Novel strategies and future directions in Immunotherapy
Glenis ScaddingRNTNE Hospital, London
Disclosures
• Research funds:ALK-Abello, GSK ,
• Advisory Boards:ALK-Abello, Allergen Therapeutics, GSK,
Merck, Uriach, USB
• Speaker/Chair:ALK-Abello, GSK , Merck, Uriach
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
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.
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.
Problems with SCIT
• Injections• Time-consuming• Long term • Expensive• Severe adverse events• Few allergy patients can be treated <5%
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
Novel approaches to immunotherapy
•Adjuvants•Alternative routes•Peptides•Fusion proteins •Recombinant allergens
Novel approaches to immunotherapy
•Adjuvants•Alternative routes•Peptides•Fusion proteins •Recombinant allergens
Adjuvants
• Alum• Lipopolysaccharide (MPL)• Immunostimulatory sequences (ISS,CpG)• Anti-IgE
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.
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.
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.
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.
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
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
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
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
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
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.
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
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
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
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
Adjuvants
• Alum• Lipopolysaccharide (MPL)• Immunostimulatory sequences (ISS,CpG)• Anti-IgE
Novel approaches to immunotherapy
•Adjuvants•Alternative routes•Peptides•Fusion proteins •Recombinant allergens
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
J Allergy Clin Immunol 2007; 120: 1338-45
J Allergy Clin Immunol 2007; 120: 1338-45
Sublingual Grass Tablet Immunotherapy
J Allergy Clin Immunol 2008;12:512-518
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)
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)
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)
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.
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.
Specific Allergen ImmunotherapyRisk and Benefit
Efficacy ++ Safety +
Efficacy +Safety ++
SCITSCIT SLITSLIT
Specific Allergen ImmunotherapyRisk and Benefit
Efficacy ++ Safety +
Efficacy ++/-Safety ++
SCITSCIT
SLITSLIT
Ask the patient!
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).
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)
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
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
Novel approaches to immunotherapy
•Adjuvants•Alternative routes•Peptides•Fusion proteins •Recombinant allergens
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
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
Improved ability to tolerate exposure to cats following peptide immunotherapy
Oldfield WLG, Larché M, Kay AB. Lancet 2002
Novel approaches to immunotherapy
•Adjuvants•Alternative routes•Peptides•Fusion proteins •Recombinant allergens
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)
Novel approaches to immunotherapy
•Adjuvants•Alternative routes•Peptides•Fusion proteins •Recombinant allergens
J Allergy Clin Immunol 2005; 116: 608-13
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)
Combined symptom/medication scores
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)
Allergen-specificantibodies
IgE
IgG4
IgG1
• 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
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.