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Novel strategies and future directions in Immunotherapy
Glenis ScaddingRNTNE Hospital, London
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Disclosures
• Research funds:ALK-Abello, GSK ,
• Advisory Boards:ALK-Abello, Allergen Therapeutics, GSK,
Merck, Uriach, USB
• Speaker/Chair:ALK-Abello, GSK , Merck, Uriach
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Learning Objectives
• To address how to improve the efficacy and safety of immunotherapy
• To review new therapeutic entities in trial
• To consider the implications of immunotherapy for the allergic march
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Immunotherapy for Allergic RhinitisSubcutaneousCalderon M, 2007
SCIT 51*, n = 2,871
SMD (95%CI) p
Symptoms -0.73 (-0.97, -0.50) < 0.00001
Medication -0.57 (-0.82, -0.33) < 0.00001
SMD = Standardised Mean Difference*Total numbers of studies analyzed
Cochrane Database Syst Rev 2007; (1):CD001936.
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Long-term efficacy of allergen immunotherapy
• Durham SR et al. Long-term clinical efficacy of grass-pollen immunotherapy . New Engl J Med 1999; 341:468-75
• Pajno G et al. Prevention of new sensitizations in asthmatic children monosensitized to house dust mite by specific immunotherapy. A six-year follow-up study.Clin Exp Allergy. 2001; 31: 1392-7.
• Moller C et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study).J Allergy Clin Immunol. 2002; 109: 251-6.
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Problems with SCIT
• Injections• Time-consuming• Long term • Expensive• Severe adverse events• Few allergy patients can be treated <5%
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Immunotherapy(high dose Ag)
Th1
IFNγ
IgG
Tr
IL-10 TGF-β
IgG4 IgA
APCNatural
exposure (low dose Ag)
+ IgE
Th2
B cell
Eosinophil
IgE
IL-4
IL-5
Allergy(-)
(-)
Robinson DS, Larche ML and Durham SR J Clin Invest 2004; 114: 1389-97
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Novel approaches to immunotherapy
•Adjuvants•Alternative routes•Peptides•Fusion proteins •Recombinant allergens
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Novel approaches to immunotherapy
•Adjuvants•Alternative routes•Peptides•Fusion proteins •Recombinant allergens
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Adjuvants
• Alum• Lipopolysaccharide (MPL)• Immunostimulatory sequences (ISS,CpG)• Anti-IgE
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0
1000
2000
3000
4000
5000 * nsns
Antigen + + + + + +Alum - + - + - +
IL-5 IL-10(x10)
IFNγA
mou
nt (
pg/m
l)
Influence of Aluminium Hydroxide (Alum) on allergen-stimulated cytokine production
Wilcock LK, Francis JN, Durham SR Clin Exp Allergy 2004; 34: 1373-8.
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Randomised controlled trial with alum-adsorbed grass pollen extract for seasonal allergic rhinoconjunctivitis
UK Immunotherapy Study Group26 centres, n=410100,000 SQ, 10,000 SQ and placebo
Frew AJ et al, JACI 2006;117: 319-25.
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Reduction in symptom and medication score over placebo – whole season
0 10 20 30 40 50 60
Medication
Symptoms
Percent reduction
Alutard 100,000 SQ median Alutard 10,000 SQ median
Frew AJ et al, JACI 2006;117: 319-25.
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p<0.001
p=0.027
p=0.027
Rhinoconjunctivitis QoL score
0
0.5
1
1.5
2
2.5
Baseline Season Baseline/Season
100,000 SQ-U 10,000 SQ-U Placebo
0
0.5
1
1.5
2
3
P=0.027
P=0.027
Frew AJ et al, JACI 2006;117: 319-25.
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OH O
O H
C
N H
H O
AO H
H O P
O
H O
OO
N H
B
O
Monophosphoryl Lipid A
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0
2500
5000
7500
10000
12500 ** ***ns
Antigen + + + + + +MPL - + - + - +
IL-5 IL-10(x10)
IFNγA
mou
nt (
pg/m
l)
Influence of Monophosphoryl lipid A (MPL)on allergen-stimulated cytokine production
Puggioni F, Durham SR, Francis JN Allergy 2005; ; 60:678-84
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Results
• Symptom score eye, lung
and nose:
reduced in active group
p=0.003
• Combined
Symptom/Rx score:
reduced in active
group p=0.013
• Skin test results in
active group; reduction
in wheal size p=0.04,
reduction in sensitivity
threshold p=0.03-0.10
0.00
0.10
0.20
0.30
0.40
0.50
0.60
1 2 3 4 5 6 7 8 9 1011121314151617181920212223242526272829303132
0
50
100
150
200
250
300
350
400
Active Placebo Pollen
Day - Observation period: 15/5/99 - 15/6/99
Drachenberg KJ et al., Allergy 2001; 56: 498-505
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ImmunoStimulatory DNA Sequences (ISS)
• ISS are oligonucleotides containing unmethylated CGsequences
• ISS mimic the innate immune response to microbial DNA
• ISS act primarily on antigen-presenting cells to:– Enhance antigen uptake and presentation– Induce proinflammatory cytokine production– Stimulate Th1 and inhibit Th2 T cell
development
• ISS are recognized by Toll-like receptor 9
5’-TGACTGTGAACGTTCGAGATGA-3’ISS 1018
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AIC - 1018 ISS Linked to Amb a 1
Amb a 1
ISS
ISS
ISS
ISS
Vaccine: Amb a 1 linked to a mean of 4 molecules of 1018 ISS
Goal: To reduce Th1 and enhance Th2 responses to Amb a 1, the dominant allergen in hayfever due to ragweed
If successful, AIC therapy would replace current 30-60 injection desensitization with a course of 6-7 weekly injections
Kind permission Dr R Coffman
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Immunotherapy with a Ragweed–Toll-Like Receptor 9 Agonist Vaccine for
Allergic Rhinitis.Creticos PS& Immune Tolerance Network Group (2006):
New Engl J Med 355: 1445-1455, 2006.
• 2001-55% decrease in peak Nasal Symptom Complex Score (NSCS) (p=0.03)
• 2002 ragweed season 53% reduction in NSCS, p=0.02 with no additional therapy.
• Clinically significant quality of life improvements.
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0
1000
2000
3000
4000
5000
6000*** **
IL-5 IL-10(x10)
IFNγ
Antigen + + + + + +ISS - + - + - +
Am
ount
(pg
/ml)
***
Influence of Immunostimulatory sequences (ISS) on allergen-stimulated cytokine production
Francis JN et al 2006
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Adjuvant
Alum
MPL
ISS
IL-5 IL-10 IFNγ
Francis JN and Durham SR. Curr Opin Allergy Clin Immunol 2004; 4: 543-8.
Influence of adjuvants on allergen-stimulated cytokine production: Summary
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Anti-IgE and rush Ragweed immunotherapy
Ragweed season
Screening
anti-IgE
Placebo
IT + anti-IgE
Placebo IT + anti-IgE
1-day
RIT
-
IT + placebo anti-IgE
Placebo IT + placebo anti-IgE
Week 0 Week 12
Pretreatment Maintenance IT + study drugRIT
Week -12
Follow-up
-
+
+
Specimen Collection
n=39
n=40
n=40
n=40
Week -9
Ragweed season
Screening
anti-IgE
Placebo
IT + anti-IgE
Placebo IT + anti-IgE
1-day
RIT
-
IT + placebo anti-IgE
Placebo IT + placebo anti-IgE
Week 0 Week 12
Pretreatment Maintenance IT + study drugRIT
Week -12
Follow-up
-
+
+
Specimen CollectionSpecimen Collection
n=39
n=40
n=40
n=40
Week -9
Pretreatment Maintenance IT + study drug Follow-up
Ragweed season
n = 7
n = 11
n = 9
n = 9
Pre-anti-IgE, Pre-IT > 2 weeks anti-IgE Post-rush, Pre-season Mid-season End of study Follow-up, Pre-season
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Average daily allergy severity scores over the primary ragweed season
Placebo / Placebo Placebo / IT anti-IgE / Placebo anti-IgE / IT
0.0
0.4
0.8
1.2
1.6
Ave
rage
Dai
ly A
llerg
y S
ever
ity S
core
Anti-IgE:
Reduced anaphylaxis x5 ,p=.026
Reduced symptoms,P=.044
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Adjuvants
• Alum• Lipopolysaccharide (MPL)• Immunostimulatory sequences (ISS,CpG)• Anti-IgE
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Novel approaches to immunotherapy
•Adjuvants•Alternative routes•Peptides•Fusion proteins •Recombinant allergens
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Meta-Analysis (2007)
-1 +1
BetterNo difference between placebo and treatment Worse
SCITCalderon
2007
-0.73
-0.97 -0.50
-0.43
SLITRadulovic
2007
-0.57 -0.28
-0.42
SLITWilson2003
-0.69 -0.15
0
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J Allergy Clin Immunol 2007; 120: 1338-45
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J Allergy Clin Immunol 2007; 120: 1338-45
Sublingual Grass Tablet Immunotherapy
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J Allergy Clin Immunol 2008;12:512-518
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GT-08 study design
Follow Up
Follow Up
Grass AIT (Grazax®) Treatment
2005 2007 2008 20092006
Placebo Treatment
4th year
End of treatment
Durham SR et al J Allergy Clin Immunol 2009 (in press)
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improvement One year after grass AIT
treatment
0
1
2
3
4
5
Year 1 Year 2 Year 3 Year 4
PlaceboGrass AIT
End
of t
reat
men
t 31%37%44%
32%
Total rhinoconjunctivitis symptom score(median values)
Sym
ptom
sco
re (
med
ian)
NB. Both treatment groups had free access to sympto matic mediations
Durham SR et al J Allergy Clin Immunol 2009 (in press)
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medication use One year after grass AIT
treatment
0
1
2
3
Year 1 Year 2 Year 3 Year 4
PlaceboGrass AIT
End
of t
reat
men
t
73%
Total rhinoconjunctivitis medication score(median values)
Med
icat
ion
scor
e (m
edia
n)
55%60%
52%
Durham SR et al J Allergy Clin Immunol 2009 (in press)
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0%
10%
20%
30%
40%
50%
60%
Didier Dahl Frew
Symptom scores Medication scores
Median
% decrease
SubcutaneousSublingual
Sublingual immunotherapy: the ‘big trials’ in adults
Durham SR Curr. Opin.Allergy Clin Immunol 2008; 8 :577-84.
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Sublingual immunotherapy
• SLIT is effective compared to placebo
• SLIT is safe with only minor local side effects
• Comparative studies, longterm studies and more paediatric studies are needed.
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Specific Allergen ImmunotherapyRisk and Benefit
Efficacy ++ Safety +
Efficacy +Safety ++
SCITSCIT SLITSLIT
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Specific Allergen ImmunotherapyRisk and Benefit
Efficacy ++ Safety +
Efficacy ++/-Safety ++
SCITSCIT
SLITSLIT
Ask the patient!
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Intralymphatic allergen administration renders specific immunotherapy faster and safer: a randomized controlled trial.
Senti G et al Proc Natl Acad Sci U S A. 2008 Nov 18;105(46):, 17908-12. Epub 2008 Nov 10
• Open-label trial • 165 patients with GP rhinoconjunctivitis • randomized to 54 s.c. injections with
pollen extract over 3 years [cumulative allergen dose 4,031,540 (SQ-U)]
• or 3 intralymphatic injections over 2 months (cumulative allergen dose 3,000 SQ-U).
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Results• ILIT 3 doses increased tolerance to GP
nasal provocation within 4 months (P < 0.001).
• equivalent to 3 years SCIT(P = 0.291 )• ILIT decr.hay fever symptoms (P < .001)
reduced skin prick test reactivity(P < .001), • decreased specific serum IgE (P < .001), • fewer AE than SCIT (P = .001), • enhanced compliance (P < .001), • less painful than venepuncture (P = .018)
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COMPARISON
SCIT
• 3 YEARS
• Special centre
• AE common, can be severe
• Effective
ILIT
• 8 WEEKS
• Special centre
• AE less common, none severe
• More quickly effective
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Epicutaneous allergen administration as a novel method of allergen-specific
immunotherapy.Senti G et al. J Allergy Clin Immunol. 2009 Nov;124(5):997-
1002. Epub 2009 Sep 5.
• RDBPCT 37 patients GP +ve• Patches- allergen (21) or placebo (16)
before & in GP season• Primary outcome= nasal provocation-
improved in both groups yr 1(p<.001;<.03) allergen only yr 2( p<.003)
• Eczema at site in active group
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Novel approaches to immunotherapy
•Adjuvants•Alternative routes•Peptides•Fusion proteins •Recombinant allergens
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Fel d 1 Chain 1 EICPAVKRDVDLFLTGTPDEYVEQVAQYKALPVVLENARILKNCVDAKMTE EDKENALSLLDKIYTSPLC EICPAVKRDVDLFLTGT
LFLTGTPDEYVEQVAQY EQVAQYKALPVVLENA KALPVVLENARILKNCV RILKNCVDAKMTEEDKE KMTEEDKENALSLLDK KENALSVLDKIYTSPL
Fel d 1 Chain 2 VKMAETCPIFYDVFFAVANGNELLLKLSLTKVNATEPERTAMKKIQDCYVE NGLISRVLDGLVMTTISSSKDCMGEAVQNTVEDLKLNTLGR VKMAETCPIFYDVFFA
CPIFYDVFFAVANGNEL GNELLLKLSLTKVNAT LTKVNATEPERTAMKK TAMKKIQDCYVENGLI CYVENGLISRVLDGLV SRVLDGLVMTTISSSK ISSSKDCMGEAVQNTV AVQNTVEDLKLNTLGR
Fel d 1: multiple peptides “prototype vaccine”
Kaiser et al,. J. Biol. Chem 2003
Poorly soluble
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PIT reduces the cutaneous late phase reaction to Fel d1
baseline
follow-up1
follow-up2
Placebo
baseline
follow-up1
follow-up2
MOP
8000
6000
4000
2000
0
p=0.0001
p=0.0002
p=0.005
Reactionsize
(mm2)
Oldfield WLG, Larché M, Kay AB. Lancet 2002
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Improved ability to tolerate exposure to cats following peptide immunotherapy
Oldfield WLG, Larché M, Kay AB. Lancet 2002
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Novel approaches to immunotherapy
•Adjuvants•Alternative routes•Peptides•Fusion proteins •Recombinant allergens
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A novel human immunoglobulin Fc γγγγ−Fcεεεε bifunctional fusion protein inhibits Fc εεεεRI-mediated degranulationDaocheng Zhu, Christopher L. Kepley, Min Zhang, Ke Zhang and Andrew Saxon Nature Medicine 8, 518 - 521 (2002)
Inhibition of basophil histamine release
LynLyn
FcεεεεRIITIMITIM
FcγγγγRIIb
ITIMITIM
FcγγγγRIIbαααα
ββββ γγγγ
ITAMITAM
αααα
ββββ γγγγ
ITAMITAM
-FcεεεεRI
Fcγγγγ-Fcεεεε construct (GE2)
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Novel approaches to immunotherapy
•Adjuvants•Alternative routes•Peptides•Fusion proteins •Recombinant allergens
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J Allergy Clin Immunol 2005; 116: 608-13
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Vaccine
• Alum-adsorbed recombinant allergen mixture (endotoxin free)
– Phl p2 5 mcg– Phl p5a 10 mcg– Phl p5b 10 mcg– Phl p6 5 mcg– Phl p1 10 mcg
• Alum-adsorbed histamine (0.125 mg/ml)
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Combined symptom/medication scores
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Results (mean data, per protocol set) n=57
• Symptoms - 36.5% reduction, p=0.015
• Rescue medication- 36.5% reduction, p=0.66
Combined Sx/Rx score- 38.9% reduction, p=0.44
- 38.5% for ITT population, (p=0.051)
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Allergen-specificantibodies
IgE
IgG4
IgG1
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• A recombinant grass allergen mixture can be an effective and safe treatment to ameliorate symptoms of allergic rhinitis
• Associated increases in Allergen specific IgG antibodies with a reduction in IgE antibodies
Jutel M et al J Allergy Clin Immunol 2005; 116: 608-13
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SummaryAllergen immunotherapy• reduces symptoms and Rx needs
• has long-lasting benefits• with potential to modify the natural history of
allergic disease.
Novel approaches with documented clinical benefit include :
• sublingual ,lymph node and epicutaneous routes
• the use of adjuvants• use of recombinant allergens
• and of anti-IgE.