKINR induced

reorientation from only Th2 to diversified and mixed response

Doi:10.1016/j.clim.2009.03.251

Epicutaneous immunotherapy in human

Epicutaneous Immunotherapy In Severe Cow Milk Allergy: A Double Blind Pilot Trial

RATIONALE Immunotherapy has promising results in food hypersensitivity

but significant side effects with oral route

METHODS DBPC study investigated safety and efficacy of new method,

EPIT Using patch (Viaskin, DBV Technologies) in children with severe cow’s milk allergy (CMA). In 19 children, 8 m-6y (med 3y), with IgE-mediated CMA in 2 French pediatric centers

JACI .vol.123 ,No.2:s183


METHODS patch coated with 1 mg cow milk powder was applied every

other day, during 3 months, on the children’s back (treated group, n = 10, drop out 1; placebo group, n = 9, drop out 2)

cumulated tolerated dose of milk (CTD),measured during an open challenge at days 0 and 90, allowed to calculate a tolerance index (CTD90 - CTD0)/CTD0

SPTs, milk sIgE and sIgG were assayed monthly. From days 90 to 180, all patients could receive active treatment.



RESULTS : At day 90 in treated group, CTD was x10 in 5 and x3 in 1, unchanged in 3 With the placebo, it was x2 in 4 and unchanged in 3 tolerance index was 101 in treated group and 0.68 with placebo

(p =0.13) The additional 3-month treatment (n = 11) significantly increased

the CTD (p 0.02) SPTs, sIgE and IgG subclasses levels exhibited individual

variations, with no detectable common profile Adverse events were similar in 2 groups except for GI symptoms,

diarrhea (2) and vomiting (1) reported only in the active group.


Epicutaneous Immunotherapy In Severe Cow Milk Allergy: A Double Blind Pilot Trial results

SPT : substantial reduction in wheal diameter,little change in placebo

CONCLUSIONS This pilot study shows the EPIT feasibility. These promising results need

confirmation (larger studies, additional allergens)

Active Rx placebo P value

Mean maximum tolerated dose at baseline

2.1mL (SD 2.6 ) 4.4 mL (SD 5.9)

Mean maximum tolerated dose at 3 mo.

21 ( SD 24.3 ) 5.4 ( SD 5.9 ) P=0.37

Median change from baseline

5.6 mL 0.17 mL P=0.02


Epicutaneous allergen administration as a novel method of allergen-specific immunotherapy

METHODSStudy population

Inclusion criteria Exclusion criteria

J Allergy Clin Immunol 2009;124:997-1002

Inclusion criteria age 18 to 65 years Hx of summer hay fever > 2 seasons positive reactions to grass pollen allergen extract in nasal provocation Positive skin prick tests (Phleum pratense)

Exclusion criteria atopic eczema, perennial allergic rhinitis ,moderate to severe asthma infection of upper airways within last 2 wks surgical intervention within last 30 days Hx of HIV/AIDS, malignancy, mastocytosis,uncontrolled high BP pregnancy or lactation presence or Hx of significant cardiovascular, renal, pulmonary, liver, infe

ctious, hematologic, autoimmune, neurologic, and psychiatric disease intake of antihistamines within last 2 wks or systemic or topic steroids wi

thin last 5 d intake of contraindicated medicaments for specific IT eg. b-blockers or

ACEI, ARB within last week participation in another clinical trial within last 60 d


Study design monocentric phase I/II randomized,

placebo-controlled, double-blind trial

evaluate the safety and clinical efficacy


Clinical endpoints main objective : assess safety and efficacy of ep

icutaneous allergen immunotherapy primary outcome

change in allergic response assessed by NPTs Secondary outcome

hay fever symptoms by visual analog scale use of medication occurrence of local reactions and adverse events


Test drug

The patch consisted of a 3 * 5 cm polyethylene pouch that was filled with grass pollen extract in Vaseline. The side of the pouch that faced the skin was perforated. The pouch was held onto the skin by a self-adhesive tape.


Statistical analysis

detect changes in symptom scores of NPTs from baseline ( intragroup ) between allergen and placebo group

Efficacy increase of threshold dose in NPTs of >0.8 (log 10) fr

om the baseline ranks and a difference of 0.9 (log 10) between allergen treatment and placebo

2-tailedWilcoxon signed-rank test for related samples or with the exact Mann-Whitney U test for independent samples.


Results


Safety and tolerability

10 pts. used topical corticosteroidsfor total duration of 13 +/- 20 days J Allergy Clin Immunol 2009;124:997

-1002

Nasal provocation

differences between 2 groups not reach statistical significance September 2006, P = .66; April 2007, P = .55; October-December 2007, P = .15


Subjective symptom scores


Use of rescue medication

similar in 2 test groups symptoms were significantly better controlled in

verum group Patients receiving verum used significantly more

topical corticosteroids to treat eczema under the patch than the placebo group (P = .04)

none of placebo-treated patients used topical steroids,

10 patients from allergen-treated group (47.6%) applied topical steroids.


Discussion

in 1950s, Blamoutier performed allergen-specific immunotherapy by needle scarification of the volar forearm in an area 4*4 cm1

Blamoutier observed formation of wheal-like plate, and majority of treated patients experienced improvement or complete relief from hay fever for 3 days - 3 weeks2

1. Presse Med 1959;67:2299-3012. Acta Allergologica 1965;XXI:261-7.

Discussion

scratching enhances allergen penetration into epidermis and activates keratinocytes (allergen-pulsed Langerhans cells) leave epidermis and migrate into regional LN for stimulation of lØ

In this study, replaced scarification with adhesive tape stripping method

Tape stripping induces bystander effect mediated by keratinocyte-derived proinflammatory cytokines

inducing secretion of IL-1, IL-6, IL-8, andTNF-a induce production of IL-12 and IFN-g in skin increase expression of MHC class II, CD86, CD40,CD54, and CD11

c on Langerhans cells enhanced expression of TLR 9 in keratinocytes, producing an enviro

nment favoring induction of allergy-protective immune responses mediated by Langerhans cells


Limitation of study Most patches applied at home, quality control of correct application

difficult. 8 patches applied during pollen season, clear distinction between ha

y fever symptoms and systemic allergic reactions more difficult than first 4 patches applied before pollen season.

score improvements of actual symptoms compared with those of previous pollen seasons may contain recall bias, same for both placebo and verum patients.

grass pollen patches induced eczema contrast with placebo, one may argue that blinding of study was limited. Occurrence of eczema, however, had no influence on study outcome, because those verum patients with eczema at application site showed no significantly better improvement (48%+/- 20%) than those verum patients without eczema (57% +/- 23%).

At visit 3, a sample size of 35 required to yield statistically significant result with power of 80% . Although sample size at visit 3 was only 1 patient fewer than required—that is,34, patient numbers at visits 4 and 5 were only 26 and 30, respectively.


Limitation of study

grass pollen patches induced eczema contrast with placebo, one may argue that blinding of study was limited.

Occurrence of eczema no influence on study outcome, because verum pts. with eczema at application site showed no significantly better improvement (48%+/- 20%) than verum pts. without eczema (57% +/- 23%).

At visit 3, sample size of 35 required to yield statistically significant result with power of 80% . Although sample size at visit 3 —that is,34, at visits 4 and 5 were only 26 and 30, respectively.


Discussion

expect symptom amelioration to last longer than the 1½ years of observation time in this study, but longer studies will be necessary to evaluate longevity of the treatment effect.

In conclusion, first trial in human beings suggested that epicutaneous allergen i

mmunotherapy was safe, well tolerated, and significantly stronger symptom amelioration than placebo.

epicutaneous immunotherapy could also be used to treat other IgE-mediated allergies.

Because needle-free and can be applied at home, epicutaneous allergen administration may represent promising alternative to other methods of immunotherapy.


Conclusion

meta-analysis => useful both Sc and SL IT Immunological mechanism

Regulatory T cell IgG blocking Ab

Epicutaneous immunotherapy Novel and interestmay be effective and causative treatment against IgE-

mediated allergies that is safe and encourages patient compliance

epicutaneous immunotherapy

Health & Medicine

metaanalysis sl

metaanalyses of randomized

current metaanalysis

open studies

metaanalysis data sources

ann allergy asthma immunol

blinded studies ofasthma

wk pollen