Development of HLA-A2- and HLA-A24-re stricted peptide vaccines from a nove l osteosarcoma antigen, papillomaviru s binding factor S Kawaguchi, T Tsukahara, T Wada, S Nagoya, M Kaya, T Torigoe, N Sato, T Ishii, S Tatezaki, T Yamashita Sapporo Medical University, Chiba Cancer Center Hospital
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Development of HLA-A2- and HLA-A24- restricted peptide vaccines from a novel osteosarcoma antigen, papillomavirus binding factor S Kawaguchi, T Tsukahara,
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Development of HLA-A2- and HLA-A24-restricted peptide vaccines from a novel osteosarcoma antigen, papillomavirus binding factor
S Kawaguchi, T Tsukahara, T Wada, S Nagoya, M Kaya, T Torigoe, N Sato, T Ishii, S Tatezaki, T Yamashita
Sapporo Medical University,Chiba Cancer Center Hospital
Osteosarcoma
Introduced by Alexis Boyer in 1814.
Campbell CJ, Cohen J, Enneking WF: New therapies for osteogenic sarcoma. J Bone Joint Surg Am 57:143-144, 1975.
Immunotherapy for osteosarcoma
- Immunotherapy - Methotrexate- Adriamycin
Amputation
Autologous tumor cell vaccination as adjuvant therapy
Marcove et al, CA, 1973
T cell
Tumor cell
Current immunotherapy
TCR
Vaccination
Antigenic peptide
Peptide vaccines
Tumor cell
T cell
T cell
T cell
T cell
T cellT cell
T cell
T cell
Dendritic cell
Patients
T cell
T cell
T cell
Injection
T cell
Active immunotherapy (vaccination)
MAGE-3
Peptide vaccination for malignant melanoma
Coulie PG, Universite de Louvain , Brussels
Efficacious peptide vaccinesfor Osteosarcoma
Goal
To identify tumor antigens and antigenic peptides
Tumor
T cellTCR HLA
class I
16 y.o. F, Osteosarcoma
TcOScl-303
OS2000
Nabeta et al., J Orthop Sci, 2003.
0
5
10
15
20
25
30
35
40
%sp
ecif
ic ly
sis
5050 1616E/T ratioE/T ratio
OS2000 IFN-γ(+)
OS2000 IFN-γ(-)
▲ 293EBNAK562
33
OS2000+
TcOScl-303
TcOScl-303 kills OS2000, but not 293EBNA or K562 cells
OS2000
Antigenic peptide
Expression cloning
Cloning of a gene encoding the antigenic peptide
TCR HLA class I
TcOScl-303
Papillomavirus Binding Factor (PBF)as a novel osteosarcoma antigen
Clone 1B9.1H4 ↑3' UTR (432bps)
704 PolyAΔN-PBF
PBF
337 1878↑5' UTR
5'
Open reading frame Zn finger
-Protein that binds to the E2 binding site of human papillomavirus type 8
Vaccination ProtocolPeptide (1mg) + IFA (Montanide ISA 51)
Case Age Peptide Vaccination Immune response
1 18 A24.2 2 ND 2 16 A2.2 2 ND
Toxicity Tumor - PD - PD
For many years osteogenic sarcoma has been the “bete noire” of the chemotherapeutist.
A giant step forward – If….
Burchenal JH, New Engl J Med: 1974
1970s High-dose MTX Rosen G
A clue
2000s High-dose Rosenberg SA cell transfer
1. In the staged translational research, we found that papillomavirus binding factor (PBF) serves as a novel antigen, a poor prognostic factor, and an apoptosis regulator with BAT3, of osteosarcoma.
2. PBF-derived peptides were recognized by peripheral T cells of patients with osteosarcoma and they induced specific cytotoxicity.
3. Safety and efficacy of PBF-derived peptide vaccines are currently in clinical evaluation.