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PHASE I VACCINATION TRIAL OF SYT-SSX JUNCTION PEPTIDE AND ITS HLA-A*2402 ANCHOR SUBSTITUTE IN PATIENTS WITH DISSEMINATED PowerPoint Presentation
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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.

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slide1

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

slide3

Survival rate

Guillou Let al., J Clin Oncol, 2004

slide4

Peptide immunotherapy for

malignant melanoma

Peptide

vaccination

(MAGE-3)

Coulie PG, Universite de Louvain ,Brussels

slide5

T cell

T cell

T cell

Peptide immunotherapy

Patient

Antigenic peptide

Injection

T cell

T cell

Dendritic cell

T cell

T cell

T cell

T cell

T cell

T cell

T cell

Tumor cell

slide6

Antigenic peptide

Antigenic

peptide

Protein

HLA

TCR

T cell

Gene

Tumor cell

Activation

slide7

Desirable antigenic peptide

  • Tumor specific expression
  • High affinity to HLA
  • 3. Immunogenicity
slide8

Desirable antigenic peptide

  • Tumor specific expression
  • High affinity to HLA
  • 3. Immunogenicity
slide9

Specific fusion gene

Tumor Fusion gene Frequency (%)

Synovial sarcoma SYT-SSX1 65

SYT-SSX2 35

Ewing sarcoma EWS-FLI1 85

EWS-ERG 5-10

Liposarcoma TLS-CHOP >95

RMS PAX3-FKHR >75

Clear cell sarcoma EWS-ATF1 >80

DFSP COL1A1-PDGFb >99

slide10

Desirable antigenic peptide

  • Tumor specific expression
  • High affinity to HLA
  • 3. Immunogenicity
slide11

6

5

7

1

4

8

10

10

3

2

2

9

9

HLA-A24-binding motif

T cell

T cell receptor

2nd Portion

Y, F, W, or M

9th or 10th Portion

F, L, I, W, R, or K

HLA-A24

Tumor cell

slide12

SYT

SSX(1, 2)

……

PQQRPYGYDQIMPKKPA

EHAWTHRLRERK

SYT-SSX peptides

Peptides

A:PYGYDQIMPKC:AWTHRLRER

B:GYDQIMPKK D:AWTHRLRERK

Y, W, K, R: HLA-A24 binding motif

slide13

Binding affinity to HLA-A24

1.8

1.6

1.4

1.2

1.0

0.8

0.6

0.4

0.2

0

EBV

NA24

F4.2

A

B

C

D

SYT-SSX peptides

slide14

Desirable antigenic peptide

  • Tumor specific expression
  • High affinity to HLA
  • 3. Immunogenicity
slide15

1.17%

T cell

(CD8)

Reactivity to circulating T cells

  • HLA-A24-positive
  • Synovial sarcoma patients : 16
  • Other sarcoma patients : 10
  • Healthy individuals : 10

FACS

HLA/Peptide

Tetramer

slide16

Reactivity to circulating T cells

0.6

SYT-SSX A

SYT-SSX B

SYT-SSX C+D

0.5

0.4

Positive cells (%)

0.25

0.1

0

-0.1

Synovial

sarcoma

Other

sarcomas

Healthy

Individuals

slide17

Cr release assay

51

Induction of cytotoxic T lymphocytes (CTL)

Synovial sarcoma

Cell line

Peptide stimulation

(SYT-SSX B)

Mixed Culture

T cells

slide18

CTL induction

HLA-A24 SYT-SSX

●Fuji (+) (+)

○HS-SY-II (+) (+)

■SW982-A24 (+) ()

□K562 () ()

40

30

%Specific Lysis

20

10

0

Sato et al., J Immunol, 2002

30

10

3

E/T ratio

slide19

SYT-SSX B peptide

  • Tumor specific expression
  • High affinity to HLA-A24
  • 3. Immunogenicity
slide20

Rationale

SYT-SSX B

T cell

SYT-SSX

HLA-A24

SYT

SSX

・・PQQRPYGYDQIMPKKPA・・・

slide21

T cell

T cell

T cell

Phase I clinical trial

Patient

SYT-SSX B peptide

Injection

T cell

T cell

Dendritic cell

T cell

T cell

T cell

T cell

T cell

T cell

T cell

Synovial sarcoma cell

slide22

Purpose

  • To evaluate
    • Toxicity
    • Immunological property
    • Anti-tumor effect
  • of SYT-SSX B peptide vaccine in patients with disseminated synovial sarcoma
slide23

Eligibility

1. Histologically diagnosed synovial sarcoma

2. SYT-SSX positive

3. HLA-A*2402 positive

4. Unresectable tumors

5. One month or more after chemotherapy

slide24

Protocol

Peptide: SYT-SSX B: GYDQIMPKK

Schedule: Every two weeks

Dose:0.1mg in 3 patients

1.0mg in 3 patients

0

2

4

6

8

10

slide25

Evaluation

  • 1. Toxicity
  • National Cancer Institute of Common Toxicity Criteria
  • 2. Immunological property
    • Delayed-type hypersensitivity (DTH)
    • HLA-A*2402/peptide tetramer
    • In vitro CTL induction
  • 3. Anti-tumor effect
  • CT scan
slide27

Participants

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

6

26

M

1mg

4

slide28

Toxicity and DTH

Case

Toxicity

DTH

1

2

3

4

5

Fever

(Grade1)

6

slide29

Tetramer analysis (Case 4)

Before vaccination

After 1st vac.

After 6th vac.

0.47

0.41

0.06

B tetramer

0.01

0.00

0.01

HIV tetramer

slide30

Tetramer analysis

Case Pre-vac. 1st vac. 3rd vac. 6th vac.

  • 0.02 0.02 3.05 N.D
  • 0.420.490.520.62
  • 0.06 0.410.360.47
  • 0.500.520.090.03
  • 0.02 0.15 0.08 N.D
slide31

CTL induction

Case Pre-vac. 1st vac. 3rd vac. 6th vac.

  • Failure Failure Success ND
  • Success Success Success Failure
  • Failure Success Success ND
  • Failure Success Failure Failure
  • Failure Failure Failure ND
slide33

Anti-tumor effect (Case 5)

July 8

July 22

Sept 16

Aug 19

slide35

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 5/14

Class II

slide36

Modification of peptide and protocol

  • Anchor motif substitution
  • 2. Adjuvant and cytokine
  • 3. Class II peptides
  • 4. Protocol at the adjuvant setting
slide37

Anchor motif substitution

L (leucine)

SYT-SSX B

peptide

F (phenylalanine)

I (isoleucine)

M

I

P

G

Q

K

D

K

Y

W(tryptophan)

HLA-A24

Tumor

slide38

E/T=30

40

E/T=10

E/T=3

30

20

10

0

40

30

20

10

0

CTL induction

B peptide

K9I peptide

%Specific Lysis

Fuji HS-SYII SW982 K562

Fuji HS-SYII SW982 K562

Ida et al., J Immunol, 2004

slide39

0.41

0.02

B tetramer

0.01

0.00

HIV tetramer

Vaccination of K9I peptide

Before vaccination

After 1st vaccination

slide40

Conclusion

  • The safety and efficacy of SYT-SSX B peptide were evaluated in 6 patients with disseminated synovial sarcoma.
  • 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.
  • The present trial demonstrated the safety and immunogenicity of the peptide. Subsequent trial using a modified peptide and adjuvants is currently underway.