intralymphatic immunotherapy ilit...intralymphatic immunotherapy for cat allergy induces tolerance...
TRANSCRIPT
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
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
Pollen
season
baseline
Pollen
season
1
Pollen
season
2+3
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
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
Pollen
season
baseline
Pollen
season
1
Pollen
season
2+3
Sept
Oct
Jan
Feb
Sept
Oct
Sept
Oct
Evaluation
visits
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
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
Pollen
season
baseline
Pollen
season
1
Pollen
season
2+3
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
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
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
Senti et al. JACI 2012
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.
Senti et al. JACI 2012
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
Senti et al. JACI 2012
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
Senti et al. JACI 2012
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
JACI 2013 Feb;131(2):412-20
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.
JACI / The Journal of allergy and clinical immunology 129: 128-135.
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.
JACI / The Journal of allergy and clinical immunology 124: 997-1002.
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.
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