醫(yī)學英語課件資料：HOW TO DEVELOP VACCINES FOR THE TREATMENT OF BREAST CANCER

1、HOW TO DEVELOP VACCINES FOR THE TREATMENT OF BREAST CANCERFRAMEINTRODUCTIONBREAST CANCERepidemiologytherapiesmore informationCANCER VACCINEStheorycomparisonchallengessituation brest-cancer vaccinesEXPERIMENTAL STAGE Vaccine developmentClinical development phase 1 trial phase 2 trial phase 2b trial p

2、hase 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,

3、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-1

4、NYESO-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

5、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:

6、 clinical study application clinical evaluation license applicationpostmarketingVaccine testingpast adverse experiencesthe best current knowledgeVaccine storageTemperature controlVaccine administrationoral vaccinemicroneedle approachexperimental needle-freeDeep intramuscular injectionINTRODUCTION劉冰2

7、01201033500 000 deaths per yearall 8.2 million deaths in 2012521 000 by breast cancer most common causes of cancer deathlung, liver, stomach, colorectal, breast & oesophagealmost common invasive cancer in women22.9% of invasive cancers16% of all female cancers1 200 000 cases per yearBREAST CANCER: e

8、pidemiologyBREAST CANCER: epidemiologyIncidence greatest in the more-developed countriesBREAST CANCER: epidemiologyBREAST CANCER: epidemiologysurgerychemotherapyradiotherapyendocrinotherapyBREAST CANCER: therapies/p-575348651095.htmlcausemanifestationdiagnosisanatomy & histologypathological classifi

9、cationmetastasiscancer stagingBREAST CANCER: more informationspecific stimulation of the immune system by active immunizationto prevent or treatThe keysspecific & efficient antigenappropriate and efficient antigen-presenting system CANCER VACCINES: theoryminimal toxicitylimited by the number of effe

10、ctor cells induced by the vaccine vs immunosuppressive entitiesCANCER VACCINES: comparisonimmune systemdual roletumor microenvironmentimmunosuppressive factorsmulti-modality adjuvant therapy CANCER VACCINES: challengesCANCER VACCINES: situationnotable curative effectSipuleucel-T for prostate cancerC

11、ANCER VACCINES: situationmainly animal experimentno post-market vaccinegreat prospects for both treatment & preventionCANCER VACCINES: situation of breast cancer楊俊201201063EXPERIMENTAL STAGEVaccine developmentAssay developmentspecific methods & criteria to evaluate vaccine Clinical developmenteffect

12、s 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 individualsphase 2b: nonlicensure proof-of-conceptphase 3 trial：safety and efficacy trials at a licensure standard. phase 4

13、 trial：Postlicensure studies of safety and efficacyProcess developmentmaking preparations of test vaccine for clinical testbulk manufacturingVaccine formulationAntigenAdditivepreservatives or antibioticsstabilizersadjuvantsenhancing immune responses GM-CSF（granulocyte-macrophage colony-stimulating f

14、actor）delivery systemspresenting vaccine antigen(s) to appropriate cells of the immune system preserving or stabilizing the integrity or conformation of antigen(s) in vivoMucin-1(MUC-1)polymorphic, O-linked, glycosylated proteins20 amino acid sequence tandemly repeated 25100 times lower glycosylatio

15、nbind and activate the T-cell receptorTheratope: Sialyl-Tn (STn) + carrier protein +adjuvant 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 bu

16、t not mutatedHER-2/neu overexpression activate T cells Vaccine E75 peptide: phase I/II trialsGP2 peptide: phase II trialMammaglobin-A(MAM-A)Secretary protein expressed almost exclusively in breast cancer Overexpressed in up to 80% of primary metastatic breast cancersA phase I clinical trial of a mam

17、maglobin-A DNA vaccine showed tumoricidal function Prime candidate for breast cancer vaccine therapyOther antigenspeptides derived from CEA or portions of carcinoembryonic antigen(CEA)human telomerase reverse transcriptase (hTERT)tumor protein p53cancer-testis antigens (New York esophageal antigen-1

18、NYESO-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 activi

19、ty in advanced breast cancer 吉利201201022Clinical trials: new paradigm for breast cancer vaccine2 phase/stageProof-of-principle trials Efficacy trialsflexible and focused clinical development process with early and informed decision2 phase/stageProof-of-principle trials Efficacy trials “go” or “no go

20、”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 estab

21、lished tumor massMTD This trial is based on two assumptions: Antitumor activity is inevitably connected to serious toxicity risks. Maximizing dose should maximize efficacy.But :Cancer vaccines are generally much safer than cytotoxic agents. The dose that yields sufficient immunogenicity and biologic

22、 activity is unlikely to confer significant toxicity. Justification should be based on biologic or clinical activityTheres not a linear relationship between dose of peptide administered and the magnitude/potency (量級/效能) of a T-cell or clinical response.Response EvaluationConvention: based on shrinka

23、ge of tumor massHowever, cancer vaccines involves :immune activationbuilding of an immune response over time.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 targ

24、et small quantities of cancer cells or minimal residual (殘留) 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 pointsResponse EvaluationProof-of-p

25、rinciple trialsWe dont need to :establish the MTDcharacterize PKs (藥代動力學)We need :more rapid assessment of therapeutic potentialProof-of-principle trialsQ: How can we design a set of Proof-of-principle trials? 20 homogenous patients Patients should not be in a rapidly progressive state to allow vacc

26、ines adequate time to induce biologic activity (which should include immune and molecular markers). 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

27、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-princi

28、ple trials：establish an active dose regimen (給藥方案) 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 trialsRandomized studies formally Bridge over the gap o

29、f the no longer recommended conventional phase 2 trials Phase 2 Phase 33. Confirm the data obtained in proof-of-principle trials and demonstrate efficacy陳芳瑩201201042Vaccine Manufacturing Manufacturing ProcessGeneration of the antigenRelease and isolation of the antigenPurificationAddition of other componentsPackagingpacka