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
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
Synovial sarcoma
Survival rate
Guillou L et al., J Clin Oncol, 2004
Peptidevaccination(MAGE-3)
Peptide immunotherapy for malignant melanoma
Coulie PG, Universite de Louvain , Brussels
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
Gene
T cell
ProteinAntigenic peptide
Tumor cell
Antigenic peptide
HLATCR
Activation
Desirable antigenic peptide
1.Tumor specific expression
2. High affinity to HLA
3. Immunogenicity
Desirable antigenic peptide
1.Tumor specific expression
2. High affinity to HLA
3. Immunogenicity
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
Desirable antigenic peptide
1.Tumor specific expression
2. High affinity to HLA
3. Immunogenicity
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
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
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
Desirable antigenic peptide
1.Tumor specific expression
2. High affinity to HLA
3. Immunogenicity
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
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
Induction of cytotoxic T lymphocytes (CTL)
Peptide stimulation(SYT-SSX B)
Mixed CultureCr release assay51
T cells
Synovial sarcomaCell line
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
SYT-SSX B peptide
1.Tumor specific expression
2. High affinity to HLA-A24
3. Immunogenicity
SYT-SSX
SYT SSX
T cellHLA-A24
SYT-SSX B
Rationale
・・ PQQRPYGYDQIMPKKPA・・・
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
To evaluate
(i) Toxicity
(ii) Immunological property
(iii) Anti-tumor effect
of SYT-SSX B peptide vaccine in patients with disseminated synovial sarcoma
Purpose
Eligibility1. Histologically diagnosed synovial sarcoma
2. SYT-SSX positive
3. HLA-A*2402 positive
4. Unresectable tumors
5. One month or more after chemotherapy
Protocol
2 108640
Peptide: SYT-SSX B: GYDQIMPKK
Schedule: Every two weeks
Dose: 0.1mg in 3 patients
1.0mg in 3 patients
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
Results
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
Toxicity DTH
－ －－ －－ －－ －
Fever(Grade1)
－
Toxicity and DTH
Case
12345
－ －6
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)
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
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
May 15 June 18
Anti-tumor effect (Case 3)
Anti-tumor effect (Case 5)
July 8 July 22
Sept 16Aug 19
Discussion
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
Modification of peptide and protocol
1. Anchor motif substitution
2. Adjuvant and cytokine
3. Class II peptides
4. Protocol at the adjuvant setting
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 ）
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
Before vaccination After 1st vaccination
Vaccination of K9I peptideH
IV
tetr
amer
B t
etra
mer 0.02
0.00
0.41
0.01
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