Immunotherapy for Prostate Cancer: Progress and Status

Charles G. Drake M.D. / Ph.D. Assistant Professor: Medical Oncology, Immunology and Urology Johns Hopkins Kimmel Cancer Center

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Disclosure Of Financial Relationships • Institutional: Under a licensing agreement between Cell Genesys Inc. and the Johns Hopkins University, the University is entitled to milestone payments and royalties on the sale of immunotherapy products. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies. • Personal: Cell Genesys Inc. has agreed to provide salary support for a translational research fellow in the Drake laboratory.

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Disclaimer GVAX® immunotherapy for prostate cancer, Prostvac -VF and Provenge cancer immunotherapy products are being developed for the treatment of prostate cancer; no product has been demonstrated to be safe or effective, nor has any product received regulatory approval from the US FDA or any other regulatory authority. These immunotherapy products are restricted to investigational use only. ®

®

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Overview Three Major Immunotherapy Technologies Under Development: – Ex-vivo pulsed dendritic cells – Viral vectors – GM-CSF transduced tumor cells • Ongoing Trials • The Future …..

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Immunotherapy “Immunotherapy”

Patients OWN Immune System Activated to Attack Cancer Cells

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Dendritic Cell-Based Immunotherapy •Provenge®

Patient White Blood Cells Extracted

Cells ACTIVATED

Cells MIXED with Prostate Protein

Cells infused BACK into Patient (IV) to stimulate immune response

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Cell-Based Cancer Immunotherapy …

Inflammatory Cytokine X Inflammatory Cytokine X

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GM-CSF is a Potent Inducer of Antitumor Immunity in Preclinical Models 80 60 40

MIF

MIP-1β

MIP-1α

M-CSF

IL-10

IL-5

IL-1RA

ICAM-1

CD2

B7-1

TNFα

IFNγ

IL-2

IL-7

IL-2 + IL-1R

G-CSF

SCF

IL-6

IL-4

0

IL-3

20 GM-CSF

% Tumor-free

100

• Whole cells modified to secrete cytokines or express receptors Data on file, Cell Genesys Inc. Dranoff et al. Proc Natl Acad Sci. 1993;90:3539. Levitsky et al. J Immunol. 1996;156:3858.

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GVAX Immunotherapy for Prostate Cancer

•

2 prostate cancer cell lines are used in GVAX immunotherapy for prostate cancer

•

These cells are modified to secrete GMCSF

•

Irradiation prevents further cell division, but cells remain metabolically active

GM-CSF = granulocyte-macrophage colony-stimulating factor.

GM-CSF

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Immunotherapy Based on Modified Viral Vectors Virus (Vaccinia, Fowlpox, MVA, AAV)

Cancer Protein

“Immunotherapy”

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Advantages / Disadvantages #1 - Dendritic Cell Immunotherapy • Advantages:

– May overcome dendritic cell dysfunction in cancer patients – Single antigen, immune monitoring facilitated – Potentially close to FDA approval

• Disadvantages

– Manufacture requires leukopheresis and shortterm ex-vivo culture – Single antigen, potential possibility of “escape” 18 Sept 2006

Advantages / Disadvantages #2 - Cell Based Immunotherapy • Advantages: – Multiple cancer associated antigens – Manufacture = Standard Cell Culture

• Disadvantages – Immune monitoring of antigen-specific response difficult

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Advantages / Disadvantages #3 – Modified Viral Immunotherapy • Advantages: – Simplest manufacture – Single antigen, immune monitoring facilitated • Disadvantages – Viral immunotherapies may induce “regulatory” T cells – Single antigen, potential possibility of “escape”

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Clinical Trials of Dendritic-Cell Based Immunotherapy for Prostate Cancer

www.dendreon.com

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D9901 – Randomized Placebo Controlled Phase III Trial in AIPC

• Metastatic AIPC • IHC(+) for PAP • No visceral mets

R (n=45) A Placebo q2 wksx3 N D O M I (n=82) Provenge q2 wksx3 Z E

• Primary end point: • Secondary end point: 2005 Prostate Cancer Symposium www.ASCO.org Updated Small et al JCO 2006; 24(19):3089

P R O G R E S S I O N

Eligible for Provenge q2 wksx3

Follow

TTP Survival at 36 mos 18 Sept 2006

Results

•Docetaxel-based chemotherapy was received by 35.9% patients in the Sipuleucel-T arm and 47.6% patients in the placebo arm after completion of study treatment

Small et al JCO 2006; 24(19): 3089

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Adverse Events with Significant Differences Between Treatment Groups* Total

Grade 1 and 2

Grade 3 and 4

Sip-T

Placebo

Sip-T

Placebo

Sip-T

Placebo

Rigors

60%

9%

55%

9%

5%

0%

Pyrexia

29%

2%

27%

2%

2%

0%

Tremor

10%

0%

10%

0%

0%

0%

Feeling cold

9%

0%

9%

0%

0%

0%

*P 10% of Patients

• malaise (16%) • myalgia (11%). Data on file, Cell Genesys, Inc.

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Adverse Events in Phase 3 Taxotere HRPC Trials

Tannock et al. N Engl J Med. 2004;351:1502.

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HRPC Trials: Taxotere and Immunotherapy for Prostate Cancer Trial

N

Median Survival (mo)

SWOG 9916

338*

18.0

TAX 327

335*

18.9

D9901

82

25.9

G-9803

34

26.2

G-0010

22†

≥29.1‡

*Patients treated on q21d schedule for docetaxel; †High-dose group only; ‡Median OS expected to meet or exceed 29.1 months based on patients still in follow-up. SWOG = Southwest Oncology Group. Petrylak et al. N Engl J Med. 2004;351:1513; Small et al. ASCO Prostate, 2006. Abstract 254. Updated from poster presentation; Tannock et al. N Engl J Med. 2004;351:1502.

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Phase 3 Trial GVAX Immunotherapy vs Docetaxel and Prednisone in Patients with Asymptomatic Metastatic HRPC (VITAL-1): Design

• Asymptomatic metastatic HRPC • No prior chemotherapy

R A N (N=600) D O M I Z E

• Primary end point: • Secondary end points:

GVAX prostate q14d*

Docetaxel 75 mg/m2 q21d + prednisone 10 mg/d

Overall survival Bone related events, progression of bone metastases, time to onset of bone pain

• Trial open and enrolling patients !!! *GVAX immunotherapy administered as 1 priming dose of 5 × 108 cells followed by boosting doses of 3 × 108 cells q14d × 12, then q28d. At: http://www.clinicaltrials.gov/ct/show/NCT00089856. Accessed May 2006.

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Phase 3 Trial GVAX Immunotherapy + Docetaxel vs Docetaxel + Prednisone in Patients With Symptomatic Metastatic HRPC (VITAL-2): Design • Symptomatic metastatic HRPC • 1 prior chemotherapy permitted • No prior taxanes

R A N (N=600) D O M I Z E

• Primary end point: • Secondary end points:

GVAX prostate* q21d + docetaxel 75 mg/m2 q21d

Docetaxel 75 mg/m2 q21d + prednisone 10 mg/d

Overall survival Time to radiologic progression, time to progression of pain

• Trial open and enrolling patients !!! *GVAX immunotherapy administered with docetaxel as 1 priming dose of 5 × 108 cells followed by boosting

doses of 3 × 108 cells q21d × 9, then as immunotherapy alone q28d. At: http://www.clinicaltrials.gov/ct/show/NCT00133224. Accessed May 2006.

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The Future of Prostate Cancer Immunotherapy • Earlier Treatment

– Less tumor burden – Less immune tolerance

• Combination With Conventional Therapies – Taxotere (Vital-2) – Cyclophosphamide – Androgen-Ablation*

• Combination With Novel Immune Modulators – Anti-CTLA-4 (MDX 010)

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ECOG Trial: E3806

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Conclusions • Immunotherapy for prostate cancer may soon be a treatment option • Several competing technologies with relative advantages / disadvantages • Important ongoing phase III trials – Enrollment of minority patients?

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More Info? www.cellgenesys.com www.clinicaltrials.gov, keyword GVAX www.dendreon.com www.clinicaltrials.gov, keyword Provenge

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