18 Sept 2006

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

18 Sept 2006

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.

18 Sept 2006

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.

18 Sept 2006

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

Patient White Blood Cells Extracted

•Provenge®

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

Models100

0

20

40

60

80

% T

umor

-free

IL- 7

GM

-CSF IL-3

IL-6

IL-4

SCF

G-C

SFIL

-2 +

IL-1

R

IL-2

TNFα

IFNγ

MIF

B7-

1

M-C

SF

CD

2

IL-1

0

ICA

M-1

IL-5

MIP

-1β

MIP

-1α

IL-1

RA

• 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.

18 Sept 2006

GVAX Immunotherapy for Prostate Cancer

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

• These cells are modified to secrete GM-CSF

• 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)

“Immunotherapy”Cancer Protein

18 Sept 2006

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 short-

term ex-vivo culture– Single antigen, potential possibility of “escape”

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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”

18 Sept 2006

Clinical Trials of Dendritic-Cell Based Immunotherapy for Prostate Cancer

www.dendreon.com

18 Sept 2006

D9901 – Randomized Placebo Controlled Phase III Trial in AIPC

(n=45)

• Metastatic AIPC

• IHC(+) for PAP• No visceral

mets

Placebo q2 wksx3

Provenge q2 wksx3(n=82)

RANDOMIZE

PROGRESSION

Follow

Eligible forProvenge q2 wksx3

• Primary end point: TTP• Secondary end point: Survival at 36 mos

2005 Prostate Cancer Symposium www.ASCO.orgUpdated Small et al JCO 2006; 24(19):3089

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

18 Sept 2006

Adverse Events with Significant Differences Between Treatment Groups*

Total Grade 1 and 2 Grade 3 and 4Sip-T Placebo Sip-T

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%

PlaceboSip-T Placebo

*P <=0.05 vs. placebo, all gradesValues rounded to nearest whole number

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

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Clinical Trials of Viral-Based Immunotherapy for Prostate Cancer

www.therionbio.com

18 Sept 2006

TBC-PRO-002

• Phase II • Metastatic Hormone Refractory Prostate Cancer• Randomized, Double Blind (2:1 immunotherapy: empty

vector)– Multi-Center– Approximately 120 Patients

• Primary endpoint – Progression Free Survival

2006 ASCO Annual Meeting (www.asco.org)

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Overall Survival(secondary endpoint)

2006 ASCO Annual Meeting (www.asco.org)

18 Sept 2006

Clinical Trials of GVAX Immunotherapy for Prostate Cancer

Trial Population Phase N Status

G-9803 Asymptomatic metastatic HRPC 2

2

3

3

34* Completed

G-0010 Asymptomatic metastatic HRPC 80 Completed

VITAL-1 Asymptomatic metastatic HRPC 600 Enrolling

VITAL-2 Symptomatic metastatic HRPC 600 Enrolling

*An additional 21 patients were enrolled with PSA-only disease.Data on file, Cell Genesys, Inc. Updated from Simons et al. ASCO, 2002. Abstract 729.Updated from Simons et al. ASCO, 2005. Abstract 2517.

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Phase 2 Trial of GVAX Immunotherapy in HRPC (G-0010): Design

• Metastatic HRPC• No prior chemotherapy• No prior immunotherapy• No bone pain

GVAX immunotherapy(5 dose levels)

(N=80)

End points: MTD, GM-CSF pharmacokinetics, safety, PSA response, TTP (PSA and clinical criterion)

MTD = maximum tolerated dose; TTP = time to progression.Data on file, Cell Genesys, Inc.Updated from: Simons et al. ASCO, 2005. Abstract 2517.

18 Sept 2006

Phase 2 Trial of GVAX Immunotherapy in HRPC (G-0010): Overall Survival

10 20 30 5000

0.2

0.4

0.6

0.8

1.0

40Prop

ortio

n of

pat

ient

s su

rviv

ing

Months

Median (mo)High dose (n=22) 29.1*Mid dose (n=25) 20.0Low dose (n=33) 23.1

*Median survival expected to meet or exceed 29.1 months based on patients still in follow-up; 4 censoredpatients in the analysis withdrew consent for follow-up.Data on file, Cell Genesys, Inc.Updated from Simons et al. ASCO 2005. Abstract 2517.

18 Sept 2006

Injection Site Reactions in Phase 2 GVAX®

Immunotherapy in HRPC Trials • Injection site reactions seen in ALL patients (100%)

– included erythema,induration, pruritus, andpain/soreness

– Post-injection care: aloe, oatmeal or other natural soothers; oral analgesics, prescription antipruritics

– Avoid topical steroids or antihistamines as well as hot/cold compresses

• No dose-limiting toxicities• No evidence of auto-immunity

Data on file, Cell Genesys, Inc.

18 Sept 2006

Don’t Ask, Don’t Tell:Systemic Events* in Phase 2 GVAX® Immunotherapy in HRPC

TrialsG-9803 (Reported)G-0010 (ELICITED)

Mild-moderate: • fatigue (71%), • headache (53%)• malaise (49%)• myalgia (48%)• arthralgia (48%)• systemic pruritus (44%)• chills (39%)• systemic rash (26%)• hives (16%)• rigors (15%).

Severe• fatigue (19%), • malaise (16%)• myalgia (11%).

Mild-moderate:• fatigue (25%), • fever (18%)• flu-like syndrome (18%)• chills (14%)

Severe• None

* Occurring in > 10% of Patients

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.

18 Sept 2006

Phase 3 Trial GVAX Immunotherapy vs Docetaxel and Prednisone

in Patients with Asymptomatic Metastatic HRPC (VITAL-1): Design

(N=600)• Asymptomatic

metastatic HRPC• No prior

chemotherapy

RANDOMIZE

GVAX prostate q14d*

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

• Primary end point: Overall survival• Secondary end points: 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.

18 Sept 2006

Phase 3 TrialGVAX Immunotherapy + Docetaxel vs Docetaxel + Prednisone

in Patients With Symptomatic Metastatic HRPC (VITAL-2): Design

(N=600)

• Symptomatic metastatic HRPC

• 1 prior chemotherapy permitted

• No prior taxanes

RANDOMIZE

GVAX prostate* q21d +docetaxel 75 mg/m2 q21d

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

• Primary end point: Overall survival• Secondary end points: 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.

18 Sept 2006

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)

18 Sept 2006

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?

18 Sept 2006

More Info?

www.cellgenesys.comwww.clinicaltrials.gov, keyword GVAX

www.dendreon.comwww.clinicaltrials.gov, keyword Provenge