恶性黑色素瘤药物发展

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1、恶性黑色素瘤药物发展AlexanderM.M.Eggermont,MD,PhDErasmusMC-DanieldenHoedCancerCenterRotterdamShanghai,CSCO,2008黑色素瘤治疗靶点全身治疗化疗细胞因子抗体型疫苗新的分子靶向药物促凋亡剂抗BRAF抗VEGFR2EGFR,MEK,ERK抗整合素抗血管生成制剂转移潜能无限增值血管生成自主生长信号肿瘤抑制缺失阻断凋亡(Hanahan&Weinberg,2000)已知肿瘤细胞特征IV期黑色素瘤的III期临床试验(1)EggermontIV期黑色素瘤含干扰素的III期临床试验(2)IV期黑

2、色素瘤的III期临床试验(1)化疗+IL-2+IFN黑色素瘤生物化疗的纪念(从今开始)一线治疗的研究药物CTLA4阻断抗CTLA-4单克隆抗体IL-2B7MHCTCRCD28...............~AntigenAPCT-cellCTLA-4B7MHCTCRCD28~AntigenB7MHCTCRCD28CTLA-4...............Antigen抗CTLA-4单克隆抗体MHCIL-2~T细胞受体:MHC抗原CD28:B7CTLA-4:B7疫苗?CTLA-4:T细胞激活的“刹车”Copyright©2003bytheNationalAcademy

3、ofSciences断层扫描示治疗前病变(左侧)，治疗后达到完全缓解：病例13（A与B）及病例11（C-F）Ipilimumab联合多肽类疫苗治疗进展期黑色素瘤(NCI)PhanGQ,etal.Proc.Natl.Acad.Sci.2003;100:8372-8377.一例进展期黑色素瘤患者Ipilimumab相关性皮疹Ipilimumab刺激黑色素细胞免疫识别(A)网状红斑样皮疹(B)血管周围淋巴细胞浸润突破表皮(C)CD4+T细胞临近死亡的黑色素细胞(D)CD8+T细胞临近死亡的黑色素细胞1.HodiSF,etal.ProcNatlAcadSci.2003;10

4、0:4712-4717.1.AttiaP,etal.JClinOncol.2005;23:6043-6053.2.BeckK,etal.JClinOncol.2006;24:2283-2289.OverviewofGastrointestinal(GI)irAEsDiarrheaisafrequentirAEs1,2MostcasesaremildormoderateWaterytofrankbloodBiopsyusuallydemonstratesinflammatorycolitisManagementalgorithmestablishedMostcase

5、srespondtoeithersymptomatictreatmentorsteroidsCanrarelyleadtoGIperforation(<1%)requiringsurgery21.Robinsonetal.JImmunother.2004;27:478.2.Phanetal.ProcNatlAcadSciUSA.2003;100:8372.Ipilimumab-InducedColitisResemblesIBDandUsuallyResolvesWithoutSequelaWithAppropriateTherapyBlansfieldetal.

6、JImmunother.2005;28:593-598.OverviewofirAEsinEndocrineOrgansHypophysitisSymptomsatpresentation:memoryloss,fatigue,impotence,headacheManagementDiscontinueipilimumabTemporarycorticosteroidadministrationHormonalreplacementPatientsareasymptomaticSlowreturnofsomeendocrinefunction6/30/04Bas

7、eline(4.5mm)12/3/04Headache/Fatigueafter5doses(10.8mm)Blansfieldetal.JImmunother.2005;28:593-598.Ipilimumab-RelatedPituitarySwellingandDysfunctionCorrelationBetweenIRAEsandClinicalResponse”EnterocolitisinPatientsWithCancerAfterAntibodyBlockadeofCytotoxicT-Lymphocyte–AssociatedAntige