Why immunotherapy fails ?
Stephen Durham
Imperial College and
Royal Brompton Hospital,
London UK
Declaration
• Research funding, consultancy and lecture
fees from ALK Abello
• Lecture fees from Allergy Therapeutics
Why immunotherapy fails ?
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wrong set up
wrong patient
wrong allergen(s)
wrong dose
wrong duration
Why immunotherapy succeeds ?
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•
right set up
right patient
right allergen(s)
right dose
right duration
Why immunotherapy succeeds ?
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•
right set up
right patient
right allergen(s)
right dose
right duration
Immunotherapy clinic
Immunotherapy clinic
• Leadership/organisation of allergy clinic
• Staff competencies (induction/training)
• Clinic facilities
– bookings, observation space
– storage for vaccines / skin test reagents
– safety procedures
– rescue equipment
• Immunotherapy protocols
Alvarez-Cuesta E et al Allergy 2006; 61 Suppl. 82: 1-20
Staff competencies
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Evaluation of the patients’ condition
Entering data in “Immunotherapy Record Form”
Injection technique
Dose modification
Active observation of patients
Early recognition of anaphylactic reactions
Treatment /monitoring of anaphylactic reactions
How to perform scheduled assessments
Factors determining whether to continue/stop IT
Alvarez-Cuesta E et al Allergy 2006; 61 Suppl. 82: 1-20
Why immunotherapy succeeds ?
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•
•
•
•
right set up
right patient
right allergen(s)
right dose
right duration
Selection of patients for
immunotherapy
• Symptoms induced by allergen
• IgE to relevant allergen
(SPT/RAST)
• Symptoms due to one or few
allergens
• No contra-indications (severe
asthma, beta/blockers, inability to
comply with IT)
Immunotherapy in adults with birch allergy
Arvidsson M, Löwhagen O Rak S J Allergy Clin Immunol 2002;109:777-83
Immunotherapy in children with perennial asthma
and multiple allergen sensitivities
Franklin Adkinson N et al New Engl J Med 1999;
Why immunotherapy succeeds ?
•
•
•
•
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right set up
right patient
right allergen(s)
right dose
right duration
Selection of allergen extracts
• Standardisation
- in-house reference standards (IHRs)
- units of biologic potency
- major allergen content (5-20 mcg major Ag)
- recombinant allergens
• Documented benefit (controlled trials)
- efficacy
- safety
- children and adults
- longterm effects
J Allergy Clin Immunol 2006; 117: 319-25
26 centres, n=410
100,000 SQ, 10,000 SQ and placebo
Grass pollen immunotherapy:
UK immunotherapy study
Frew AJ et al, J Allergy Clin Immunol 2006; 117: 319-25
Rhinoconjunctivitis QoL score
3
p<0.001
2.5
2
1.5
p=0.027
P=0.027
1
p=0.027
P=0.027
0.5
0
Baseline
Season
100,000 SQ-U
10,000 SQ-U
Baseline/Season
Placebo
Frew AJ et al, J Allergy Clin Immunol 2006; 117: 319-25
Why immunotherapy succeeds ?
•
•
•
•
•
right set up
right patient
right allergen(s)
right dose
right duration
J Allergy Clin Immunol 2007; 120: 1338-45
Sublingual Grass Tablet
Immunotherapy
J Allergy Clin Immunol 2007; 120: 1338-45
Sublingual Grass Tablet
Immunotherapy
J Allergy Clin Immunol 2007; 120: 1338-45
Randomised DBPC trial (n=855). 3 doses v placebo
• 2,500 SQ-T
• 25,000 SQ-T
• 75,000 SQ-T
Once daily 8 weeks pre-season and continued throughout season
Sublingual Grass Tablet
Immunotherapy
Entire pollen season
Peak pollen season
18
P=0.071
P=0.047
16
Percentage
14
12
P=0.46
P=0.19
10
8
6
4
2
0
2,500 SQ-T
25,000 SQ-T
75,000 SQ-T
n=136
n=139
n=141
Durham SR et al. J Allergy Clin Immunol 2006; 117: 802-9
Why immunotherapy succeeds ?
•
•
•
•
•
right set up
right patient
right allergen(s)
right dose
right duration
Why immunotherapy succeeds ?
•
•
•
•
•
right set up
right patient
right allergen(s)
right dose
right duration
- efficacy
- tolerance
50.0%
P-value medication score
Medication score reduction compared to placebo
P-value symptom score
Symptom score reduction compared to placebo
45.0%
0.50
0.45
40.0%
0.40
35.0%
0.35
30.0%
0.30
25.0%
0.25
20.0%
0.20
15.0%
0.15
10.0%
0.10
5.0%
0.05
0.0%
0.00
0
2
4
6
8
P-value
Reduction in rhinoconjunctivitis score compared to placebo
8 Weeks Pre-Seasonal Treatment
10 12 14 16 18 20 22 24 26 28 30 32 34 36
Pre-seasonal treatment (Weeks)
17% reduction in average seasonal daily rhinoconjunctivitis symptom (p<0.05)
23% reduction in average seasonal daily medication scores ( p<0.05)
Calderon MA et al. Allergy 2007
50.0%
P-value medication score
Medication score reduction compared to placebo
P-value symptom score
Symptom score reduction compared to placebo
45.0%
0.50
0.45
40.0%
0.40
35.0%
0.35
30.0%
0.30
25.0%
0.25
20.0%
0.20
15.0%
0.15
10.0%
0.10
5.0%
0.05
0.0%
0.00
0
2
4
6
8
P-value
Reduction in rhinoconjunctivitis score compared to placebo
> 8 Weeks Pre-Seasonal Treatment
10 12 14 16 18 20 22 24 26 28 30 32 34 36
Pre-seasonal treatment (Weeks)
37% reduction in average seasonal daily rhinoconjunctivitis symptom (p<0.0001)
47% reduction in average seasonal daily medication scores ( p<0.0001)
Calderon MA et al. Allergy 2007
Why immunotherapy succeeds ?
•
•
•
•
•
right set up
right patient
right allergen(s)
right dose
right duration
- efficacy
- tolerance (persistent efficacy after withdrawal)
1
Grass pollen IT in adults: 3 years duration
induces tolerance
0
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6
0
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e3
Durham SR et al New Engl J Med 1999;341:468-75
J
hy ar y
House dust mite IT in children : 3 years duration
induces tolerance
Des Roches A et al, Allergy 1996; 51 :430-3
Can sublingual immunotherapy induce tolerance?
J Allergy Clin Immunol 2008;12:512-518
Phase III – Safety and Efficacy
Medication score relative to placebo (mean)
On-going and Long-term Study
Percentage
100
90
38%
46%
80
p<0.0001
p<0.0001
Year
2004
2005
2006
2007
2008 and 2009
70
60
n= 316
50
n=188
Grass Tablet 75,000 SQSQ-T once daily
No treatment
Placebo
No treatment
40
Randomisation
30
20
10
0
n=318
Placebo
Grazax 2005
n=163
Grazax 2006
Trial extended to additionally 2 years of treatment followed by a 2-year follow-up (Protocol amendment)
Why immunotherapy succeeds ?
•
•
•
•
•
right set up
right patient
right allergen(s)
right dose
right duration
- efficacy
- tolerance
Why immunotherapy fails?
•
•
•
•
•
wrong set up
wrong patient
wrong allergen(s)
wrong dose
wrong duration
- no efficacy
- no tolerance
Immunotherapy
(high dose Ag)
IgE
IL-4
Natural
exposure
(low dose Ag)
+ IgE
APC
B cell
Allergy
Th2
(-)
(-)
IL-5
Eosinophil
Tr
Th1
IFNg
IL-10
TGF-b
IgG
IgG4
IgA
Robinson DS, Larche ML and Durham SR J Clin Invest 2004; 114: 1389-97
Two types of regulatory T cells
Natural
Thymus
Treg
CD4+CD25+ T cells
Foxp3 transcription factor
Adaptive
Tr1
Tr1 cells
IL-10
Foxp3?
Thn
Th3
Th3 cells
TGF-b
Phenotypic Tregs in the nasal mucosa
J Allergy Clin Immunol 2008; April 17th epub
p=0.1
p=0.01
p=0.35
(36.7)
+
Foxp3 CD4
2
cells/mm
+
20
10
0
CD3
CD25
Foxp3
CD3
IL-10
Foxp3
Norm al
controls
Controls
In season
Before
Placebo
After
IT
hayfever Immunotherapy
Out of season
Th2 responses prevent tolerance induction?
Th2
IL-4
resistor
GATA3
negative feedback
naive
NFAT
FOXP3
Treg
Amplifier
Positive feedback
Anti-IL-4 directed
therapy to augment
tolerance induction
against allergens
TGF-β,
IL-10
TGF-b
IL-27
IL-10
IL-35
Mantel P-Y et al,
PLOS Biology 2007;
5 (12): e329
Can we predict success or failure
of immunotherapy?
Change in response
Time course of biomarkers during immunotherapy
2 weeks
IL-10 production
Grass pollen
count
0
2
4
6
8
12
16
20
24
28
32
36
late phase response
40
44
Duration of allergen immunotherapy (weeks)
J Allergy Clin Immunol 2008; 121(5):1120-1125
48
52
Time course
of changes
in IL-10
and
Time course
of biomarkers
during
immunotherapy
IgG-associated inhibitory activity
Change in response
Late allergen-induced Skin Response
4 weeks
Grass Pollen season
0
2
4
6
8
12
16
20
24
28
32
36
40
44
48
52
Duration of allergen immunotherapy (weeks)
late phase response
J Allergy Clin Immunol 2008; 121(5):1120-1125
Change in response
IgG4
IgE-FAB
inhibition
Pollen count
8 weeks
0
2
4
6
8
12
Early skin response
16
20
24
28
32
36
40
44
48
Duration of allergen immunotherapy (weeks)
52
Correlation between clinical response (Sx/Rx)
IgG4 and IgE-FAB inhibitory activity
IgE-FAB
IgG4
100
80
r= - 0.6 5
p = 0.02
60
Phl p 5 specific IgG4
(% binding)
% Inhibition of allergen/IgE
binding to B cells
100
r= 0.0 5
50
p= 0.9
0
40
0
2500
5000
7500
10000
Symptom/Medication score
0
2500
5000
7500
10000
Symptom/Medication score
Shamji M et al 2008, unpublished
Immunotherapy
(high dose Ag)
IgE
IL-4
Natural
exposure
(low dose Ag)
+ IgE
APC
B cell
Allergy
Th2
(-)
(-)
IL-5
Eosinophil
Tr
Th1
IFNg
IL-10
TGF-b
IgG
IgG4
IgA
Robinson DS, Larche ML and Durham SR J Clin Invest 2004; 114: 1389-97
Allergy and Clinical Immunology, Imperial College
and Royal Brompton Hospital, London, UK
M Calderon
D R Wilson
C Pilette
S Radulovic
K T Nouri-Aria
M R Jacobson
J N Francis
M Shamji
G Paraskavopoulos
L Wilcock
C Schmidt-Weber
S J Till