1. Emmanuel Gomez Jennifer Dao Phan Gaëlle Datchoua UEI2 Scientific communication Workshop February 11 & 12, 2010
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5. Summary for Prostate Cancer epidemiology Jemal et al. CA Cancer J Clin. 2009;225-249. Commun Oncol 2007;4:447–452 15% Metastatic disease Prostate cancer Initial diagnosis 85 % localized early disease 60-70% Localized disease 30-40% Relapse disease ~ 18-36 months
6. Diagnosis of advanced prostate cancer Gleason’s score PSA doubling time Residual testosteronemia > 50 ng/mL Digital Rectal Examination+Biopsy Blood test Research of metastases
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9. Gleason’s Score + PSA DT = predictive for PCa outcome Freedland SJ, Humphreys EB, Mangold LA, et al. Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA . 2005;294:433-439. Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA . 1999;281:1591-1597.
10. Asymptomatic metastatic PCa : no approved therapies in European guidelines A gap for brand new treatment strategies? Asymptomatic metastatic PCa: a medical unmet need Adaptated from : Nature Reviews Cancer 2 , 389-396 (May 2002) Progrès en Urologie (2008), Suppl. 7, S343–S348 Commun Oncol 2007;4:447–452
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17. Antigen Presentation to T Cells (BARAS, LICHTMAN, Cellular and Molecular Immunology, Saunders ed., 5e ed., 2003) Secondary lymphoid organs Peripheral tissues Th1/Th2 pathway Macrophage/ B cell activation Cytotoxic effect against targeted cells
18. How to break the tolerance CD 4 – CD8 LFA - 3 ICAM – 1(=CD54) CD 40 B7 (CD80 and CD86) LFA - 1 CD 2 CD 40 L -S–S - CD 28 T-Cell Antigen Presenting Cells MHC peptide Complexe, I or II -S– S - TCR - CD 3 Peptide
31. Consistency Across Phase 3 Studies *Unadjusted Cox model & log rank **Cox model adjusted for PSA and LDH
32. Keep an eye on … Group Sipuleucel-T n / N (%) Placebo n / N (%) Odds Ratio (95% CI) p-value All Subjects All CVA’s 18 /461 (3.9%) 6/231 (2.6%) 1.52 (0.596, 3.892) 0.510 Deaths attributed to CVAs 7 / 461 (1.5%) 2 / 231 (0.9%) 1.76 (0.364, 8.566) 0.725 AIPC (Proposed Indication) All CVA’s 17 / 345 (4.9%) 3 / 172 (1.7%) 2.92 (0.84, 10) 0.092 Deaths attributed to CVAs 7 / 345 (2.0%) 2 / 172 (1.2%) 1.76 (0.36, 8.6) 0.724 ADPC (P-11) All CVA’s 1 / 116 (0.9%) 3 / 59 (5.1%) 0.16 (0.016, 1.596) 0.112 Deaths attributed to CVAs 0 0 --- ---
33. PROTECT (P11): PROVENGE Treatment and Early Cancer Treatment. Ongoing Phase 3 trial with enrollment completed
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38. Sipuleucel-T (Provenge ® ) production and delivery PROVENGE® (sipuleucel-T) Cellular, Tissue, and Gene Therapies Advisory Committee Meeting March 29, 2007 The Mattson Jack Group, Cancer Metric Database 2009 COMPLETE COURSE OF THERAPY: 3 CYCLES 100 000 patients in USA with metastatic AIPC in 2010 100 000 X 3 = 300 000 doses to prepare and to deliver on time How will Dendreon make it? Day 1 Leukapheresis Apheresis Center Day 2-3 Manufacturing Dendreon’s facility Day 3-4 Infusion Doctor’s Office
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41. Exemple of a workstation to manufacture Provenge
70. Type of « vaccine » in clinical study Trade name What’s that? Company Type of drug Phase Provenge Autologous (reimplanted) dendritic cells complexed with the Prostatic Acid Phosphatase (PAP) antigen and GM-CSF Dendreon Cell therapy Phase 3 DCVax Prostate Whole cells derived from two prostate cancer lines modified to secrete GM-CSF and irradiated to arrest growth. Northwest Biotherapeutics Cellular vaccine Phase 3 GVax . Patients dendritic cells boosted with Prostate Membrane Specific Antigen (PMSA) Cell Genesis Cellular vaccine Phase 3 Trovax Designed to induce an immune response against the tumor-associated antigen 5T4 using a viral vector, Modified Vaccinia Ankara (MVA). The 5T4 tumor antigen is expressed at high levels in the majority of epithelial-derived cancers such as colorectal, renal, prostate, lung and breast. Oxford Biomedical Viral vector Phase 2 PROSTVAC Vaccinia-PSA-TRICOM and Fowl pox-PSA-TRICOM Bavarian Nordic Viral vector Phase 2
Editor's Notes
Once metastatic androgen-independent prostate cancer (AIPC) develops, responses to alternative hormonal therapy or chemotherapy are not durable, with a median overall survival of approximately 18 months with docetaxel based chemotherapy.
IL4 ?
Les CD sont les seules cellules présentatrices capables d'activer les lymphocytes T naïfs lors d'une immunisation primaire, et les meilleures pour activer les lymphocytes T mémoire.
Sans oublier les multiplications exvivo de virus ou la survenue de maladies autoimmune.
Sipuleucel-T is manufactured APCs are seperated from other white blood cells using proprietary technology. APCs are combined with Dendreon’s Antigen Delivery Cassette for approximatively 40 hours
In March,an FDA advisory committee voted 13-4 that Provenge was effective and 17-0 that Provenge was safe. It was later discovered that two of the Doctors on the panel that voted against the effectiveness of the treatment - and who also subsequently lobbied heavily for the FDA to deny Provenge approval - were found to have previously undisclosed financial interests in companies in direct competition to Dendreon
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