最新恶性黑色素瘤生物治疗进展-(1)资料(3)课件PPT.ppt 60页

'恶性黑色素瘤生物治疗进展-(1)资料(3) 恶性黑色素瘤黑色素细胞的恶性肿瘤。在美国，每年约有69,000例新发病例。在中国，每年新诊断患者约20,000例。近年来，发病率迅速增长。具有高死亡风险的皮肤癌，总体5年生存率低于10%，晚期恶性黑色素瘤5年生存率仅为5%左右。 目前恶黑的治疗方法根据黑色素瘤的分期来决定治疗方式。多种治疗方法可选用：外科手术化学治疗放射治疗免疫治疗 IFN-α2b已被FDA批准。用于具有高复发风险的术后患者的辅助治疗。IFN-α2b主要通过抗增值、诱导分化，修饰肿瘤细胞抗原、促进机体识别相关抗原和清除肿瘤细胞，以及抗血管生成等作用达到治疗效果。大剂量IFN-α2b(HDI)治疗可延长黑色素瘤切除术后高危患者的无复发生存时间，提高总生存率。 生物化疗生物化疗指化疗与IFN和/或IL-2联合应用。 免疫检查点疗法是一类通过调节T细胞活性来提高抗肿瘤免疫反应的治疗方法。免疫检查点是免疫系统中的抑制性通路，它们本来的作用是为了避免自身过度免疫，但在肿瘤患者中却与肿瘤的免疫逃逸息息相关免疫检查点抑制剂 免疫检查点细胞毒性淋巴细胞相关抗原4(CTLA-4)程序性死亡受体1（PD-1）与其配体PD-L1 细胞毒性淋巴细胞相关抗原4（CTLA-4）.CTLA-4是第一个应用于临床的T细胞免疫检查点，主要表达于T细胞表面，是其活性的负性调节蛋白。 CTLA-4单抗的作用机制：特异性地结合CTLA-4，阻断其与B7的相互作用，恢复CD28/B7共刺激信号，从而恢复T细胞的免疫活性。常见的CTLA-4单抗主要有易普利单抗（Ipilimumab）和曲美目单抗（Tremelimumab）。 索拉非尼+达卡巴嗪安慰剂+达卡巴嗪中位PFS21.1w11.7wHR,0.665P=0.068中位TTP21.1w11.7wHR,0.619P=0.039OS45.651.3HR,1.002P=0.927Ⅱ期:索拉非尼+达卡巴嗪Vs达卡巴嗪索拉非尼与达卡巴嗪联合可延长PFS，但对延长OS无优势。 JClinOncol.2009Jun10;27(17):2823-30Ⅲ期:索拉非尼+卡铂/紫杉醇二线治疗 Ⅲ期一线治疗(E2603)A组卡铂AUC=6i.v.紫杉醇225mg/m2i.v.安慰剂2tabletsp.o.,bidQ3weeks×10cyclesB组卡铂AUC=6i.v.紫杉醇225mg/m2i.v.索拉非尼400mgp.o.,bidQ3weeks×10cycles紫杉醇+卡铂±索拉非尼N=823C/P/SC/POS11.1m11.3m中位PFS4.9m4.1mRR18%16%P>0.05forallcomparisonsJClinOncol.28:15s,2010(suppl;abstr8511). PLX4032PLX4032Ⅰ期临床试验:V600EBRAF突变为治疗靶点。PLX4032显示了对于V600EBRAF突变的肿瘤具有抗瘤活性。9例达到部分缓解肝脏、肺脏以及骨转移灶消退许多患者症状缓解表明V600EBRAF是一个有效的治疗靶点。ASCO,2009,abstract#9000 甲磺酸伊马替尼的Ⅱ期试验21%的肿瘤存在KIT的突变或扩增。ASCO,2009,abstract#9001 Ⅱ期:替莫唑胺联合贝伐单抗的一线治疗中位随访时间:14.1个月。12个月内的疾病稳定率(CR,PR,SD):52%。RR:16.1%.中位反应时间:5个月。PFS:4.2个月。OS:9.3个月。BRAF野生型患者反应率和OS显著提高。毒副作用较小。ASCO,2010,abstract#8521 白蛋白结合紫杉醇与贝伐单抗联合一线治疗III期和IV期无法切除的患者ASCO,2009,abstract#9061初步的结果表明:–白蛋白结合紫杉醇与贝伐单抗联合治疗与过去的研究对比显示对延长PFS和OS具有优势。–安全性好。–由于病例数较少以及较短的随访时间，无法对安全性和疗效做进一步的评价。 Ⅱ期:贝伐单抗与高剂量IFN联合PR:61例治疗212周SD:5例(>24周)(30–122周)PD:14例(12–20周)中位PFS:4.9个月OS:18.4个月ASCO,2010,abstract#8520临床反应率:24%。疾病长期稳定的达到20%。 抗CTLA-4抗体IpilimumabTremelimumab Ipilimumab剂量摸索试验：ipilimumab治疗不可手术的Ⅲ/Ⅳ期患者。CR+PR(%)P=0.0015JClinOncol2008,26(15s):abstract9025 IpilimumabASCO,2009,abstract9038Ipilumumab+DTICVsDTIC试验已经结束，结果有望在年内公布。 Ⅲ期:ipilimumab,gp100肽疫苗(MDX010-20)Ipilimumabvsgp100Ipilimumab+gp100vsgp100Ipilimumab+gp100vsipilimumab结果:与单用gp100肽疫苗相比,Ipilimumab±gp100肽疫苗可延长复治患者的OS。NEnglJMed,July29,2010Ipilimumab有望成为下一个FDA批准的用于IV期恶黑治疗的药物。 Ⅱ期:Tremelimumab+HDIFNN=36(IV期,2例有中枢神经系统转移病史,大多数患者曾接受过其他治疗)。SD:12例(36%)PFS(6个月):53%中位PFS:6.4个月OS一年:57.8%中位OS:15.9个月ASCO,2010,abstract#8524与治疗效果相关的预后指标：–基线CRP<2.5ULN–发生自身免疫性病症 过继性细胞吗免疫治疗Naturereviewscancer,8,299-308,2008 T细胞治疗1988200220062008使用自体TIL治疗转移性恶黑采用淋巴细胞清除性预处理提高TIL在转移性恶黑中的治疗效果使用MART-1特异性识别TCR基因修饰的正常自体淋巴细胞治疗分选、扩增特异性针对NY-ESO-1的自体CD4+T细胞克隆用于恶黑治疗HunderNN,NEnglJMedRosenberg,NEnglJMedScience,2006:126Science,2002:298 CurrOpinImmunol.2009:233 疫苗设计全细胞蛋白/肽DNA传统佐剂细胞因子DC负性调控分子的阻断抗原+佐剂=疫苗MART-1gp100tyrosinase-relatedprotein1gangliosidesGM-CSFIncompleteFreundadjuvantIL-2DC Gp100肽疫苗Ⅲ期多中心随机临床试验：gp100肽疫苗联合HDIL-2治疗转移性恶黑。JClinOncol27:18s,2009.RRandPFS优于HDIL-2单独治疗组。第一次证实疫苗治疗恶黑具有临床优势。 Thankyou! Chapter1TheGeneralSurveyofaWordI. DefinitionofawordFromthelexicologicalpointofview,awordisacombinationofform(phonological)andmeaning(lexicalandgrammatical).Inaddition,awordactsasastructuralunitofasentence.(P301)词是语音、意义和语法特点三者统一的整体。词又是语句的基本结构单位。Awordisaminimalfreeformofalanguagethathasagivensound,meaningandsyntacticfunction. II. Soundandmeaning（语音与意义）Twopointsofviewabouttherelationbetweensoundandmeaningofaword:TheNaturalists(自然派)maintainthatthereisanaturalconnectionbetweensoundandmeaning.TheConventionalists(习惯派)holdthattherelationsbetweensoundandmeaningareconventionalandarbitrary Wordsthatconveythesamemeaninghavedifferentphonologicalformsindifferentlanguages:我们(Chinese)，we(English),nous(French)Thesamephonologicalformsmayconveydifferentmeanings:sight,site,cite;忙，盲，氓，茫，芒 IIIMeaningandconceptConceptisacategoryofhumancognition.Itisanabstractionfromthingsofthesamekind.Itreferstosomethingingeneralwhilethemeaningofawordcanrefertosomethingbothingeneralandinparticular.e.g.(1)Wehavebeguntorealizethattheautomobileisamixedblessing.(2)Theautomobilewasstalledinasnowstorm.Page301IV.Lexicalitemandvocabulary(P302-303) ClassificationofWordsbyusefrequency:basicwordstock(基本词汇)andnonbasicvocabularybynotion:contentwords/fullwordsandfunctionalwords/formwords byorigin:nativewordsandborrowedwordsbymorphology:simplewords,compoundsandderivedwords BasicWordStockandNonbasicVocabulary1).AllNationalCharacterNaturalphenomenaHumanbodyandrelationsNamesofplantsandanimalsAction,size,domain,stateNumerals,pronouns,prepositions,conjunctions 2)Stability3)ProductivityWordsofthebasicwordstockaremostlyrootwordsormonosyllabicwords.Theycaneachbeusedalone,andatthesametimecanformnewwordswithotherrootsandaffixes,e.g. e.g.foot,footage（以英尺表示的）尺码,football,footpath,footer,footprintandsoon.Inthesameway,dogisthefatherofdoglike,dogcheap,dogfight混战,狗咬狗,dog-ear书页的折角,dogpaddle,dogsleep(不时惊醒的睡眠),tonamejustafew. 4)PolysemyMostwordsofthebasicwordstockhaveundergonetransformationsinsemanticstructureinthecourseofuseandbecomepolysemous.5)CollocabilityManywordsofthebasicwordstockenterquiteanumberofsetexpressions,idiomaticusages,proverbialsayingsandthelike. Takeheartforexample:achangeofheart(改变主意,变心);aheartofgold(道德高尚的人);atheart(在内心里);afterone‘sownheart(完全符合自己的心意);breakone’sheart;crossone‘sheart(在胸口划十字);cryone’sheartout(痛哭欲绝);haveone"sheartinone"smouth(Tobeextremelyfrightenedoranxious极其害怕或担心); heartandsoul;one‘sheartsinkswithinone(某人消沉泄气);takesomethingtoheart(Totakeseriouslyandbeaffectedortroubledby认真对待…，受…影响或困扰);wearone’sheartuponone‘ssleeve(infmltoshowone’struefeelingsopenlyinsteadofhidingthem流露真实的感情);eatone‘sheartout(暗自伤神,忧伤). Words,voidofthestatedcharacteristics,donotbelongtothecommoncoreofthelanguage.Theyincludethefollowing: (1)TerminologyThisreferstotechnicaltermsusedinparticulardisciplinesandacademicareasasinmedicine:photoscanning(光扫描,摄影扫描),hepatitis(肝炎),penicillin;inmathematics:algebra(代数学),calculus(微积分学);inmusic:symphony,sonata(奏鸣曲),concerto(协奏曲);ineducation:audiovisual(视听的),microteaching(微型教学),etc. (2)Jargon(行话)(3)Slang(4)Argot(隐语，黑话)(5)DialectalWordsAustralianEnglish:chook=chicken,station=ranch,beauty=excellent,greatScot:hame=home,coo=cow (6)ArchaismsArchaismsarewordsorformsthatwereonceincommonusebutarenowrestrictedonlytospecializedorlimiteduse.Theyarefoundmainlyinolderpoems,legaldocumentsandreligiouswritingorspeech.Thou—you,ye—(pluralyou),thee(objectiveyou),wilt—will,brethren—brothers,quoth—said,hereof—ofthis,concerningthis,wherein—inwhat 2.ContentWordsandFunctionalWords3.NativeWordsandBorrowedWordsApartfromthecharacteristicsmentionedofthebasicwordstock,nativewordshaveafewotherfeatures. 1)NeutralinStyleSincenativewordsdenotethecommonestthingsinhumansociety,theyareusedbyallpeople,inallplaces,onalloccasions,andatalltimes.Theyarenotstylisticallyspecific.Thiscanbeillustratedbyacomparisonbetweensynonyms. begin(E)—commence(F)brotherly(E)—fraternal(F)kingly(E)—royal(F)—regal(L)rise(E)—mountF)—ascend(L)Stylistically,nativewordsareneitherformalnorinformalwhereaswordsborrowedfromFrenchorLatinareliteraryandlearned,thusappropriateinformalstyle. 2)FrequentinUseBorrowedwordsorloanwordscanbedividedintofourgroupsaccordingtothedegreeofassimilationandmannerofborrowing.1)Denizens同化词2)Aliens非同化词3)TranslationLoans译借词4)SemanticLoans借义词 1)Denizens同化词Denizensarewordstakenfromaforeignlanguagewithatransformationoftheforeignsoundandspellingintonativeforms.WordsofthisgroupareearlyborrowingsfromLatin,Greek,FrenchandScandinavian,e.g.port(L),cup(L),pork(F),change(F),get,egg,sky,skill(Scandinavian). 2)Aliens非同化词Aliensareborrowedwordswhichhaveretainedtheiroriginalpronunciationandspelling.Thesewordsareimmediatelyrecognizableasforeigninorigin.Statusquo现状(L),bazaar集市(Per),raja王侯(Hindi),automobile(F),coupd’etat政变(F) 3)TranslationLoans译借词Translationloansarewordsandexpressionsborrowedfromforeignlanguagesbymeansoftranslation.Mothertonguefromlinguamaternal(L),blackhumourfromhumournoir(F),lamafromlama(CHdial),teafromt"e(CHdial) 4)SemanticLoans借义词Wordsofthiscategoryarenotborrowedwithreferencetotheformbuttothemeaning.Inotherwords,Englishhasborrowedanewmeaningforanexistingwordinthelanguage. TheoldEnglishwordgiftmeant"thepriceofawife",whiletheScandinavianwordgiptmeant"gift,present".ThewordhasacquiredanewmeaningundertheinfluenceoftheScandinavianlanguage. Pioneeroncesignified"explorer"onlyor"persondoingpioneeringwork",anditnowhastakenonthenewmeaningof"amemberoftheYoungPioneer"fromRussian. Don’ttellhimanything.Hehasabigmouth.Hehastopullhissocksupifhewantstostayintheteam.Doyouhaveasweettooth?Helivesinatinycottageinthemiddleofnowhere. Ifsomeoneisorhasabigmouth,theyoftensaythingswhicharemeanttobekeptsecretpullone’ssocksup--tomakeanefforttoimproveyourworkorbehaviourbecauseitisnotgoodenough 鼓足干劲，加紧努力(in)themiddleofnowhere--describesaplacefarawayfromanytownsandcitiesandwherefewpeoplelive在偏远地方haveasweettooth--lovetoeatcandyorothersweets.'