Immunotherapy Therapy for Prostate Cancer

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1 2006 Prostate Health Education Network African American Prostate Cancer Disparity Summit Immunotherapy Therapy for Prostate Cancer Glen W. McWilliams, MD Chief of Urology James J. Peters VAMC Assistant Clinical Professor of Urology Mount Sinai School of Medicine

The Prostate Cancer Treatment Continuum A Gap in Options for AIPC Patients Androgen Dependent PCa Primary Therapy Early Stage Androgen Deprivation Androgen Independent PCa Asymptomatic Advanced Stage

2 The Prostate Cancer Treatment Continuum A Gap in Options for AIPC Patients Androgen Dependent PCa Primary Therapy Early Stage Androgen Deprivation Androgen Independent PCa Asymptomatic Advanced Stage Symptomatic Radical Prostatectomy Brachytherapy Radiation Therapy Cryotherapy Watchful Waiting Lupron Zoladex Casodex Eulexin Ketoconazole Taxotere Palliative Interventions Bisphosphonates Taxotere Novantrone Emcyt Taxotere Is the Only Option

3 Natural History of Metastatic Prostate Cancer Castration Chemotherapy Rx Tumor volume and activity Secondary hormonal Rx Time

4 Current Standard of Care in Metastatic Prostate Cancer To date, Taxotere is the only approved chemotherapy to show a survival benefit Two to two and a half month benefit 1 infusion every 3 weeks combined with Prednisone 20% of Stage IV patients get Tax Majority of those are most advanced (symptomatic, met.)

5 Patients Dissatisfied with Current Treatment Options 100% 80% 60% 52% Prostate cancer patients 65% 75% 40% 20% 0% Would consider chemo as a TRx option Believe chemo impact on QOL outweighs its benefit Have negative perceptions of chemo side effects QOL=quality-of-life Us TOO Survey Press Release, September 8, 2005; 2006 Prostate Cancer Symposia Poster #222.

6 Patients Dissatisfied with Current Treatment Options (cont d) Men with late-stage disease need more options. These men and their families shouldn t t have to compromise their quality of lives. We need better treatments that fight this disease, address the most painful symptoms and lessen the side effects of treatment. - Thomas Kirk President and CEO of Us TOO International

7 Immune Antigens: PSA, PSMSA, PAP Targeted Therapies Vascular: Anti-VEGF Thalidomide Small molecule FTI (BMS ) PD98059 Grb2/Shc Sos Ras Raf Flavopiridol MEK MAPK Proteasome inhibitors (PS341) Ansamycins PI3K AKT LY PTEN NF-kB Src Cyclin D/ CDK4 Bad S ER Altered gene expression PD173855/PD G2 G1 AR BCL-2 mtor M SERM3 Antisense (G3139) Rapamycin, CCI-779 Tubulin (epothilone B) Bicalutamide HDAC inhibitors (SAHA) Vit D, retinoids

8 Types of Targeted Therapy Antigen specific immunotherapy PSA, PSMA, acid phosphatase Organ specific Bone atrasentan (zoledronic acid) Mechanism specific Angiogenesis-- bevacizumab PSA=prostate-specific antigen; PSMA=prostate-specific membrane antigen

9 Immunotherapies on the Horizon for PCa Agents in Phase II and above: Company Product Phase Type Dendreon Cell Genesys sipuleucel-t (PROVENGE) GVAX III Filing 2006 III Patient Specific Whole Cell NW Biotherapeutics DCVAX III Patient Specific Therion PROSTVAC-VF VF II Antigen Specific Geron GRNVAC1 I/II Antigen Specific

10 Why Immunomodulation for the Treatment of Prostate Cancer? Urgent need for new approaches for the treatment of AIPC Defects in cellular immunity (immunologic tolerance) commonly seen in patients with malignancies, including CaP CaP recognized as an immunogenic tumor Recent exploration of improved methods for Presentation of tumor-associated antigens Restoration of tumor-specific immune responses AIPC=androgen-independent prostate cancer; CaP=cancer of the prostate

11 Active Cellular Immunotherapy Makes Sense For Treating Prostate Cancer Prostate gland is susceptible to immunotherapy Highly differentiated Contains many organ-specific antigens (substance that stimulates the immune system) Prostatic acid phosphatase (PAP) Antigen in sipuleucel-t PAP is very specific to the prostate, leaving the rest of your body alone

12 Immunomodulating Approaches in Development for Treatment of AIPC Tumor antigen vaccines Vaccinate patient with antigens that activate tumor-specific T-cell T responses Autologous dendritic cells (DCs) Cytokines and DC stimulation CTLA-4 4 blockade Small molecule agents with immunomodulating activities CTLA-4=cytotoxic T lymphocyte-associated antigen 4

13 Tumor Vaccines Active immunotherapy Ideal candidates for vaccine therapy PSA progression secondary to development of androgen resistance Low tumor burden Target tumor antigens under investigation include PSA Prostate acid phosphatase (PAP) PMSA MUC-1, others

14 Autologous DC Vaccination DCs (antigen presenting cells) Only cells in the body that stimulate naïve T cells Can activate B cells to make antibodies Strategy Eradicate CaP cells by induction of immunity to CaP antigens Sternberg CN. Eur J Cancer. 2003;39:

15 What is sipuleucel-t? Sipuleucel-T is an Active Cellular Immunotherapy (ACIs) ACIs are a new class of drug, often referred to as cancer vaccines ACIs are very different from traditional vaccines Traditional vaccines: Cancer Vaccine/ ACIs: PREVENT disease by exposing the immune system to weakened virus or portion of a virus TREAT disease by using the body s immune system to fight the cancer. Immunotherapies are designed to be specific, affecting only cancer cells.

16 How Does sipuleucel-t Work? sipuleucel-t is a PERSONALIZED medicine Utilizes the body s s own materials to make the product, specifically Antigen Presenting Cells (APCs) APCs are cells which can: Take up and process an antigen Display the antigen on its surface And then activate T-cells T in the body to seek out and attack cancers that possess the antigen

17 Active Cellular Immunotherapy with Sipuleucel-T Recombinant PAP antigen combines with the resting antigen presenting cell (APC) APC takes up the antigen Antigen is processed and presented on the surface of the APC Fully activated, the APC is now sipuleucel-t INFUSE PATIENT Active T-cell T cells proliferate and attack cancer cells Note: the precise mechanism of sipuleucel-t in prostate cancer has not been established Sipuleucel-T activates T cells in the body Inactive T cell

18 Sipuleucel-T: D9901 Pivotal Phase III Study Asymptomatic metastatic AIPC (n=127) Sipuleucel-T Q 2 weeks x 3 Placebo Q 2 weeks x 3 P R O G R E S S I O N Treated at MD discretion 2:1 Followed for survival D9903 (salvage) Q 2 weeks x 3 Endpoints Primary: Secondary: Survival: Time to progression Time to disease-related pain 36 month analysis pre-specified

19 Sipuleucel-T Manufacturing Process Day 1 Leukapheresis Day 2-3 Sipuleucel-T is manufactured Day 3-4 Patient is infused Apheresis Center Dendreon Doctor s Office COMPLETE COURSE OF THERAPY: 3 CYCLES

20 Phase III Trial D9901: Final Overall 3-year 3 Survival (ITT Population) Percent Survival APC-placebo (n=45) Median survival: 21.4 mos P=0.01 (log rank) HR=1.7 Median survival benefit=4.5 months Sipuleucel-T (n=82) Median Survival: 25.9 mos 34% (28 patients) 11% (5 patients) Survival (months)

21 D9901 and D9902A: Pooled Overall Survival (ITT Population) 100 Sipuleucel-T (n=147) Placebo (n=78) Percent Survival P = (log rank) HR = 1.5 [95% CI: 1.10, 2.05] Median survival benefit: 4.3 months Survival (months)

22 Phase III Trial D9901: Safety Profile Events Sipuleucel-T Grade 1 or 2 Grade 3 to 4 Any AE, n (%) 55 (67.0) 26 (31.7) Grade 1 or 2 Placebo Grade 3 to 4 12 (26.7) 26 (31.7) 32 (71.1) 12 (26.7) Events more frequent with sipuleucel-t Chills 47 (57.3) 4 (4.9) 4 (8.9) 0 (0.0) Pyrexia 26 (31.7) 2 (2.4) 2 (4.4) 0 (0.0) Headache 14 (17.1) 0 (0.0) 2 (4.4) 0 (0.0) Dyspnea 9 (11.0) 5 (6.1) 1 (2.2) 1 (2.2) Tremor 8 (9.7) 0 (0.0) 0 (0.0) 0 (0.0) Percent of patients with AEs: sipuleucel-t T (n=82) and placebo (n=45) Events shown represent those that occur at a statistically significantly higher rate in sipuleucel-t than in placebo. Results as of 8/15/2005.

23 Sipuleucel-T: D9902B Phase III Study Modified Design Sipuleucel-T at weeks Randomized, double blind, placebo controlled, phase III trial Asymptomatic, or mildly symptomatic, metastatic AIPC Currently enrolling patients ~500 patients to be enrolled at over 70 study centers Primary endpoint: survival Secondary endpoint: time to objective disease progression

24 Sipuleucel-T: P-11 P (ProtecT) in Early Stage Prostate Cancer Treatment at weeks Boost eligible Randomized, double blind, placebo-controlled, controlled, phase III trial Patient population Androgen dependent Biochemical recurrence following prostatectomy Enrollment complete ProtecT=Prostate Testing for Cancer and Treatment Over 170 patients enrolled at 19 sites in the US Endpoints Biochemical progression Clinical progression Data available in 2006

25 Allogeneic Vaccine Development: GVAX Allogeneic GM-CSF Transduced Tumor Cells as Prostate Cancer Vaccine LnCAP Potential antigens Mutant androgen receptor PSA PSMA PAP PC3 Potential antigens Mutant P53 CEA GST Π Transduced with replication incompetent AAV vector Appropriately certified GM-CSF=granulocyte macrophage colony stimulating factor; CEA=carcinoembryonic antigen; GST Π=glutathiaone s-transferase Pi; AAV=adeno-associated virus

26 A Phase II Trial of Allogeneic GM-CSF Transduced Tumor Cells as CaP Vaccine 80 patients with metastatic HRPC treated in dose escalation scheme No dose limiting toxicities observed 32% of patients in the highest dose group showed PSA declines In the highest dose group, 82% of patients showed antibody response Median survival=23 months HRPC=hormone-refractory prostate cancer

27 GVAX: Development Plans Phase III trial in progress GVAX vs docetaxel in metastatic HRPC Docetaxel +/- GVAX in symptomatic metastatic HRPC Phase III clinical samples as platform for antigen discovery using candidate antigen approach Phase II trial of androgen-ablation ablation prior to vaccination for patients with PSA-only relapse (based on laboratory data) Basic laboratory efforts combination ombination with radiation, chemotherapy, anti-angiogenesis angiogenesis agents

28 Conclusions Targeted therapy is a promising new approach to the treatment of prostate cancer Potential for greater specificity and less toxicity Many phase III trials are ongoing First targeted immunotherapy, Sipuleucel- T potentially available as early as next year

29 New Natural History of Metastatic Prostate Cancer Castration Immunotherapy/Targeted therapies Chemotherapy? Tumor volume and activity Secondary hormonal Rx Time

Mitchell H. Gold, M.D. President and CEO. 2 nd Annual African American Prostate Cancer Disparity Summit September 22, 2006

Mitchell H. Gold, M.D. President and CEO 2 nd Annual African American Prostate Cancer Disparity Summit September 22, 2006 1 Dendreon Corporation: A Biotechnology Company on the Verge of Changing the Way