intralymphatic immunotherapy ilit...intralymphatic immunotherapy for cat allergy induces tolerance...

Intralymphatic Immunotherapy ILIT

Gabriela Senti

Center for Clinical Research

University and University Hospital Zurich

Subcutaneous Immunotherapy

Problems

Intralymphatic Immunotherapy

Protein Vaccines

subcutaneous

into lymph node

IgG ?

Anti-P

LA

2 I

gG

2a

101

102

103

104

105

0 4 8 12

Anti-P

LA

2 I

gE

101

102

Time (weeks)

0 4 8 12 0 4 8 12

0.01 g 0.1 g 10 g

Anti-P

LA

2 I

gG

2a

101

102

103

104

105

0 4 8 12

Anti-P

LA

2 I

gE

101

102

Time (weeks)

0 4 8 12 0 4 8 12

0.01 g 0.1 g 10 g

● intralymphatic (ILIT) □ subcutaneous (SCIT) Δ intraperitoneal

Allergen Administration Route

Injection into Lymph Nodes

Inguinal Lymph Nodes

no large vessels

little movement

close to vessels

leg movement

into

lymph node Subcutaneous

20 Min

25 h

Senti et al.

Curr Opin Allergy

Clin Immunol 2009

Clinical Trial ZU-BV-001

5 years

Alle

rgen

(~80 injections)

3 injections

2 wk intervals

100g

10g

Alle

rgen

Before After

0

1

2

3

4 p=0.0012

Vaccination

BV

sti

ng

ch

all

en

ge s

co

re

Sting Provocation

Fig. 4

Screened for eligibility

n=172

Randomized

n=154

Allocated to

Intralymphatic SIT

n=66

Baseline

n=58 (Tree=19)

4 months

n=58 (Tree=19)

1 year

n=54 (Tree=17)

3 years

n=38 (Tree=15)

Received treatment

n=58 (Tree=19)

Allocated to

Subcutaneous SIT

n=87

Baseline

n=54 (Tree=19)

4 months

n=54 (Tree=19)

1 year

n=53 (Tree=16)

3 years

n=32 (Tree=12)

Received treatment

n=54 (Tree=19)

Excluded n=18

Not meeting inclusion

criteria n=18

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║Alle

rge

n (

SQ

-U)

Cum. dose = 4‘031‘540 SQ-U

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║Alle

rge

n (

SQ

-U)

Cum. dose = 4‘031‘540 SQ-U

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║

weeks

Alle

rge

n (

SQ

-U)

Cum. dose

= 3‘000 SQ-U

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║

weeks

Alle

rge

n (

SQ

-U)

Cum. dose

= 3‘000 SQ-U

baseline 4 months 1 year 3 years

Evaluation visits

Fig. 4


n=172

Randomized

n=154

Allocated to

Intralymphatic SIT

n=66

Baseline

n=58 (Tree=19)

4 months

n=58 (Tree=19)

1 year

n=54 (Tree=17)

3 years

n=38 (Tree=15)

Received treatment

n=58 (Tree=19)

Allocated to

Subcutaneous SIT

n=87

Baseline

n=54 (Tree=19)

4 months

n=54 (Tree=19)

1 year

n=53 (Tree=16)

3 years

n=32 (Tree=12)

Received treatment

n=54 (Tree=19)

Excluded n=18


criteria n=18

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║Alle

rge

n (

SQ

-U)

Cum. dose = 4‘031‘540 SQ-U

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║Alle

rge

n (

SQ

-U)

Cum. dose = 4‘031‘540 SQ-U

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║

weeks

Alle

rge

n (

SQ

-U)

Cum. dose

= 3‘000 SQ-U

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║

weeks

Alle

rge

n (

SQ

-U)

Cum. dose

= 3‘000 SQ-U


Evaluation visits

Pollen

season

baseline

Pollen

season

1

Pollen

season

2+3

Fig. 4


n=172

Randomized

n=154

Allocated to

Intralymphatic SIT

n=66

Baseline

n=58 (Tree=19)

4 months

n=58 (Tree=19)

1 year

n=54 (Tree=17)

3 years

n=38 (Tree=15)

Received treatment

n=58 (Tree=19)

Allocated to

Subcutaneous SIT

n=87

Baseline

n=54 (Tree=19)

4 months

n=54 (Tree=19)

1 year

n=53 (Tree=16)

3 years

n=32 (Tree=12)

Received treatment

n=54 (Tree=19)

Excluded n=18


criteria n=18

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║Alle

rge

n (

SQ

-U)

Cum. dose = 4‘031‘540 SQ-U

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║Alle

rge

n (

SQ

-U)

Cum. dose = 4‘031‘540 SQ-U

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║

weeks

Alle

rge

n (

SQ

-U)

Cum. dose

= 3‘000 SQ-U

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║

weeks

Alle

rge

n (

SQ

-U)

Cum. dose

= 3‘000 SQ-U


Evaluation visits

Fig. 4


n=172

Randomized

n=154

Allocated to

Intralymphatic SIT

n=66

Baseline

n=58 (Tree=19)

4 months

n=58 (Tree=19)

1 year

n=54 (Tree=17)

3 years

n=38 (Tree=15)

Received treatment

n=58 (Tree=19)

Allocated to

Subcutaneous SIT

n=87

Baseline

n=54 (Tree=19)

4 months

n=54 (Tree=19)

1 year

n=53 (Tree=16)

3 years

n=32 (Tree=12)

Received treatment

n=54 (Tree=19)

Excluded n=18


criteria n=18

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║Alle

rge

n (

SQ

-U)

Cum. dose = 4‘031‘540 SQ-U

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║Alle

rge

n (

SQ

-U)

Cum. dose = 4‘031‘540 SQ-U

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║

weeks

Alle

rge

n (

SQ

-U)

Cum. dose

= 3‘000 SQ-U

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║

weeks

Alle

rge

n (

SQ

-U)

Cum. dose

= 3‘000 SQ-U


Evaluation visits

Pollen

season

baseline

Pollen

season

1

Pollen

season

2+3

Sept

Oct

Jan

Feb

Sept

Oct

Sept

Oct

Evaluation

visits

Fig. 4


n=172

Randomized

n=154

Allocated to

Intralymphatic SIT

n=66

Baseline

n=58 (Tree=19)

4 months

n=58 (Tree=19)

1 year

n=54 (Tree=17)

3 years

n=38 (Tree=15)

Received treatment

n=58 (Tree=19)

Allocated to

Subcutaneous SIT

n=87

Baseline

n=54 (Tree=19)

4 months

n=54 (Tree=19)

1 year

n=53 (Tree=16)

3 years

n=32 (Tree=12)

Received treatment

n=54 (Tree=19)

Excluded n=18


criteria n=18

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║Alle

rge

n (

SQ

-U)

Cum. dose = 4‘031‘540 SQ-U

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║Alle

rge

n (

SQ

-U)

Cum. dose = 4‘031‘540 SQ-U

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║

weeks

Alle

rge

n (

SQ

-U)

Cum. dose

= 3‘000 SQ-U

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║

weeks

Alle

rge

n (

SQ

-U)

Cum. dose

= 3‘000 SQ-U


Evaluation visits

Fig. 4


n=172

Randomized

n=154

Allocated to

Intralymphatic SIT

n=66

Baseline

n=58 (Tree=19)

4 months

n=58 (Tree=19)

1 year

n=54 (Tree=17)

3 years

n=38 (Tree=15)

Received treatment

n=58 (Tree=19)

Allocated to

Subcutaneous SIT

n=87

Baseline

n=54 (Tree=19)

4 months

n=54 (Tree=19)

1 year

n=53 (Tree=16)

3 years

n=32 (Tree=12)

Received treatment

n=54 (Tree=19)

Excluded n=18


criteria n=18

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║Alle

rge

n (

SQ

-U)

Cum. dose = 4‘031‘540 SQ-U

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║Alle

rge

n (

SQ

-U)

Cum. dose = 4‘031‘540 SQ-U

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║

weeks

Alle

rge

n (

SQ

-U)

Cum. dose

= 3‘000 SQ-U

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║

weeks

Alle

rge

n (

SQ

-U)

Cum. dose

= 3‘000 SQ-U


Evaluation visits

Pollen

season

baseline

Pollen

season

1

Pollen

season

2+3

Fig. 4


n=172

Randomized

n=154

Allocated to

Intralymphatic SIT

n=66

Baseline

n=58 (Tree=19)

4 months

n=58 (Tree=19)

1 year

n=54 (Tree=17)

3 years

n=38 (Tree=15)

Received treatment

n=58 (Tree=19)

Allocated to

Subcutaneous SIT

n=87

Baseline

n=54 (Tree=19)

4 months

n=54 (Tree=19)

1 year

n=53 (Tree=16)

3 years

n=32 (Tree=12)

Received treatment

n=54 (Tree=19)

Excluded n=18


criteria n=18

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║Alle

rge

n (

SQ

-U)

Cum. dose = 4‘031‘540 SQ-U

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║Alle

rge

n (

SQ

-U)

Cum. dose = 4‘031‘540 SQ-U

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║

weeks

Alle

rge

n (

SQ

-U)

Cum. dose

= 3‘000 SQ-U

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║

weeks

Alle

rge

n (

SQ

-U)

Cum. dose

= 3‘000 SQ-U


Evaluation visits

Fig. 4


n=172

Randomized

n=154

Allocated to

Intralymphatic SIT

n=66

Baseline

n=58 (Tree=19)

4 months

n=58 (Tree=19)

1 year

n=54 (Tree=17)

3 years

n=38 (Tree=15)

Received treatment

n=58 (Tree=19)

Allocated to

Subcutaneous SIT

n=87

Baseline

n=54 (Tree=19)

4 months

n=54 (Tree=19)

1 year

n=53 (Tree=16)

3 years

n=32 (Tree=12)

Received treatment

n=54 (Tree=19)

Excluded n=18


criteria n=18

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║Alle

rge

n (

SQ

-U)

Cum. dose = 4‘031‘540 SQ-U

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║Alle

rge

n (

SQ

-U)

Cum. dose = 4‘031‘540 SQ-U

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║

weeks

Alle

rge

n (

SQ

-U)

Cum. dose

= 3‘000 SQ-U

1

10

100

1000

10000

100000

0 8 16 24 32 40 140 148 156

║

weeks

Alle

rge

n (

SQ

-U)

Cum. dose

= 3‘000 SQ-U


Evaluation visits

Pollen

season

baseline

Pollen

season

1

Pollen

season

2+3

Sept

Oct

Jan

Feb

Sept

Oct

Sept

Oct

Evaluation

visits

165 grass

allergic pat.

99

66

54

58

32

38 54

53

58

54

8

45

Patients

Senti et al. PNAS 2008

Route of administration

Pa

in s

co

re (

VA

S)

0

20

40

60

80

100

Intralymphatic injection

Venous puncture

Pain?

102

103

104

105

102

103

104

105

Pollen concentration IU/ml

Gra

ss p

olle

nS

ympto

m s

core

0

2

4

6

intralymphatic subcutaneous

0 12 24 36

Maxi

mum

tole

rate

d

concentr

ation (

log10)

4.5

5.0

5.5

6.0

0 12 24 36

subcutaneousintralymphatic

Time (months)

Medicaments

1 2 3 4

Patients

(%

)

0

10

20

30

40

50

60

70

conventional

lymphatic

VA

S s

ympto

m s

core

0

2

4

6

8

10 hayfever nasal congestion nasal itching sneezing

0

2

4

6

8

10 red eyes ocular itching

Time (years)

asthma dry cough

0 1 3 0 1 30 1 30 1 3

102 103 104 105 102 103 104 105

subcutaneous

intralymphatic

YearsMedications

0 1 3 0 1 3 0 1 3 0 1 31 2 3 4

Pa

tien

ts (

%)

Sym

pto

m s

co

re (

VA

S)

A B

DC

Grass pollen extract (SQ-U) Months

102

103

104

105

102

103

104

105

Pollen concentration IU/ml

Gra

ss p

olle

nS

ympto

m s

core

0

2

4

6

intralymphatic subcutaneous

0 12 24 36

Maxi

mum

tole

rate

d

concentr

ation (

log10)

4.5

5.0

5.5

6.0

0 12 24 36

subcutaneousintralymphatic

Time (months)

Medicaments

1 2 3 4

Patients

(%

)

0

10

20

30

40

50

60

70

conventional

lymphatic

VA

S s

ympto

m s

core

0

2

4

6

8

10 hayfever nasal congestion nasal itching sneezing

0

2

4

6

8

10 red eyes ocular itching

Time (years)

asthma dry cough

0 1 3 0 1 30 1 30 1 3

102 103 104 105 102 103 104 105

subcutaneous

intralymphatic

YearsMedications

0 1 3 0 1 3 0 1 3 0 1 31 2 3 4

Pa

tien

ts (

%)

Sym

pto

m s

co

re (

VA

S)

A B

DC

Grass pollen extract (SQ-U) Months

Nasal Provocation Test

Senti et al. PNAS 2008

endo-

lysosome

Golgi

ER

MHCII

invariant

chain (Ii)

Antigen Presentation

IhC

Tat

ER

Golgi

MHCII

Lysosom

allergen

allergen

Molecular targeting : MAT Antigen

(Modular antigen transporter)

- Tat protein for cytoplamic update

- IC for targeting MHC II Receptor

Matinez-Gómez et al. Allergy 2009

V1a V1b V2a V2b V2c V4

5d 28d 28d 28d

12 Alum + MAT-Fel d 1

8 Alum + placebo

10 g 3 g 1 g

Screening Treatment Efficacy

V3

IVN-CAT-001b

Senti et al. JACI 2012

Placebo Verum

Severity mild moderate mild moderate

Local reactions

temporary lymphnode swelling 2 1 3 1

Systemic reactions

rhinorea 1 1 0 0

sneezing 1 1 0 0

pruritus 1 1 0 0

nausea 0 0 1 0

rash 0 0 0 1

dyspnoe 2 0 1 0

headache 1 1 0 0

cough 1 0 0 0

Total 9 5 5 2

Adverse Events

Possibly drug related AE

No SAE


1 10

IL-10 (Post/Pre)

1 10

IgG

4 (

Post/

Pre

)

1

10

100

IL-10 Correlates with IgG4

p=0.0004 p=n.s.


SPT

Placebo Verum

-2

-1

0

1

2

3

Treatment group

Fo

ld im

pro

ve

me

nt

n.s.

**

IPT

Placebo Verum

-3

-2

-1

0

1

2

3

Treatment group

Fo

ld im

pro

ve

me

nt

**n.s.

Alle

rgen (

log

10)

Prick Test and Intradermal Test

SPT IDT

p<0.05 p<0.05

Improvment

Factor 3.16

Improvment

Factor 4.64


Nasal Tolerance NPT

Placebo Verum

0

1

2

3

Treatment group

Imp

rove

me

nt

(Po

st/

Pre

lo

g1

0)

73x

P<0.001


More data will be published soon

From Kopenhagen Low efficacy?

Weekly intervall too short?

From Stockholm Very positive results

We can relax again…

Interest from China Drug Development

is not easy…

Is intralymphatic specific immunotherapy with grass

pollen allergen ready for clinical use?

Malling, H; Blom, L; Poulsen, B; Poulsen, L; Witten, M

IgG4 IgE

IgG4 IgE ICT

VAS RQLQ

VAS RQLQ

4wk

IgG4 IgE SPT

NPT

VAS

JACI 2013, 07/033

JACI 2013, 07/033

JACI 2013 Feb;131(2):412-20

Practicability and safety of intralymphatic allergenspecific

immunotherapy in dogs with atopic dermatitis.

Hatzmann K, Mueller RS.

Vet Dermatol 2011

“intralymphatic allergen-specific immunotherapy is an interesting and

safe alternative to subcutaneous administration. A more prominent

decrease of pruritus score, CADESI (Canine Atopic Dermatitis Extent

and Severity Index) and total score was noted in the trial group”

3 low dose i.ln. vs. 30 high dose s.c.

“Antibodies of all four isotypes, IgG1,

IgG2, IgA, and IgM, increased in dry

secretions following immunization via

lymph node.”

Conclusions ILIT vs SCIT

Low allergen doses Improved safety

Enhanced immunogenicity Fewer injections

Practically painless Enhanced compliance

Epicutaneous Immunotherapy

1911 “prophylactic hypodermic

inoculation””

1929 “into the substance of the skin”

P = 0.002

P = 0.04

ZU-Skin-SIT 001

Ch

an

ge o

f h

ay

fev

er s

ym

pto

ms

-100

-50

0

50

100

Placebo 1mg 5mg 10mg Placebo 1mg 5mg 10mg

2008 2009

Treatment group

1.0 0.3 0.1 Placebo

Impro

vem

ent

(%)

Ch

an

ge o

f h

ay

fev

er s

ym

pto

ms

-100

-50

0

50

100

Placebo 1mg 5mg 10mg Placebo 1mg 5mg 10mg

2008 2009

Treatment group

Allergen dose

30%

better

than

placebo

ZU-Skin-SIT 002

EPIT is «en vogue»

From Paris DVB /VIASKIN

Preclinical Data

From Osaka Dissolving Microneedles

Infectious Disease Data

From Salzburg Generated micropores

using Laser Technologies

Preclinical Data

Efficacy

Allergen dose

EPIT ILIT

SCIT SLIT

Convenience Convenience

Summary

Senti G, Crameri R, Kuster D, Johansen P, Martinez-Gomez JM, Graf N, Steiner M, Hothorn

LA, Grönlund H, Tivig C, Zaleska A, Soyer O, van Hage M, Akdis CA, Akdis M, Rose H &

Kündig TM. (2012)

Intralymphatic immunotherapy for cat allergy induces tolerance after only 3

injections.

JACI / The Journal of allergy and clinical immunology 129: 1290-1296.

Senti G, von Moos S, Tay F, Graf N, Sonderegger T, Johansen P & Kündig TM. (2012)

Epicutaneous allergen-specific immunotherapy ameliorates grass pollen-induced

rhinoconjunctivitis: Adouble-blind, placebo-controlled dose escalation study.


Senti G, Graf N, Haug S, Ruedi N, von Moos S, Sonderegger T, Johansen P & Kündig TM.

(2009)

Epicutaneous allergen administration as a novel method of allergen-specific

immunotherapy.


Senti G, Prinz Vavricka BM, Erdmann I, Diaz MI, Markus R, McCormack SJ, Simard JJ,

Wüthrich B, Crameri R, Graf N, Johansen P & Kündig TM. (2008)

Intralymphatic allergen administration renders specific immunotherapy faster and

safer: a randomized controlled trial.

PNAS / Proceedings of the National Academy of Sciences of the United States of America

105: 17908-17912.

More Senti & Kündig Stories will follow

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intralymphatic immunotherapy ilit...intralymphatic immunotherapy for cat allergy induces tolerance...

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