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

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

Novel approaches to immunotherapy

•Adjuvants•Alternative routes•Peptides•Fusion proteins •Recombinant allergens

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

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

Durham SR et al J Allergy Clin Immunol 2009 (in press)

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%

Durham SR et al J Allergy Clin Immunol 2009 (in press)

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

Novel approaches to immunotherapy

•Adjuvants•Alternative routes•Peptides•Fusion proteins •Recombinant allergens

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

Novel approaches to immunotherapy

•Adjuvants•Alternative routes•Peptides•Fusion proteins •Recombinant allergens

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)

Novel approaches to immunotherapy

•Adjuvants•Alternative routes•Peptides•Fusion proteins •Recombinant allergens

J Allergy Clin Immunol 2005; 116: 608-13

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.