why immunotherapy fails ? stephen durham imperial college and royal brompton hospital, london uk

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Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

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Page 1: 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

Page 2: 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

Page 3: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

• wrong set up

• wrong patient

• wrong allergen(s)

• wrong dose

• wrong duration

Why immunotherapy fails ?

Page 4: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

• right set up

• right patient

• right allergen(s)

• right dose

• right duration

Why immunotherapy succeeds ?

Page 5: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

• right set up

• right patient

• right allergen(s)

• right dose

• right duration

Why immunotherapy succeeds ?

Page 6: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

Immunotherapy clinic

Page 7: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

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

Page 8: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

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

Page 9: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

• right set up

• right patient

• right allergen(s)

• right dose

• right duration

Why immunotherapy succeeds ?

Page 10: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

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)

Page 11: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

Arvidsson M, Löwhagen O Rak S J Allergy Clin Immunol 2002;109:777-83

Immunotherapy in adults with birch allergy

Page 12: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

Franklin Adkinson N et al New Engl J Med 1999;

Immunotherapy in children with perennial asthma and multiple allergen sensitivities

Page 13: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

• right set up

• right patient

• right allergen(s)

• right dose

• right duration

Why immunotherapy succeeds ?

Page 14: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

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

Page 15: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

J Allergy Clin Immunol 2006; 117: 319-25

26 centres, n=410100,000 SQ, 10,000 SQ and placebo

Page 16: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

Grass pollen immunotherapy:UK immunotherapy study

Frew AJ et al, J Allergy Clin Immunol 2006; 117: 319-25

Page 17: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

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

Page 18: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

• right set up

• right patient

• right allergen(s)

• right dose

• right duration

Why immunotherapy succeeds ?

Page 19: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

J Allergy Clin Immunol 2007; 120: 1338-45

Page 20: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

Sublingual Grass Tablet Immunotherapy

J Allergy Clin Immunol 2007; 120: 1338-45

Page 21: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

J Allergy Clin Immunol 2007; 120: 1338-45

Sublingual Grass Tablet Immunotherapy

Page 22: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

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

Page 23: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

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

Page 24: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

• right set up

• right patient

• right allergen(s)

• right dose

• right duration

Why immunotherapy succeeds ?

Page 25: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

• right set up

• right patient

• right allergen(s)

• right dose

• right duration- efficacy

- tolerance

Why immunotherapy succeeds ?

Page 26: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

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

Page 27: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

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

Page 28: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

• right set up

• right patient

• right allergen(s)

• right dose

• right duration- efficacy

- tolerance (persistent efficacy after withdrawal)

Why immunotherapy succeeds ?

Page 29: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

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

Page 30: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

House dust mite IT in children : 3 years duration induces tolerance

Des Roches A et al, Allergy 1996; 51 :430-3

Page 31: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

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?

Page 32: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

• right set up

• right patient

• right allergen(s)

• right dose

• right duration- efficacy

- tolerance

Why immunotherapy succeeds ?

Page 33: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

• wrong set up

• wrong patient

• wrong allergen(s)

• wrong dose

• wrong duration- no efficacy

- no tolerance

Why immunotherapy fails?

Page 34: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

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

Page 35: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

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

Page 36: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

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

Page 37: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

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

Page 38: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK
Page 39: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

Can we predict success or failure of immunotherapy?

Page 40: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

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

Page 41: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

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

Page 42: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK
Page 43: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK
Page 44: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK
Page 45: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK
Page 46: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK
Page 47: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK
Page 48: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

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

Page 49: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

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

Page 50: Why immunotherapy fails ? Stephen Durham Imperial College and Royal Brompton Hospital, London UK

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