臨床免疫學(xué)-腫瘤免疫與實(shí)驗(yàn)診斷

腫瘤免疫與實(shí)驗(yàn)診斷

TUMORIMMUNOLOGYAND

IMMUNEDIAGNOSIS

1主要內(nèi)容簡(jiǎn)要腫瘤生物學(xué)

腫瘤免疫學(xué)簡(jiǎn)介目前腫瘤診療現(xiàn)狀與前景2免疫系統(tǒng)與腫瘤強(qiáng)大的免疫功能---人類(lèi)自然

生存的前提免疫監(jiān)督是免疫功能之一3腫瘤現(xiàn)狀腫瘤是一種生物現(xiàn)象突變是自然的、必然的進(jìn)化形式成瘤也是一種適應(yīng)性進(jìn)化四千多年的歷史，治療無(wú)能為力

19世紀(jì)至20世紀(jì)初的手術(shù)20世紀(jì)初的放療1947年后的化療4ConceptsoftumorbiologyTumor:

Acell-clonemalignantdiseaseDiseasescontinuouschangingtheirnatureKindsofspecificgeneticdiseases5Cellcycle

G0MG1SG2

Cellalterationprocesses:

cellbenignprolif.beingmalig.Tumor

121061091012

TumorCellBiology

20771mm,1mg 1cm,1g1kgMonthstoyearsmonthsdays6

腫瘤發(fā)生學(xué)的主要學(xué)說(shuō)

MainhypothesisintumorigenesisSomaticmutationandgenemutation（突變）ChromosomeabnormalityEvolutiontheory（進(jìn)化）Micro-environmenthypothesis

（微環(huán)境）ChronicInflammationStemcellsetc.78Anti-tumorimmunity

Yesorno?9

Yes!Ligationtest(腫瘤結(jié)扎實(shí)驗(yàn)),morethan100yearsSyngeneicmice(等基因鼠)Clinicaldata10EvidenceforimmunesurveillanceinhumansIncreasedincidenceofEBV+BcelllymphomasintransplantpatientstreatedwithimmunosuppressivedrugsIncreasedincidenceofKaposi’ssarcoma&EBV+BcelllymphomasinAIDSpatientsGastriccancerassociatedwithH.pyloriinfectionCervicalcancercausedbyHPVLivercancercausedbyhepatitisB&C11No!HIVinfectionNudomice(裸鼠)TSA,TAA12ImmunologicalSurveillance

Ehrlich,Burnet&ThomasPaulEhrlich(1909)FirsttoconceiveoftheconceptofCancerImmunosurveillance.Predictedthatcancerwouldoccurat“incrediblefrequency”ifhostdefensesdidnotpreventtheoutgrowthofcontinuouslyarisingcancercells.LewisThomas(1957)“primaryfunctionofcellularimmunity….istoprotectfromneoplasticdisease”MacfarlandBurnet(1957)“Itisbynomeansinconceivablethatsmallaccumulationsoftumourcellsmaydevelopandbecauseoftheirpossessionofnewantigenicpotentialitiesprovideaneffectiveimmunologicalreactionwithregressionofthistumorandnoclinicalhintofitsexistence”13

Essences:TumorisautologousorheterologousOr

doesexistspecifictumorantigen?

14Essences:

Cantumorstimulateimmunesystemtoprovokeeffectiveresponse?15Essences:Howcantumorescapefromthesurveillanceofimmunesystem

(免疫監(jiān)督)Whatcanwedoindealingwithtumor16

ImmuneSystem

AwelldevelopeddefensesystemNonspecificandspecificdefensemechanisms(特異與非特異免疫)InitaveimmunityAcquiredimmunityHumoral,Cellular17Tumorantigens

KeymoleculesbetweentumorandhumanbodyClassificationTumormarkersandtumorantigens18TumorantigendiscoveringTSTATSA:alongroadtolookingforThreestages:OriginalMcAbTAATcellcloneTSA19IsTumorAntigenProvokeImmuneResponse(免疫激發(fā))longtimecontroversial

Yes!Showspecialfeatures:weakdifferentialantigen

embryonicantigenoncoviralantigenmutationgenes20Why?TumorescapingtheImmuneSystem(免疫逃逸)

inmanyways1Lowantigenicity(抗原性):MHCexpressingdefectTPACo-stimulatingmoleculesAdheringmoleculesetc.

21PathwayofAntigenPresentation

byAntigen-PresentingCells(抗原遞呈)22StructuresofClassIandClassIIMajorHistocompatabilityComplex(MHC)Molecules2324RoleofCo-stimulation

inT-CellActivation2526DendriticCells,theSurface

ChangesOccurringWithMaturation27Why?

TumorescapingtheImmuneSysteminmanyways2Introcyto-moleculesantigenicmodulationinhibitionfactors:TGFFasLTsblockingfactors28Anti-TumorImmunology29

選擇免疫治療是無(wú)奈之舉

一百多年前的腫瘤結(jié)扎試驗(yàn)

Coley`stoxin

臨床的提示30

免疫的進(jìn)展放大了人們的預(yù)期單克隆抗體的出現(xiàn)人源性抗體的問(wèn)世

人類(lèi)基因組計(jì)劃的完成免疫監(jiān)測(cè)點(diǎn)功能的發(fā)現(xiàn)CAT細(xì)胞的應(yīng)用31腫瘤免疫與與生物治療的關(guān)聯(lián)

細(xì)胞因子治療

免疫細(xì)胞治療

基因治療

分子靶向治療

抗體治療32腫瘤免疫治療目前，全球癌癥免疫治療主要包括以下三個(gè)方面：1.針對(duì)新抗原的特異性T細(xì)胞治療;2.以基因修飾為核心的ACT:CAR-T、TCR-T免疫細(xì)胞治療；3.腫瘤相關(guān)靶點(diǎn)抗體與免疫檢查點(diǎn)抗體。33

重新審視免疫平衡理論

關(guān)于免疫激發(fā)

對(duì)腫瘤發(fā)生學(xué)的影響

已展現(xiàn)一定的臨床效果34免疫檢驗(yàn)點(diǎn)抗體（immunolcheckpoint）35CAT腫瘤治療(chimericantigenreceptor，CAR)目前受世人關(guān)注，這項(xiàng)技術(shù)最早見(jiàn)于1993年以色列科學(xué)家EshharZ的報(bào)導(dǎo)。將抗體序列表達(dá)在抗腫瘤免疫細(xì)胞表面。36CAT的技術(shù)路線(xiàn)（1）靶點(diǎn)，這方面專(zhuān)利多數(shù)己過(guò)期（2）與靶點(diǎn)結(jié)合的單鏈抗體（3）跨膜區(qū)與胞內(nèi)區(qū)，所有CAR-T的差別不大，這些都是美國(guó)的專(zhuān)利（4）剎車(chē)及安全開(kāi)關(guān)（5）轉(zhuǎn)染技術(shù)，國(guó)際上常用的慢病毒載體系統(tǒng)37腫瘤治療的耐藥耐藥產(chǎn)生的基本原理---生物變異與適應(yīng)

耐藥發(fā)生的必然性抗體耐藥發(fā)生的特點(diǎn)

38Immuneresponse--twostagesImmuneexcitationrecognition,antigenpresentationImmuneresponsenon-specific,specific--humoralandcellular39

TheAnti-tumorImmuneResponse40AmountAttacktotheTumorTumorantigenicityenhancingManipulatetheimmunesystemi.etumorvaccinesAdoptedspecifictherapiescellularhumoral41CellularTumorkillingmechanism:

NKandK(MHCinhibitreceptor)CTLmacrophagesAbandhumoralmolecules42EffectorMechanismsofTumorCellKillingbyCytotoxicTCells(CTLs)AB43TheeffectmodelsofantibodyEpitopebinding:NeutralizationADCCeffectInducedcomplimentfunctionSignaltransduction4445AboutTumorDiagnosis

Preventionisnotpracticalbynow(withtheexceptoflungcancer)

Earlydiagnosisistheonlyeffectivemeasure46Earlydiagnosisdependonwhat?PathologicalthatistoolateImagingtechniquesshowlimitedrolesbecauseofmolecularfeaturesintumorcell

Serologicalavaluablefieldtodelving

Geneticmethodahopefulfield47血液(體液)腫瘤相關(guān)分子檢測(cè)1.多肽與蛋白類(lèi)2.核酸類(lèi)(基因)

（1）內(nèi)源基因的變異：基因結(jié)構(gòu)突變基因表達(dá)異常

（2）外源基因的入侵3.復(fù)合形式脂蛋白，糖蛋白,AFP異質(zhì)體，CA抗原類(lèi)等4.各種修飾形式(甲級(jí)化、磷酸化、組氨酸、乙?；?、泛素化、糖化等)48TumorMarkerExaminationBensJonesprotein

AFP,CEA

Severaldozens

BecomemoresignificantShowhopefulfuture49HistoricalBackground1846BenceJonesprotein

1940Acidphosphatase1960Immunoassay1963AFP1965CEA1975McAb1980PSACAserial1970-1980Oncogenes1990---50Characteristicsofthe“Ideal” TumorMarker

Measuredeasilysensitivityandspecificity.QuantitativelevelMultipleusages51TypesofTumorMarkers

Hormone:hCGcalcitoningastrinprolactingrowinghormones

Enzymes:

acidphosphatasealkalinephosphatase

ProteinsandGlycoproteins:PSACA

Oncofetalantigens:Receptors:

PREREGFR

Oncogenproducts:RASmycbcl

Tumorsuppressorgenes:

p53Rb52TechniquesofTumorMarkerDetectionPhysic-chemicalmethodsPrimaryimmunemethodsAmplifiedimmunemethods53AmplifiedimmunemethodsRIA,ELISA,Immunefluorescence,Luminex,Micro-particlesetc.54Significanceandlimitations

theapplicationoftumormarkersScreening

DiagnosisanddifferencialdiagnosisStagingandprognosis

TherapyassessmentsMonitoringRecurrence55TumorscreeninganddiagnosisLimitedvalue,but:AFPinChinaPSAinUSAinmalemorethan50CA-125forovarytumor

EarlydetectableTissuespecificSignificantinRiskpopulations56MarkerutilitiesTumorMarkerScreeningProg.MonitoringRecurrenceColonCEAnyyyHeptoAFPycomnyyOvaryCA125pcomnyyOvaryCEAnnyyBreaCA153nnyyPancCA199pcomyyGastroCA724pcomyyProstPSApcomyyyNon-HodgkLDHnynyMMB2-MnyyyTestiHCGnyyySquamSCCpcomyyBladdTPAnyy57CocktailUsageTumorF-markerL-markerO-markerLung