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Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,

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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Kawaguchi S , Wada T, Nagoya S, Ida K, Sato Y,

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  1. 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

  2. Synovial sarcoma

  3. Survival rate Guillou Let al., J Clin Oncol, 2004

  4. Peptide immunotherapy for malignant melanoma Peptide vaccination (MAGE-3) Coulie PG, Universite de Louvain ,Brussels

  5. 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

  6. Antigenic peptide Antigenic peptide Protein HLA TCR T cell Gene Tumor cell Activation

  7. Desirable antigenic peptide • Tumor specific expression • High affinity to HLA • 3. Immunogenicity

  8. Desirable antigenic peptide • Tumor specific expression • High affinity to HLA • 3. Immunogenicity

  9. 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

  10. Desirable antigenic peptide • Tumor specific expression • High affinity to HLA • 3. Immunogenicity

  11. 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

  12. 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

  13. 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

  14. Desirable antigenic peptide • Tumor specific expression • High affinity to HLA • 3. Immunogenicity

  15. ◇ ◇ 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

  16. 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

  17. Cr release assay 51 Induction of cytotoxic T lymphocytes (CTL) Synovial sarcoma Cell line Peptide stimulation (SYT-SSX B) Mixed Culture T cells

  18. 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

  19. SYT-SSX B peptide • Tumor specific expression • High affinity to HLA-A24 • 3. Immunogenicity

  20. Rationale SYT-SSX B T cell SYT-SSX HLA-A24 SYT SSX ・・PQQRPYGYDQIMPKKPA・・・

  21. 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

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

  23. 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

  24. 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

  25. 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

  26. Results

  27. 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

  28. Toxicity and DTH Case Toxicity DTH 1 － － 2 － － 3 － － 4 － － 5 Fever (Grade1) － 6 － －

  29. 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

  30. 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

  31. 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

  32. Anti-tumor effect (Case 3) June 18 May 15

  33. Anti-tumor effect (Case 5) July 8 July 22 Sept 16 Aug 19

  34. Discussion

  35. 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

  36. Modification of peptide and protocol • Anchor motif substitution • 2. Adjuvant and cytokine • 3. Class II peptides • 4. Protocol at the adjuvant setting

  37. 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

  38. 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

  39. 0.41 0.02 B tetramer 0.01 0.00 HIV tetramer Vaccination of K9I peptide Before vaccination After 1st vaccination

  40. 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.

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