novel strategies and future directions in immunotherapy strategies and future... · novel...

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

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

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


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


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%


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

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

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)

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.

novel strategies and future directions in immunotherapy strategies and future... · novel...

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