kawaguchi s , wada t, nagoya s, ida k, sato y,
DESCRIPTION
PHASE I VACCINATION TRIAL OF SYT-SSX JUNCTION PEPTIDE AND ITS HLA-A*2402 ANCHOR SUBSTITUTE IN PATIENTS WITH DISSEMINATED SYNOVIAL SARCOMA. Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y, Torigoe T, Sato N, Ishii T, Tatezaki S, Yamashita T Sapporo Medical University Chiba Cancer Center Hospital. - PowerPoint PPT PresentationTRANSCRIPT
![Page 1: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/1.jpg)
PHASE I VACCINATION TRIAL OF SYT-SSX JUNCTION PEPTIDE AND ITS HLA-A*2402 ANCHOR
SUBSTITUTE IN PATIENTS WITH DISSEMINATED SYNOVIAL SARCOMA
Kawaguchi S, Wada T, Nagoya S, Ida K, Sato Y,
Torigoe T, Sato N, Ishii T, Tatezaki S, Yamashita TSapporo Medical University
Chiba Cancer Center Hospital
![Page 2: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/2.jpg)
Synovial sarcoma
![Page 3: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/3.jpg)
Survival rate
Guillou L et al., J Clin Oncol, 2004
![Page 4: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/4.jpg)
Peptidevaccination(MAGE-3)
Peptide immunotherapy for malignant melanoma
Coulie PG, Universite de Louvain , Brussels
![Page 5: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/5.jpg)
Antigenic peptide
Tumor cell
T cell
T cell
T cell
T cell
T cellT cell
T cell
T cell
Dendritic cell
Patient
T cell
T cell
T cell
Injection
T cell
Peptide immunotherapy
![Page 6: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/6.jpg)
Gene
T cell
ProteinAntigenic peptide
Tumor cell
Antigenic peptide
HLATCR
Activation
![Page 7: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/7.jpg)
Desirable antigenic peptide
1.Tumor specific expression
2. High affinity to HLA
3. Immunogenicity
![Page 8: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/8.jpg)
Desirable antigenic peptide
1.Tumor specific expression
2. High affinity to HLA
3. Immunogenicity
![Page 9: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/9.jpg)
Tumor Fusion gene Frequency (%)
Synovial sarcoma SYT-SSX1 65 SYT-SSX2 35Ewing sarcoma EWS-FLI1 85
EWS-ERG 5-10Liposarcoma TLS-CHOP >95RMS PAX3-FKHR >75Clear cell sarcoma EWS-ATF1 >80DFSP COL1A1-PDGFb >99
Specific fusion gene
![Page 10: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/10.jpg)
Desirable antigenic peptide
1.Tumor specific expression
2. High affinity to HLA
3. Immunogenicity
![Page 11: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/11.jpg)
HLA-A24-binding motif
22 99 10101 3 456
7 8
2nd PortionY, F, W, or M
9th or 10th PortionF, L, I, W, R, or KHLA-A24
Tumor cell
T cell receptor
T cell
![Page 12: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/12.jpg)
SYT SSX(1, 2)
…… …PQQRPYGYDQIMPKKPA EHAWTHRLRERK
Y, W, K, R: HLA-A24 binding motif
A: PYGYDQIMPK C: AWTHRLRER
B: GYDQIMPKK D: AWTHRLRERK
Peptides
SYT-SSX peptides
![Page 13: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/13.jpg)
EBV NA24 F4.2 A B C D
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0
Binding affinity to HLA-A24
SYT-SSX peptides
![Page 14: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/14.jpg)
Desirable antigenic peptide
1.Tumor specific expression
2. High affinity to HLA
3. Immunogenicity
![Page 15: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/15.jpg)
Reactivity to circulating T cells
◇◇
◇ ◇
T cell(CD8)
HLA/Peptide Tetramer
FACS
1.17%
HLA-A24-positiveSynovial sarcoma patients : 16 Other sarcoma patients : 10 Healthy individuals : 10
![Page 16: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/16.jpg)
Synovial sarcoma
Other sarcomas
Healthy Individuals
-0.1
0
0.1
0.4
0.5
0.6
0.25
SYT-SSX A
SYT-SSX B
SYT-SSX C+D
Po
siti
ve c
ells
(%
)Reactivity to circulating T cells
![Page 17: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/17.jpg)
Induction of cytotoxic T lymphocytes (CTL)
Peptide stimulation(SYT-SSX B)
Mixed CultureCr release assay51
T cells
Synovial sarcomaCell line
![Page 18: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/18.jpg)
HLA-A24 SYT-SSX●Fuji (+) (+)
○HS-SY-II (+) (+)
■SW982-A24 (+) ()□K562 () ()
E/T ratio
30
20
10
0
40
30 10 3
%S
pec
ific
Lys
isCTL induction
Sato et al., J Immunol, 2002
![Page 19: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/19.jpg)
SYT-SSX B peptide
1.Tumor specific expression
2. High affinity to HLA-A24
3. Immunogenicity
![Page 20: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/20.jpg)
SYT-SSX
SYT SSX
T cellHLA-A24
SYT-SSX B
Rationale
・・ PQQRPYGYDQIMPKKPA・・・
![Page 21: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/21.jpg)
SYT-SSX B peptide
Synovial sarcoma cell
T cell
T cell
T cell
T cell
T cellT cell
T cell
T cell
Dendritic cell
Patient
T cell
T cell
T cell
Injection
T cell
Phase I clinical trial
![Page 22: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/22.jpg)
To evaluate
(i) Toxicity
(ii) Immunological property
(iii) Anti-tumor effect
of SYT-SSX B peptide vaccine in patients with disseminated synovial sarcoma
Purpose
![Page 23: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/23.jpg)
Eligibility1. Histologically diagnosed synovial sarcoma
2. SYT-SSX positive
3. HLA-A*2402 positive
4. Unresectable tumors
5. One month or more after chemotherapy
![Page 24: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/24.jpg)
Protocol
2 108640
Peptide: SYT-SSX B: GYDQIMPKK
Schedule: Every two weeks
Dose: 0.1mg in 3 patients
1.0mg in 3 patients
![Page 25: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/25.jpg)
1. Toxicity National Cancer Institute of Common Toxicity Criteria
2. Immunological property(i) Delayed-type hypersensitivity (DTH)(ii) HLA-A*2402/peptide tetramer(iii) In vitro CTL induction
3. Anti-tumor effectCT scan
Evaluation
![Page 26: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/26.jpg)
Results
![Page 27: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/27.jpg)
Case Age Gender Dose No. of immunization
1 69 M 0.1mg 1
2 32 M 0.1mg 3
3 21 F 0.1mg 6
4 21 M 1mg 6
5 39 F 1mg 6
Participants
6 26 M 1mg 4
![Page 28: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/28.jpg)
Toxicity DTH
- -- -- -- -
Fever(Grade1)
-
Toxicity and DTH
Case
12345
- -6
![Page 29: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/29.jpg)
Before vaccination After 1st vac. After 6th vac.
HIV
te
tram
er B
tet
ram
er 0.06 0.41 0.47
0.01 0.00 0.01
Tetramer analysis (Case 4)
![Page 30: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/30.jpg)
Case Pre-vac. 1st vac. 3rd vac. 6th vac.
2 0.02 0.02 3.05 N.D3 0.42 0.49 0.52 0.624 0.06 0.41 0.36 0.475 0.50 0.52 0.09 0.036 0.02 0.15 0.08 N.D
Tetramer analysis
![Page 31: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/31.jpg)
Case Pre-vac. 1st vac. 3rd vac. 6th vac.
2 Failure Failure Success ND3 Success Success Success Failure4 Failure Success Success ND5 Failure Success Failure Failure6 Failure Failure Failure ND
CTL induction
![Page 32: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/32.jpg)
May 15 June 18
Anti-tumor effect (Case 3)
![Page 33: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/33.jpg)
Anti-tumor effect (Case 5)
July 8 July 22
Sept 16Aug 19
![Page 34: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/34.jpg)
Discussion
![Page 35: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/35.jpg)
Clinical trials of fusion-gene peptides
Tumor Peptide Adjuvant Remission
SS Class I None 0/6
ES Class I IL-2 (9x106IU/m2) 1/12
RMS Class I IL-2 (9x106IU/m2) 0/4
CML Class I QS-21 5/14Class II
![Page 36: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/36.jpg)
Modification of peptide and protocol
1. Anchor motif substitution
2. Adjuvant and cytokine
3. Class II peptides
4. Protocol at the adjuvant setting
![Page 37: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/37.jpg)
Tumor
G D Q I M P K KY
HLA-A24
Anchor motif substitution
SYT-SSX B peptide
W ( tryptophan
)
L ( leucine )
F ( phenylalanine )I ( isoleucine )
![Page 38: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/38.jpg)
0
10
20
30
40
%S
pe
cif
ic L
ys
is
Fuji HS-SYII SW982 K562
0
10
20
30
40
E/T=30
E/T=10
E/T=3
Fuji HS-SYII SW982 K562
B peptide K9I peptide
CTL induction
Ida et al., J Immunol, 2004
![Page 39: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/39.jpg)
Before vaccination After 1st vaccination
Vaccination of K9I peptideH
IV
tetr
amer
B t
etra
mer 0.02
0.00
0.41
0.01
![Page 40: Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,](https://reader036.vdocuments.site/reader036/viewer/2022062315/5681588e550346895dc5ef7d/html5/thumbnails/40.jpg)
1. The safety and efficacy of SYT-SSX B peptide were evaluated in 6 patients with disseminated synovial sarcoma.
2. A total of 16 vaccinations were carried out, resulting in (i) no serious adverse effects or DTH reactions, (ii) tumor dormancy in 1, (iii) increases in CTL in 3, and (iv) CTL induction from 4 patients.
3. The present trial demonstrated the safety and immunogenicity of the peptide. Subsequent trial using a modified peptide and adjuvants is currently underway.
Conclusion