基因治疗课件

StateKeyLaboratoryofCancerBiology&XijingHospitalofDigestiveDiseases,FourthMilitaryMedicalUniversity,Xi’an,P.R.ChinaXin-minZhourAd-P53genetherapyfor

advancedhepatocellularcarcinoma

.tumortypeCases（10,000）RankDeaths（10,000）Ranklungcancer135.01118.01breastcancer115.0241.15colorectalcancer100.0352.94stomachcancer93.4470.02prostatecancer67.9522.16livercancer62.6659.83

ParkinDM,etal.CACancerJClin2005;55:74-108

HCCisthesixthmostcommoncancerworldwideandthethirdmostcommoncauseofdeathfromcancer.ChinaisthemostprevalentregionofHCCGlobalCancerStatistics,2002.CACancerJClin2005;55:74-108Therewere626,162newcasesofHCCworldwidein2002Chinaaccoutsfor55％ofallcasesMale-to-femaleratiosarearound3.DistributionofHCCpatientaccordingto

BCLCstaginginChinaDatafromChineseHCCstatussurveyinitiatedby

ChineseAnti-cancerAssociationstageAstageBstageCstageD53.927.115.32.6.BCLCstagingandtreatmentstrategyStage0

PST0,Child-PughAPortalpressure/bilirubinRFA=radiofrequencyablation;

PEI=percutaneousethanolinjection.HCCStageA–C

Okuda1–2,PST0–2,Child-PughA–BStageD

PST>2,

Child-PughCVeryearlystage(0)

Single<2cm

carcinomainsituEarlystage(A)

1–3nodules<3cm,

PS0Intermediatestage(B)

Multinodular,

PS0Advancedstage(C)

Portalinvasion,

N1,M1,PS1–2Endstage(D)Single3nodules≤3cmIncreasedAssociateddiseasesNormalNoYesResectionLivertransplantationPEI/RFAChemoembolizationSorafenibCurativetreatmentsPalliativetreatmentsSymptomatic

treatmentBruixJ,etal.Hepatology2011;53(3):1020-1022..TP53gene,widelyregardedasthegenomeguardianofcells,playsakeyroleincellcyclecontrol,apoptosis,andinhibitionoftumorcellproliferation.MutationsintheTP53geneareafeatureof50%ofallreportedcancercases.TP53:themostcommonlymutatedgeneinhumancancer.ChristianFrezza,et,al.DrugResistanceUpdatesVolume15,Issues5?62012258-267

p53restorationstrategiesforcancertreatment.RestoringTP53functions:genetherapyp53:17p13.1.9CDKVEGFdamagerepairgeneMDM2feedbackp21cuttingtumorbloodsupplyGD-AIFBAI-1TSPp53Ku70

DNA-PKATMreverseRTsensitivityMDRreversechemoresistancecellcyclearrestMMPInhibitinvasionandmetastasisNKbystandereffecta(II)PHcellapoptosis

Ad-p53antitumormechanisms—throughmultiplepathways.adenoviraldeliveryvehicleantitumormechanisms

regulatepatient’sphysiologicalfunctionreducethesideeffectscausedbyconventionalradio-andchemotherapyimproveappetiteandgeneralhealthstatusimprovepatient’squalityoflifeadenoviraldeliveryvehicletriggerimmuneresponseinducecytokinesandlymphocytesincreasehumoralimmunityandcellularimmunitynerve–endocrinesystemImmunesystem.Ad-p53—ApromisingtreatmentmodalityforadvancedHCCRecombinanthumanadenovirus–p53injection(GendicineTM)hasshownencouragingresultsinclinicalapplicationsfortreatmentofadvancedHCC.Gendicinecouldbeadministeredviaintravenousinjection,intraperitonealinfusionandhepaticarteryinfusion.Gendicinecouldbeappliedincombinationwithconventionaltherapiessuchasradiotherapy,chemotherapy,andsurgery..Male,63y,CTindicatedalowdensity,space-occupyinglesion,sized16×13.5cmintherightlobeoftheliverTumorstageC(BCLC),AFP12947ng/mL.Treatmentregimen:

intratumoralinjectionofGendicineviatranscatheterperfusionatadoseof2×1012VP,onceperweekfor4weeks,2daysafterTACEwascarriedout,TACEwasrepeatedaftertwomonthsResult:

Aftertwosessionsoftreatment,CTindicatedamuchsmallerlesionsized3×2cm,andserumAFPleveldecreasedto6075ng/mL,Case1.BeforetreatmentAftertreatment.Case2Female,56y,CTdepictedintrahepaticmultinodularHCC,TumorstageC(BCLC),AFP3565ng/mL.Treatmentregimen:IntravenousinjectionofGendicineatadoseof2×1012VP,onceeveryotherdayfor5timesafterTACEwascarriedout.Result:Afteronesessionsoftreatment,CTindicatedasmallerlesionscomparedwithlasttime,andserumAFPleveldecreasedto2127ng/mL,.BeforetreatmentAftertreatment.Ongoingclinicaltrial1:1randomization（n=80）rAd-P53+FOLFX4

FOLFX4

Inclusioncriteria

StagingB-CHCC

Karnofsky≥60ChildPughAstatusEffectassessmentResponseRateLifequalitySafetyassessmentAdverseeffect2×1012rAd-p53VPper2daysfor10times.ResponseratesbyResponseEvaluationCriteriainSolidTumors

groupnCRPRMRSDPDCR+PR(%)treatment

40018118345.0control

40011815627.5ResponseratesbyResponseEvaluationCriteriainSolidTumorsResponseratesbyResponseEvaluationCriteriainSolidTumors.LifeofqualitybyKarnofskygroupnimprovedStableprogressiveCR+PR(%)treatment

402410685.0control

401571855.0.SafetyNoseveresideeffectshavebeenobserve