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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.

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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 vaccines from a novel osteosarcoma antigen, papillomavirus binding factor

Introduced by Alexis Boyer in 1814.


Immunotherapy for osteosarcoma vaccines from a novel osteosarcoma antigen, papillomavirus binding factor

Campbell CJ, Cohen J, Enneking WF:

New therapies for osteogenic sarcoma.

J Bone Joint Surg Am 57:143-144, 1975.

- Immunotherapy

- Methotrexate

- Adriamycin


Autologous tumor cell vaccination vaccines from a novel osteosarcoma antigen, papillomavirus binding factor

as adjuvant therapy

Amputation

Marcove et al, CA, 1973


Current immunotherapy vaccines from a novel osteosarcoma antigen, papillomavirus binding factor

Antigenic peptide

TCR

T cell

Tumor cell

Vaccination


T cell vaccines from a novel osteosarcoma antigen, papillomavirus binding factor

T cell

T cell

Active immunotherapy (vaccination)

Patients

Peptide vaccines

Injection

T cell

T cell

Dendritic cell

T cell

T cell

T cell

T cell

T cell

T cell

T cell

Tumor cell


Peptide vaccination vaccines from a novel osteosarcoma antigen, papillomavirus binding factor

for malignant melanoma

MAGE-3

Coulie PG, Universite de Louvain ,Brussels


Goal vaccines from a novel osteosarcoma antigen, papillomavirus binding factor

Efficacious peptide vaccines

for Osteosarcoma


To identify tumor antigens vaccines from a novel osteosarcoma antigen, papillomavirus binding factor

and antigenic peptides

T cell

TCR

HLA class I

Tumor


16 y.o. F, Osteosarcoma vaccines from a novel osteosarcoma antigen, papillomavirus binding factor

OS2000

TcOScl-303


TcOScl-303 kills OS2000, vaccines from a novel osteosarcoma antigen, papillomavirus binding factor

but not 293EBNA or K562 cells

OS2000 IFN-γ(+)

OS2000

+

TcOScl-303

OS2000 IFN-γ(-)

▲293EBNA

K562

3

50

16

E/T ratio

Nabeta et al., J Orthop Sci, 2003.


Cloning of a gene encoding vaccines from a novel osteosarcoma antigen, papillomavirus binding factor

the antigenic peptide

TcOScl-303

TCR

HLA class I

OS2000

Expression cloning

Antigenic peptide


Papillomavirus Binding Factor (PBF) vaccines from a novel osteosarcoma antigen, papillomavirus binding factor

as a novel osteosarcoma antigen

PBF

Open reading frame

Zn finger

5'

337

1878

5' UTR

Clone 1B9.1H4

ΔN-PBF

704

3' UTR (432bps)

  • Protein that binds to the E2 binding site of human

  • papillomavirus type 8

Boeckle et al., Virology, 2002


Osteosarcoma vaccines from a novel osteosarcoma antigen, papillomavirus binding factorPancreas Ovary Spleen

Anti-

PBF

Immunostaining with anti-PBF antibody

Osteosarcoma 72/78

Ewing’s sarcoma 31/34

Synovial sarcoma 18/20

Tsukahara et al., Cancer Res, 2004


Stages of PBF Project vaccines from a novel osteosarcoma antigen, papillomavirus binding factor

I

II

III

IV

Identification

Function

Regulation

Application

Boeckle et al., 2002

Tsukahara et al., 2004


Stages of PBF Project vaccines from a novel osteosarcoma antigen, papillomavirus binding factor

I

II

III

IV

Identification

Function

Regulation

Application

Boeckle et al., 2002

Tsukahara et al., 2004

Prognostic significance,

Targeting/Overexpression

Associated proteins,

Expression of HLA class I

Development of peptide vaccines


Event-free Survival of OS Pts. vaccines from a novel osteosarcoma antigen, papillomavirus binding factor

PBF negative: 6

P=0.025

PBF positive: 72

Tsukahara et al., Cancer Sci, 2008


Stages of PBF Project vaccines from a novel osteosarcoma antigen, papillomavirus binding factor

I

II

III

IV

Identification

Function

Regulation

Application

Boeckle et al., 2002

Tsukahara et al., 2004

Prognostic significance,

Targeting/Overexpression

Associated proteins,

Expression of HLA class I

Development of peptide vaccines


PBF knock-out mice vaccines from a novel osteosarcoma antigen, papillomavirus binding factor

PBF (+/-)


Stages of PBF Project vaccines from a novel osteosarcoma antigen, papillomavirus binding factor

I

II

III

IV

Identification

Function

Regulation

Application

Boeckle et al., 2002

Tsukahara et al., 2004

Prognostic significance,

Targeting/Overexpression

Associated proteins,

Expression of HLA class I

Development of peptide vaccines


Yeast two hybrid screening

Bait : PBF vaccines from a novel osteosarcoma antigen, papillomavirus binding factor

Yeast Two-hybrid Screening

Yeast

Prey : cDNA library

of OS2000


open reading frame vaccines from a novel osteosarcoma antigen, papillomavirus binding factor

1126

5’

3’

Ubiquitin-like domain

NLS

(1030-1053)

HLA-B Associated Transcript 3 (BAT3)

OS2000

PBF

BAT3

Merge

Tsukahara et al., Cancer Sci, 2009


Stages of PBF Project vaccines from a novel osteosarcoma antigen, papillomavirus binding factor

I

II

III

IV

Identification

Function

Regulation

Application

Boeckle et al., 2002

Tsukahara et al., 2004

Prognostic significance,

Targeting/Overexpression

Associated proteins,

Expression of HLA class I

Development of peptide vaccines


PBF vaccines from a novel osteosarcoma antigen, papillomavirus binding factor

TcOScl-303

TCR

HLA-B55

OS2000

16 y.o. F

HLA in Japanese population

B55

A24

B61

A2

B51

HLA-restriction and HLA-limitation


PBF-peptides w/ HLA-24 binding motif vaccines from a novel osteosarcoma antigen, papillomavirus binding factor

PBF


Binding Affinity to HLA-A24 vaccines from a novel osteosarcoma antigen, papillomavirus binding factor

AYRPVSRNI


Frequency of T cells in patients with OS, reacting with the A24.2 peptide

Participants

Age

Status of

Chemotherapy

Frequency

tumor bearing

among CD8+ cells

-6

(P)

, M

7 x 10

1

18

underway

-7

6 x 10

2

42

P

not done

-6

6 x 10

3

8

(P)

underway

-7

5 x 10

4

12

(P)

underway

-6

< 1 x 10

5

65

(P), M

underway

2 x 10

6

20

(P)

underway

-6

6 x 10

7

16

(P)

underway

-6

3 x 10

8

12

(P)

underway

-6

3 x 10

9

20

P

underway

-6

9 x 10

10

18

P

done

-7

Average: 3.2 x10-6


20.2% A24.2 peptide

OS2000

OS2000+IFNγ

LCL-OS2000

HOS

U2OS

K562

CTL #034

Cytotoxicity of anti-A24.2 CTLs

Tsukahara et al., Cancer Sci, 2008

Tsukahara et al., J Transl Med, 2009


A2.2 A24.2 peptide

ALPSFQIPV

2009

Approved

Delivered

PBF-derived peptide vaccines

HLA-A24 HLA-A2

Peptide A24.2

Sequence AYRPVSRNI

Publication

IRB

GMP grade peptide

2008

Approved

Delivered


Case Age Peptide Vaccination Immune response A24.2 peptide

1 18 A24.2 2 ND

2 16 A2.2 2 ND

10w

11w

1w

2w

3w

4w

5w

6w

7w

8w

9w

12w

Peptide

+ IFA

2nd

3rd

4th

5th

1st

6th

Toxicity Tumor

- PD

- PD

Vaccination Protocol

Peptide (1mg) + IFA (Montanide ISA 51)


A giant step forward – If…. A24.2 peptide

For many years osteogenic sarcoma has been the “bete noire” of the chemotherapeutist.

Burchenal JH, New Engl J Med:1974


A clue A24.2 peptide

1970s High-dose MTX Rosen G

2000s High-dose Rosenberg SA

cell transfer


Conclusion A24.2 peptide

  • 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.

  • PBF-derived peptides were recognized by peripheral T cells of patients with osteosarcoma and they induced specific cytotoxicity.

  • Safety and efficacy of PBF-derived peptide vaccines are currently in clinical evaluation.


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