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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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slide1

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

slide2

Osteosarcoma

Introduced by Alexis Boyer in 1814.

slide3

Immunotherapy for osteosarcoma

Campbell CJ, Cohen J, Enneking WF:

New therapies for osteogenic sarcoma.

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

- Immunotherapy

- Methotrexate

- Adriamycin

slide4

Autologous tumor cell vaccination

as adjuvant therapy

Amputation

Marcove et al, CA, 1973

slide5

Current immunotherapy

Antigenic peptide

TCR

T cell

Tumor cell

Vaccination

slide6

T cell

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

slide7

Peptide vaccination

for malignant melanoma

MAGE-3

Coulie PG, Universite de Louvain ,Brussels

slide8

Goal

Efficacious peptide vaccines

for Osteosarcoma

slide9

To identify tumor antigens

and antigenic peptides

T cell

TCR

HLA class I

Tumor

slide10

16 y.o. F, Osteosarcoma

OS2000

TcOScl-303

slide11

TcOScl-303 kills OS2000,

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.

slide12

Cloning of a gene encoding

the antigenic peptide

TcOScl-303

TCR

HLA class I

OS2000

Expression cloning

Antigenic peptide

slide13

Papillomavirus Binding Factor (PBF)

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

slide14

Osteosarcoma Pancreas 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

slide15

Stages of PBF Project

I

II

III

IV

Identification

Function

Regulation

Application

Boeckle et al., 2002

Tsukahara et al., 2004

slide16

Stages of PBF Project

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

slide17

Event-free Survival of OS Pts.

PBF negative: 6

P=0.025

PBF positive: 72

Tsukahara et al., Cancer Sci, 2008

slide18

Stages of PBF Project

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

slide20

Stages of PBF Project

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

Yeast Two-hybrid Screening

Yeast

Prey : cDNA library

of OS2000

slide22

open reading frame

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

slide23

Stages of PBF Project

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

slide24

PBF

TcOScl-303

TCR

HLA-B55

OS2000

16 y.o. F

HLA in Japanese population

B55

A24

B61

A2

B51

HLA-restriction and HLA-limitation

slide27

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

slide28

20.2%

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

slide29

A2.2

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

slide30

Case Age Peptide Vaccination Immune response

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)

slide31

A giant step forward – If….

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

Burchenal JH, New Engl J Med:1974

slide32

A clue

1970s High-dose MTX Rosen G

2000s High-dose Rosenberg SA

cell transfer

slide33

Conclusion

  • 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.