Download - Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK
Why immunotherapy fails ?
Stephen DurhamImperial College and
Royal Brompton Hospital, London UK
Declaration
• Research funding, consultancy and lecture fees from ALK Abello
• Lecture fees from Allergy Therapeutics
• wrong set up
• wrong patient
• wrong allergen(s)
• wrong dose
• wrong duration
Why immunotherapy fails ?
• 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
Why immunotherapy succeeds ?
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
• 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
• right set up
• right patient
• right allergen(s)
• right dose
• right duration
Why immunotherapy succeeds ?
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)
Arvidsson M, Löwhagen O Rak S J Allergy Clin Immunol 2002;109:777-83
Immunotherapy in adults with birch allergy
Franklin Adkinson N et al New Engl J Med 1999;
Immunotherapy in children with perennial asthma and multiple allergen sensitivities
• right set up
• right patient
• right allergen(s)
• right dose
• right duration
Why immunotherapy succeeds ?
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=410100,000 SQ, 10,000 SQ and placebo
Grass pollen immunotherapy:UK immunotherapy study
Frew AJ et al, J Allergy Clin Immunol 2006; 117: 319-25
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, J Allergy Clin Immunol 2006; 117: 319-25
• right set up
• right patient
• right allergen(s)
• right dose
• right duration
Why immunotherapy succeeds ?
J Allergy Clin Immunol 2007; 120: 1338-45
Sublingual Grass Tablet Immunotherapy
J Allergy Clin Immunol 2007; 120: 1338-45
J Allergy Clin Immunol 2007; 120: 1338-45
Sublingual Grass Tablet Immunotherapy
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
0
2
4
6
8
10
12
14
16
18
2,500 SQ-T 25,000 SQ-T 75,000 SQ-T
Per
cen
tag
e
Entire pollen season Peak pollen season
P=0.46 P=0.19
P=0.071 P=0.047
n=136 n=139 n=141
Durham SR et al. J Allergy Clin Immunol 2006; 117: 802-9
Sublingual Grass Tablet Immunotherapy
• 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
Why immunotherapy succeeds ?
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36Pre-seasonal treatment (Weeks)
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
40.0%
45.0%
50.0%
Red
uctio
n in
rhi
noco
njun
ctiv
itis
scor
e co
mpa
red
to p
lace
bo
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
P-v
alue
P-value medication scoreMedication score reduction compared to placeboP-value symptom scoreSymptom score reduction compared to placebo
17% reduction in average seasonal daily rhinoconjunctivitis symptom (p<0.05)
23% reduction in average seasonal daily medication scores ( p<0.05)
8 Weeks Pre-Seasonal Treatment
Calderon MA et al. Allergy 2007
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36Pre-seasonal treatment (Weeks)
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
40.0%
45.0%
50.0%
Red
uctio
n in
rhi
noco
njun
ctiv
itis
scor
e co
mpa
red
to p
lace
bo
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
P-v
alue
P-value medication scoreMedication score reduction compared to placeboP-value symptom scoreSymptom score reduction compared to placebo
> 8 Weeks Pre-Seasonal Treatment
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
• right set up
• right patient
• right allergen(s)
• right dose
• right duration- efficacy
- tolerance (persistent efficacy after withdrawal)
Why immunotherapy succeeds ?
0
20
40
60
80
100
0
20
40
60
80
3 17 31 14 28 12 26 9 23 6 2 16 30 13 27 11 25 8 22 5 1 15 29 12 26 10 24 7 21 4
19931995
1994 1995
PollenCount/m
3
Symptoms
IT 7 yr IT 4 yr/Placebo 3 yr (from 1992) IT-naive hay fever control patients
MAY JUNE JULY AUGUST MAY JUNE JULY AUGUST MAY JUNE JULY AUGUST
(108.4)
Durham SR et al New Engl J Med 1999;341:468-75
Grass pollen IT in adults: 3 years duration induces tolerance
House dust mite IT in children : 3 years duration induces tolerance
Des Roches A et al, Allergy 1996; 51 :430-3
Medication score relative to placebo (mean)
0
10
20
30
40
50
60
70
80
90
100
Perc
en
tag
e
Placebo Grazax 2005 Grazax 2006
38%p<0.0001
46%p<0.0001
J Allergy Clin Immunol 2008;12:512-518
Phase III – Safety and Efficacy
On-going and Long-term Study
Grass Tablet 75,000 SQGrass Tablet 75,000 SQ--T once daily T once daily
PlaceboPlacebo
No treatmentNo treatment
No treatmentNo treatment
Randomisation
Year 2004 2005 2006 2007 2008 and 2009
n= 316 n=188
n=318 n=163
Trial extended to additionally 2 years of treatment followed by a 2-year follow-up (Protocol amendment)
Can sublingual immunotherapy induce tolerance?
• right set up
• right patient
• right allergen(s)
• right dose
• right duration- efficacy
- tolerance
Why immunotherapy succeeds ?
• wrong set up
• wrong patient
• wrong allergen(s)
• wrong dose
• wrong duration- no efficacy
- no tolerance
Why immunotherapy fails?
Immunotherapy(high dose Ag)
Th1
IFN
IgG
Tr
IL-10 TGF-
IgG4 IgA
APC
Natural 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
Two types of regulatory T cells
Tr1
Th3
Tr1 cells IL-10
Foxp3?
Th3 cells TGF-
Adaptive
Thn
Treg
CD4+CD25+ T cells
Foxp3 transcription factor
Natural
Thymus
J Allergy Clin Immunol 2008; April 17th epub
Phenotypic Tregs in the nasal mucosa
CD3CD25Foxp3
CD3IL-10Foxp3
BeforePlacebo
Normalcontrols
AfterIT
0
10
20
Fo
xp3
+C
D4
+
ce
lls
/mm
2
p=0.1
Out of season
(36.7)
In season
p=0.01
p=0.35
Controls hayfever Immunotherapy
Th2 responses prevent tolerance induction?
Positive feedback
Amplifier
naivenaivenaivenaive TreTregg
TreTregg
FOXP3TGF-β, TGF-β, IL-10IL-10IL-27IL-27IL-35IL-35
TGF-β, TGF-β, IL-10IL-10IL-27IL-27IL-35IL-35
NFAT
Th2Th2Th2Th2
GATA3
resistor
negative feedback
Anti-IL-4 directed therapy to augment tolerance induction against allergens
IL-4
TGF-IL-10
Mantel P-Y et al, PLOS Biology 2007;5 (12): e329
Can we predict success or failure of immunotherapy?
late phase response
IL-10 production
Duration of allergen immunotherapy (weeks)
0 2 4 6 8 12 16 20 24 28 32 36 40 44 48 52
Change in r
esp
onse
2 weeks
Grass pollencount
Time course of biomarkers during immunotherapy
J Allergy Clin Immunol 2008; 121(5):1120-1125
Early skin response
late phase response
IgE-FAB inhibition
Duration of allergen immunotherapy (weeks)0 2 4 6 8 12 16 20 24 28 32 36 40 44 48 52
Change in r
esp
onse
IgG4
Duration of allergen immunotherapy (weeks)
0 2 4 6 8 12 16 20 24 28 32 36 40 44 48 52
Change in r
esp
onse
4 weeks
8 weeks
Late allergen-induced Skin Response
Grass Pollen season
Time course of changes in IL-10 and IgG-associated inhibitory activity
J Allergy Clin Immunol 2008; 121(5):1120-1125
Pollen count
Time course of biomarkers during immunotherapy
0 2500 5000 7500 10000
0
50 r= 0.0 5
p= 0.9
Symptom/Medication scorePh
l p 5
spe
cific
IgG
4 (%
bin
ding
)
100
p = 0.02
0 2500 5000 7500 10000
40
60
80
100
r= - 0.6 5
% In
hibi
tion
of a
llerg
en/I
gE
bind
ing
to B
cel
ls
Symptom/Medication score
Correlation between clinical response (Sx/Rx) IgG4 and IgE-FAB inhibitory activity
IgG4IgE-FAB
Shamji M et al 2008, unpublished
Immunotherapy(high dose Ag)
Th1
IFN
IgG
Tr
IL-10 TGF-
IgG4 IgA
APC
Natural 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
Allergy and Clinical Immunology, Imperial College and Royal Brompton Hospital, London, UK
M Calderon K T Nouri-Aria G Paraskavopoulos D R Wilson M R Jacobson L Wilcock
C Pilette J N Francis C Schmidt-Weber
S Radulovic M Shamji S J Till