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Immunotherapy for Prostate Cancer:Progress and StatusCharles G. Drake M.D. / Ph.D.Assistant Professor: Medical Oncology, Immunology and UrologyJohns Hopkins Kimmel Cancer Center18 Sept 2006
Disclosure Of Financial Relationships Institutional:Under a licensing agreement between Cell Genesys Inc. andthe Johns Hopkins University, the University is entitled tomilestone payments and royalties on the sale ofimmunotherapy products. The terms of this arrangementare being managed by the Johns Hopkins University inaccordance with its conflict of interest policies. Personal:Cell Genesys Inc. has agreed to provide salary support for atranslational research fellow in the Drake laboratory.18 Sept 2006
DisclaimerGVAX immunotherapy for prostate cancer,Prostvac -VF and Provenge cancer immunotherapyproducts are being developed for the treatmentof prostate cancer; no product has beendemonstrated to be safe or effective, nor has anyproduct received regulatory approval from the USFDA or any other regulatory authority. Theseimmunotherapy products are restricted toinvestigational use only. 18 Sept 2006
OverviewThree Major Immunotherapy Technologies Under Development:– Ex-vivo pulsed dendritic cells– Viral vectors– GM-CSF transduced tumor cells Ongoing Trials The Future .18 Sept 2006
Immunotherapy“Immunotherapy”Patients OWNImmuneSystemActivated toAttack CancerCells18 Sept 2006
Dendritic Cell-Based Immunotherapy Provenge Patient White BloodCells ExtractedCells ACTIVATEDCells MIXED withProstate ProteinCells infused BACKinto Patient (IV) tostimulate immuneresponse18 Sept 2006
Cell-Based Cancer Immunotherapy InflammatoryCytokine XInflammatoryCytokine X18 Sept 2006
GM-CSF is a Potent Inducer ofAntitumor Immunity in IL-5IL-1RAICAM-1CD2B7-1TNFαIFNγIL-2IL-7IL-2 IL-1RG-CSFSCFIL-6IL-40IL-320GM-CSF% Tumor-free100 Whole cells modified to secrete cytokines or express receptorsData 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 forProstate Cancer 2 prostate cancer cell lines are used inGVAX immunotherapy for prostate cancer These cells are modified to secrete GMCSF Irradiation prevents further cell division,but cells remain metabolically activeGM-CSF granulocyte-macrophage colony-stimulating factor.GM-CSF18 Sept 2006
Immunotherapy Based on ModifiedViral VectorsVirus(Vaccinia, Fowlpox,MVA, AAV)CancerProtein“Immunotherapy”18 Sept 2006
Advantages / Disadvantages#1 - Dendritic Cell Immunotherapy Advantages:– May overcome dendritic cell dysfunction incancer 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 responsedifficult18 Sept 2006
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 BasedImmunotherapy for Prostate Cancerwww.dendreon.com18 Sept 2006
D9901 – Randomized Placebo ControlledPhase III Trial in AIPC MetastaticAIPC IHC( ) for PAP No visceralmetsR (n 45)APlacebo q2 wksx3NDOMI (n 82)Provenge q2 wksx3ZE Primary end point: Secondary end point:2005 Prostate Cancer Symposium www.ASCO.orgUpdated Small et al JCO 2006; 24(19):3089PROGRESSIONEligible forProvenge q2 wksx3FollowTTPSurvival at 36 mos18 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 treatmentSmall et al JCO 2006; 24(19): 308918 Sept 2006
Adverse Events with SignificantDifferences Between Treatment Groups*TotalGrade 1 and 2Grade 3 and elingcold9%0%9%0%0%0%*P 0.05 vs. placebo, all gradesValues rounded to nearest whole numberSmall et al JCO 2006; 24(19): 308918 Sept 2006
Clinical Trials of Viral-BasedImmunotherapy for Prostate Cancerwww.therionbio.com18 Sept 2006
TBC-PRO-002 Phase II Metastatic Hormone Refractory Prostate Cancer Randomized, Double Blind (2:1 immunotherapy: emptyvector)– Multi-Center– Approximately 120 Patients Primary endpoint – Progression Free Survival2006 ASCO Annual Meeting (www.asco.org)18 Sept 2006
Overall Survival(secondary endpoint)2006 ASCO Annual Meeting (www.asco.org)18 Sept 2006
Clinical Trials of GVAX Immunotherapyfor Prostate cmetastatic HRPC234*CompletedG-0010Asymptomaticmetastatic HRPC280CompletedVITAL-1Asymptomaticmetastatic HRPC3600EnrollingVITAL-2Symptomaticmetastatic HRPC3600Enrolling*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 2517.18 Sept 2006
Phase 2 Trial of GVAX Immunotherapyin HRPC (G-0010): Design Metastatic HRPCNo prior chemotherapyNo prior immunotherapyNo bone painEnd points:(N 80)GVAX immunotherapy(5 dose levels)MTD, GM-CSF pharmacokinetics, safety, PSAresponse, 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
Proportion of patients survivingPhase 2 Trial of GVAX Immunotherapyin HRPC (G-0010): Overall Survival1.0Median (mo)High dose (n 22)29.1*Mid dose (n 25)20.0Low dose (n 33)23.10.80.60.40.2001020304050Months*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, oatmealor other natural soothers;oral analgesics, prescriptionantipruritics– Avoid topical steroids or antihistamines as well as hot/coldcompresses No dose-limiting toxicities No evidence of auto-immunityData on file, Cell Genesys, Inc.18 Sept 2006
Don’t Ask, Don’t Tell:Systemic Events* in Phase 2 GVAX Immunotherapy in HRPCTrialsG-0010 (ELICITED)Mild-moderate: fatigue (71%), headache (53%) malaise (49%) myalgia (48%) arthralgia (48%) systemic pruritus (44%) chills (39%) systemic rash (26%)G-9803 (Reported)Mild-moderate: fatigue (25%), fever (18%) flu-like syndrome (18%) chills (14%)Severe None hives (16%) rigors (15%).Severe fatigue (19%),* Occurring in 10% of Patients malaise (16%) myalgia (11%).Data on file, Cell Genesys, Inc.18 Sept 2006
Adverse Events in Phase 3 Taxotere HRPC TrialsTannock et al. N Engl J Med.2004;351:1502.18 Sept 2006
HRPC Trials: Taxotere andImmunotherapy for Prostate CancerTrialNMedian Survival (mo)SWOG 9916338*18.0TAX 327335*18.9D99018225.9G-98033426.2G-001022† 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 TrialGVAX Immunotherapy vs Docetaxel and Prednisonein Patients with Asymptomatic Metastatic HRPC(VITAL-1): Design Asymptomaticmetastatic HRPC No priorchemotherapyRAN(N 600) DOMIZE Primary end point: Secondary end points:GVAX prostate q14d*Docetaxel 75 mg/m2 q21d prednisone 10 mg/dOverall survivalBone related events, progression of bonemetastases, 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 of3 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 Prednisonein Patients With Symptomatic Metastatic HRPC(VITAL-2): Design Symptomaticmetastatic HRPC 1 priorchemotherapypermitted No prior taxanesRAN(N 600) DOMIZE Primary end point: Secondary end points:GVAX prostate* q21d docetaxel 75 mg/m2 q21dDocetaxel 75 mg/m2 q21d prednisone 10 mg/dOverall survivalTime to radiologic progression, time toprogression of pain Trial open and enrolling patients !!!*GVAX immunotherapy administered with docetaxel as 1 priming dose of 5 108 cells followed by boostingdoses 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 CancerImmunotherapy 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: E380618 Sept 2006
Conclusions Immunotherapy for prostate cancer may soon be atreatment option Several competing technologies with relativeadvantages / disadvantages Important ongoing phase III trials– Enrollment of minority patients?18 Sept 2006
More Info?www.cellgenesys.comwww.clinicaltrials.gov, keyword GVAXwww.dendreon.comwww.clinicaltrials.gov, keyword Provenge18 Sept 2006
Under a licensing agreement between Cell Genesys Inc. and the Johns Hopkins University, the University is entitled to . - Multi-Center . Primary endpoint - Progression Free Survival 2006 ASCO Annual Meeting (www.asco.org) 18 Sept 2006 Overall Survival (secondary endpoint) 2006 ASCO Annual Meeting (www.asco.org) 18 Sept 2006
