资源描述
FRAMEINTRODUCTIONBREAST CANCERepidemiologytherapiesmore informationCANCER VACCINEStheorycomparisonchallengessituation brest-cancer vaccinesEXPERIMENTAL STAGE Vaccine developmentClinical development phase 1 trial phase 2 trial phase 2b trial phase 3 trial phase 4 trial Process developmentAssay development Vaccine content=vaccine formulationpreservatives or antibiotics stabilizers adjuvants delivery systems Antigens of breast cancer and present related vaccineMucin(MUC)-1Theratope Human epidermal growth factor receptor-2/neu(HER-2/neu,erbB2)E75 peptide(NeuVax nelipepimut-S)GP2 peptideMammaglobin-A(MAM-A)mammaglobin-A DNA vaccine Other antigenspeptides derived from CEA or portions of carcinoembryonic antigen(CEA)human telomerase reverse transcriptase(hTERT)tumor protein p53cancer-testis antigens(New York esophageal antigen-1NYESO-1,A melanoma antigen MAGE,B melanoma antigenBAGE and G melanoma antigen GAGE)Autologous Dendritic Cell Vaccines Lapuleucel-TClinical developmentProof-of-principle trialsEfficacy trialsNoncomparative Randomized Phase 2 TrialsComparative Randomized Phase 2 TrialsComparative Randomized Phase 2 Trials With Adaptive ComponentConventional Phase 3 TrialsTandem Proof-of-principle and Efficacy Trials Vaccine ManufacturingThe production of a vaccineGeneration of the antigenRelease and isolation of the antigenPurificationAddition of other componentsPackagingRegulation of vaccinespre-IND stageIND:clinical study application clinical evaluation license applicationpostmarketingVaccine testingpast adverse experiencesthe best current knowledgeVaccine storageTemperature controlVaccine administrationoral vaccinemicroneedle approachexperimental needle-freeDeep intramuscular injection 500 000 deaths per yearall 8.2 million deaths in 2012521 000 by breast cancer most common causes of cancer deathlung,liver,stomach,colorectal,breast&oesophageal most common invasive cancer in women22.9%of invasive cancers16%of all female cancers1 200 000 cases per yearIncidence greatest in the more-developed countries surgery chemotherapy radiotherapy endocrinotherapyhttp:/ cause manifestation diagnosis anatomy&histology pathological classification metastasis cancer staging specific stimulation of the immune system by active immunization to prevent or treat The keysspecific&efficient antigenappropriate and efficient antigen-presenting system minimal toxicity limited by the number of effector cells induced by the vaccine vs immunosuppressive entities immune systemdual role tumor microenvironment immunosuppressive factors multi-modality adjuvant therapy notable curative effect Sipuleucel-T for prostate cancer mainly animal experiment no post-market vaccine great prospects for both treatment&preventionVaccine developmentl Assay developmentspecific methods&criteria to evaluate vaccine l Clinical developmenteffects of vaccine:safety,immunogenicity,efficacyphase 1 trial：early safety and immunogenicity in small numbersphase 2 trial：safety,dose ranging,and immunogenicity in 200 to 400 individualsu phase 2b:nonlicensure proof-of-conceptphase 3 trial：safety and efficacy trials at a licensure standard.phase 4 trial：Postlicensure studies of safety and efficacyl Process development making preparations of test vaccine for clinical test bulk manufacturingVaccine formulationlAntigenlAdditive preservatives or antibiotics stabilizers adjuvantsu enhancing immune responsesu GM-CSF（granulocyte-macrophage colony-stimulating factor）delivery systemsu presenting vaccine antigen(s)to appropriate cells of the immune system u preserving or stabilizing the integrity or conformation of antigen(s)in vivoMucin-1(MUC-1)polymorphic,O-linked,glycosylated proteins 20 amino acid sequence tandemly repeated 25100 times lower glycosylation bind and activate the T-cell receptor Theratope:Sialyl-Tn(STn)+carrier protein+adjuvant u phase 1/2/3 trialsHuman epidermal growth factor receptor-2/neu(HER-2/neu,erbB2)Transmembrane tyrosine kinase moleculeEncoded by the ERBB2(HER-2/NEU)gene,amplified on tumors in 2030%of breast cancers but not mutatedHER-2/neu overexpression activate T cells Vaccine u E75 peptide:phase I/II trialsu GP2 peptide:phase II trialMammaglobin-A(MAM-A)l Secretary protein expressed almost exclusively in breast cancer l Overexpressed in up to 80%of primary metastatic breast cancersl A phase I clinical trial of a mammaglobin-A DNA vaccine showed tumoricidal functionl Prime candidate for breast cancer vaccine therapyOther antigensl peptides derived from CEA or portions of carcinoembryonic antigen(CEA)l human telomerase reverse transcriptase(hTERT)l tumor protein p53l cancer-testis antigens(New York esophageal antigen-1NYESO-1,A melanoma antigen MAGE,B melanoma antigenBAGE and G melanoma antigen GAGE)Autologous Dendritic Cell Vaccines Lapuleucel-T autologous peripheral blood mononuclear cells(containing APCs)recombinant fusion protein of portions of HER2 linked to GM-CSF.An initial phase I trial,modest activity in advanced breast cancer Clinical trials:new paradigm for breast cancer vaccine2 phase/stage1.Proof-of-principle trials 2.Efficacy trialsflexible and focused clinical development process with early and informed decision2 phase/stageProof-of-principle trials Efficacy trials“go”or“no go”Proof-of-principle trialsVSConventional early experimentsConventionalImplemented for conventional cytotoxic drugsBased on several assumptions that are not relevant to the development of therapeutic cancer vaccines:1)MTD(maximum tolerated dose)2)Response Evaluation is based on shrinkage of established tumor mass MTD This trial is based on two assumptions:1.Antitumor activity is inevitably connected to serious toxicity risks.2.Maximizing dose should maximize efficacy.But:1.Cancer vaccines are generally much safer than cytotoxic agents.The dose that yields sufficient immunogenicity and biologic activity is unlikely to confer significant toxicity.Justification should be based on biologic or clinical activity2.Theres not a linear relationship between dose of peptide administered and the magnitude/potency(量级/效能)of a T-cell or clinical response.Response EvaluationConvention:based on shrinkage of tumor massHowever,cancer vaccines involves:1.immune activation2.building of an immune response over time.3.a long-term clinical impact on the target diseaseDisease stabilization or survival improvement will be better to measure the effect of vaccine.It is currently assumed,immune more likely target small quantities of cancer cells or minimal residual(残留)disease(MRD)and less likely target bulk of tumor.In a wordcytotoxic drugs:a linear dose-potency relationship Vscancer vaccines:not a linear association between dose,immunogenicity and clinical end points Response EvaluationProof-of-principle trialsWe dont need to:establish the MTDcharacterize PKs(药代动力学)We need :more rapid assessment of therapeutic potentialProof-of-principle trialsQ:How can we design a set of Proof-of-principle trials?1.20 homogenous patients 2.Patients should not be in a rapidly progressive state to allow vaccines adequate time to induce biologic activity(which should include immune and molecular markers).3.The objectives should include determination of dose and schedule,and demonstration of biologic activity.Proof-of-principle trialsBiologic activity：shown by biologic markers as study end points,for example,clinical,molecular,or immune response.If proof-of-principle trials show such immune response,or other biologic or clinical activity,efficacy trials may be initiated.If none of these end points is met,the vaccine fails to pass PPTs.Proof-of-principle trialsKey points of proof-of-principle trials：establish an active dose regimen(给药方案)which can prove the principle.generate sufficient safety data to permit the design of randomized trials;that is,data that determines efficacy of the vaccine in the target population.Efficacy trials1.Randomized studies formally 2.Bridge over the gap of the no longer recommended conventional phase 2 trials Phase 2 Phase 33.Confirm the data obtained in proof-of-principle trials and demonstrate efficacyVaccine Manufacturing Manufacturing Process Generation of the antigen Release and isolation of the antigen Purification Addition of other components PackagingpackageGood Manufacturing PracticesvesselsdistributionSterile stoppersRegulatory reviewPremarketing PhasesPostmarketing Phases Pre-Investigational New Drug(IND)stageIND phasesprelicensurePre IND stageApplication for clinical studyIND phase 3 phases Efficacy Immunogenicity safetyLicense phage Product establishmentPostmarketing phageProvide additional assessments or rare adverse events Further assess the duration of vaccine-induced immunity continued surveillance manufacturers production activitiesVaccine testing prelicensure&postlicensure phase past adverse experiences&best current knowledge AdministrationStorageReference Vaccines,6th Edition,Stanley Plotkin,Walter Orenstein,Paul Offit,ISBN9781455700905 ELECTRONIC ARTICLE:Risk Factors for Improper Vaccine Storage and Handling in Private Provider Offices Pediatrics,2001(6):e100 药品临床试验管理规范(GCP)2015 Immune targeting in breast cancer Cimino-Mathews A.,Foote J.B.,Emens L.A.ONCOLOGY(United States)2015 29:5
展开阅读全文