Why immunotherapy fails

1
Why immunotherapy fails ?

• Stephen Durham
• Imperial College and
• Royal Brompton Hospital,
• London UK

2
Declaration

• Research funding, consultancy and lecture fees
  from ALK Abello
• Lecture fees from Allergy Therapeutics

3
Why immunotherapy fails ?

• wrong set up
• wrong patient
• wrong allergen(s)
• wrong dose
• wrong duration

4
Why immunotherapy succeeds ?

• right set up
• right patient
• right allergen(s)
• right dose
• right duration

5
Why immunotherapy succeeds ?

• right set up
• right patient
• right allergen(s)
• right dose
• right duration

6
Immunotherapy clinic
7
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
8
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
9
Why immunotherapy succeeds ?

• right set up
• right patient
• right allergen(s)
• right dose
• right duration

10
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)

11
Arvidsson M, Löwhagen O Rak S J Allergy Clin
Immunol 2002109777-83
Immunotherapy in adults with birch allergy
12
Immunotherapy in children with perennial asthma
and multiple allergen sensitivities
Franklin Adkinson N et al New Engl J Med 1999
13
Why immunotherapy succeeds ?

• right set up
• right patient
• right allergen(s)
• right dose
• right duration

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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

15
J Allergy Clin Immunol 2006 117 319-25
26 centres, n410 100,000 SQ, 10,000 SQ and
placebo
16
Grass pollen immunotherapyUK immunotherapy
study
Frew AJ et al, J Allergy Clin Immunol 2006 117
319-25
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Rhinoconjunctivitis QoL score
3
plt0.001
2
p0.027
1.5
P0.027
1
p0.027
P0.027
0.5
0
Frew AJ et al, J Allergy Clin Immunol 2006 117
319-25
18
Why immunotherapy succeeds ?

• right set up
• right patient
• right allergen(s)
• right dose
• right duration

19
J Allergy Clin Immunol 2007 120 1338-45
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Sublingual Grass Tablet Immunotherapy
J Allergy Clin Immunol 2007 120 1338-45
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Sublingual Grass Tablet Immunotherapy
J Allergy Clin Immunol 2007 120 1338-45
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Randomised DBPC trial (n855). 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
23
Sublingual Grass Tablet Immunotherapy
Durham SR et al. J Allergy Clin Immunol 2006
117 802-9
24
Why immunotherapy succeeds ?

• right set up
• right patient
• right allergen(s)
• right dose
• right duration

25
Why immunotherapy succeeds ?

• right set up
• right patient
• right allergen(s)
• right dose
• right duration
• - efficacy
• - tolerance

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8 Weeks Pre-Seasonal Treatment
17 reduction in average seasonal daily
rhinoconjunctivitis symptom (plt0.05) 23
reduction in average seasonal daily medication
scores ( plt0.05)
Calderon MA et al. Allergy 2007
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gt 8 Weeks Pre-Seasonal Treatment
37 reduction in average seasonal daily
rhinoconjunctivitis symptom (plt0.0001) 47
reduction in average seasonal daily medication
scores ( plt0.0001)
Calderon MA et al. Allergy 2007
28
Why immunotherapy succeeds ?

• right set up
• right patient
• right allergen(s)
• right dose
• right duration
• - efficacy
• - tolerance (persistent efficacy after
  withdrawal)

29
Grass pollen IT in adults 3 years duration
induces tolerance
Durham SR et al New Engl J Med 1999341468-75
30
House dust mite IT in children 3 years duration
induces tolerance
Des Roches A et al, Allergy 1996 51 430-3
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Can sublingual immunotherapy induce tolerance?
J Allergy Clin Immunol 200812512-518
32
Why immunotherapy succeeds ?

• right set up
• right patient
• right allergen(s)
• right dose
• right duration
• - efficacy
• - tolerance

33
Why immunotherapy fails?

• wrong set up
• wrong patient
• wrong allergen(s)
• wrong dose
• wrong duration
• - no efficacy
• - no tolerance

34
Robinson DS, Larche ML and Durham SR J Clin
Invest 2004 114 1389-97
35
Two types of regulatory T cells
Natural
CD4CD25 T cells Foxp3 transcription
factor
Treg
Thymus
Adaptive
Tr1 cells IL-10 Foxp3?
Tr1
Th3
Th3 cells TGF-b
36
Phenotypic Tregs in the nasal mucosa
J Allergy Clin Immunol 2008 April 17th epub
CD3 CD25 Foxp3
CD3 IL-10 Foxp3
Controls hayfever Immunotherapy
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Th2 responses prevent tolerance induction?
IL-4
TGF-b IL-10
naive
Mantel P-Y et al, PLOS Biology 2007 5 (12)
e329
38

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Can we predict success or failure of
immunotherapy?
40
Time course of biomarkers during immunotherapy
2 weeks
IL-10 production
Grass pollen count
Change in response
late phase response
0
2
4
6
8
12
16
20
24
28
32
36
40
44
48
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Duration of allergen immunotherapy (weeks)
J Allergy Clin Immunol 2008 121(5)1120-1125
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Time course of changes in IL-10 and
IgG-associated inhibitory activity
Time course of biomarkers during immunotherapy
Late allergen-induced Skin Response
4 weeks
Grass Pollen season
Change in response
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
IgG4
IgE-FAB inhibition
Change in response
Pollen count
8 weeks
Early skin response
0
2
4
6
8
12
16
20
24
28
32
36
40
44
48
52
Duration of allergen immunotherapy (weeks)
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Correlation between clinical response (Sx/Rx)
IgG4 and IgE-FAB inhibitory activity
IgG4
IgE-FAB
p 0.02
Shamji M et al 2008, unpublished
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Robinson DS, Larche ML and Durham SR J Clin
Invest 2004 114 1389-97
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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