Nieuwe Ontwikkelingen

in de

Behandeling van Kanker

prostaatkanker

Testosteron

Testosteron geeft zakenvrouwen boostAMSTERDAM - Wil je als zakenvrouw slagen in de financile

wereld dan heb je geluk als je over een hoog testosterongehalte beschikt.

1. LHRH agonist (zoladex, lucrin, eligard)

2. Anti-androgenen

Abiteraterone

MDV3100

CholesterolCyp11A

PregnenoloneCyp17

Progesterone

Cyp17

17-hydroxyprogesterone

Cyp17/HSD32

Androstenedione

17HSD

Testosterone

CYP3A4/3A5

CYP1B1

Testosteronebreakdown

SRD5A2SRD5A1

DHT

AR AAG

17-hydroxypregnenolone

Cyp17

Cyp17

DHEA

CYP17: een belangrijk enzyme

Abiteraterone (na chemotherapie)

16/34 (47%) pts 50% PSA daling

22/34 (65%) pts 30% PSA daling

MDV3100: Androgeen Receptor Antagonist (small molecule)

Hormonale therapie

voor start chemotherapie

na chemotherapie

nieuwe studies

Nieuwe Ontwikkelingen

in de

Behandeling van Kanker

chemotherapie

Wanneer te starten met chemotherapie ?

Botuitzaaingen: pijn destructie dwarslesie beenmerg suppressie

Uitzaaingen in lymfklieren: obstructie nierfunctie verlies

Docetaxel3 wkly

Docetaxel wkly Mitoxantrone

Pain Response Rate*n, evaluable 153 154 157Response rate (%) 35 31 22P-value (vs. mitoxantrone) 0.01 0.07

PSA Response Rate*n, evaluable 291 282 300PSA response rate (%) 45 48 32P-value (vs. mitoxantrone) 0.0005

Anti-angiogenesisRemming bloedvatvorming

Docetaxel + Thalidomide Overleving

Dahut et al J Clin Oncol, 2004

Thalidomide + Docetaxelmedian 26.9 months

DocetaxelMedian 14 months

P=0.0407

Remming bloedvatvorming

Bevacizumab

CALBG Phase II study: N=97

estramustine day 1-5docetaxel day 2bevacizumab day 2

PSA response 81%

Median survival 21 months

Anti -angiogenesis

Docataxel + Thalidomide II (N=60) 90% PSA 63% Response+ Bevacizumab

Docetaxel + sunitinib (Sutent) II (N=44) 50% PSA 39% Response

Chemotherapie

start niet te laat

combinatie met remmers

van bloedvatvorming hoopvol

nieuwe studies

Verspreiding van

tumorcellen

ERK/MAPK

HGF/SF

Ras

Raf Shp2

Gab1

Proliferation

c-Met

SosGrb2

Control Scatter factor

100 % van de uitzaaingen hebben c-MET (receptor)

Bloedvatvorming

Verspreiding van tumorcellen

Studie: Mitoxantrone + AMG102

Immunotherapie(versterking afweer tegen kanker)

T-lymfocyte Dendritische cel

Provenge (dendritische cel therapie)

APC takes up the antigen

Recombinant Prostatic Acid Phosphatase (PAP)

antigen combines with resting antigen presenting

cell (APC)

Fully activated, the APC is now sipuleucel-

T

The precise mechanism of sipuleucel-T in prostate cancer has not been established.

Antigen is processed and presented on

surface of the APC

INFUSE PATIENT

T-cells proliferate and attack

cancer cells

Sipuleucel-T activates T-cells in

the body

Active T-cell

Inactive T-cell

Sipuleucel-T (Provenge)Manufacturing Process

COMPLETE COURSE OF THERAPY:3 CYCLES

Day 1Leukapheresis

Day 2-3Sipuleucel-T is manufactured

Day 3-4Patient is infused

Apheresis Center Dendreon Doctors Office

Copyright Am erican Society o f Clinical Oncology

Small, E. J. et al. J Clin Oncol; 24:3089-3094 2006

D9901Fig 2. Primary end point, time to disease progression (intent-to-

treat population)

Copyright Am erican Society o f Clinical Oncology

Small, E. J. et al. J Clin Oncol; 24:3089-3094 2006

D9901Fig 3. Final overall survival (intent-to-treat population)

Ipilimumab (MDX-010)

anti-human CTLA-4 Antibody

fully human IgG1k antibody

blocks the binding of CTLA-4 to B7

does not mediate ADCC

Ipilimumab (MDX-010)

Radiotherapy of bone lesions + Ipilimumab

Radiotherapy bone lesions + Ipilimumab

Prostate cancer (immunotherapy)

Irradiated, autologous tumor cells transduced with the GM-CSF gene

Dendritic cellT - cell

Anti-tumor Activity

GVAX Phase 2 Studies in HRPC

Pijn ter plaatse van injecties Jeuk, zwelling

Overleving: bemoedigend 2.5 jaar

Prostate GVAX Phase 3 Program

survival

Docetaxel + Pred

GVAXVITAL-1

HRPC w/ metsChemo-naiveasymptomatic

N = 600survival

Docetaxel + Pred

Docetaxel + GVAXVITAL-2

HRPC w/ metsTaxane-naivesymptomatic

N = 600

GVAX Immunotherapy (CG1940/CG8711) + Ipilimumab (MDX-010: anti-CTLA-4) for HRPC

Prostate Cancer Program VUmc1. rising PSA ET-1A urologie

2. HRPC before chemo G-VAX + MDX retreatmentAbiraterone pending

3. HRPC 1e line NEPRO open

5. HRPC 2nd line AMG102 open

5. HRPC 2nd line RT + MDX pending

6. HRPC 3rd lne MDV3100 pending