恶性黑色素瘤药物发展

1、会计学1恶性黑色素瘤药物发展恶性黑色素瘤药物发展转移潜能转移潜能无限增值无限增值血管生成血管生成自主生长信号自主生长信号肿瘤抑制缺失肿瘤抑制缺失阻断阻断凋亡凋亡(Hanahan & Weinberg, 2000)EggermontIV期黑色素瘤的III期临床试验(1)化疗+ IL-2 + IFNIL-2B7MHCTCRCD28. . . . . . . . . . . . . . . AntigenAPCT-cellCTLA-4B7MHCTCRCD28AntigenB7MHCTCRCD28CTLA-4. . . . . . . . . . . . . . . Antigen抗抗CTLA

2、-4 单克隆抗体单克隆抗体MHCIL-2T细胞受体: MHC抗原CD28: B7 CTLA-4: B7疫苗? CTLA-4: T细胞激活的“刹车”Copyright 2003 by the National Academy of Sciences断层扫描示断层扫描示治疗前病变治疗前病变(左侧左侧)，治疗后达到完全，治疗后达到完全缓解：病例缓解：病例13（A与与B）及病例及病例11（C-F）Ipilimumab联合多肽类疫苗治疗进展期黑色素瘤(NCI)Phan GQ, et al. Proc. Natl. Acad. Sci. 2003;100:8372-8377.Ipilimumab 刺激黑色

3、刺激黑色素素细细胞免疫胞免疫识别识别 (A) 网状网状红红斑斑样样皮疹皮疹 (B) 血管周血管周围围淋巴淋巴细细胞胞浸浸润润突破表皮突破表皮(C) CD4+ T细细胞胞临临近近死亡的黑色素死亡的黑色素细细胞胞(D) CD8+ T细细胞胞临临近近死亡的黑色素死亡的黑色素细细胞胞1. Hodi SF, et al. Proc Natl Acad Sci. 2003;100:4712-4717. 1. Attia P, et al. J Clin Oncol. 2005;23:6043-6053.2. Beck K, et al. J Clin Oncol. 2006;24:2283-2289.1.

4、 Robinson et al. J Immunother. 2004;27:478.2. Phan et al. Proc Natl Acad Sci USA. 2003;100:8372.Blansfield et al. J Immunother. 2005;28:593-598.6/30/04 Baseline(4.5 mm)12/3/04 Headache/Fatigue after 5 doses (10.8 mm) Blansfield et al. J Immunother. 2005;28:593-598.p= 0.0065 p= 0.0016Beck K, et al. J

5、 Clin Oncol. 2006;24:2283-2289.抗CTLA-4PET = positron emission tomographyCourtesy of Steven J. ODay, The Angeles Clinic and Research Institute一例男性患者，59岁，1994年诊为右臂恶性黑色素瘤（原发病灶不明）, 接受了5年的疫苗治疗，2000年及2002年发生了腹部的移行复发，均给予手术治疗。2003年发生第三次的腹部移行复发（PET+），患者接受了4次 剂量为3mg/kg的ipilimumab治疗以及 6次达卡巴嗪治疗。 患者出现1级的瘙痒，患者入组研

6、究后未再接受其他抗肿瘤治疗。至2005年3月份，仍未出现新发病灶。Tumor size (%)Post-treatment initiation (weeks)SD(PET+)SD(PET-) SDPR无新病灶无新病灶= ipilimumab治疗治疗0 6 12 18 24 30 36 42 48 54 60患者接受 gp100疫苗 + 3 mg/kg ipilimumab 每3周 共5次，并出现4级的IRAEs垂体炎以及1级的瘙痒. Tumor size (%)初始治疗后初始治疗后 (周周) PR + non- 靶病灶靶病灶 缓解缓解PD + 新病灶新病灶= ipilimumab治疗治疗CR

7、 +患者存活患者存活 超过超过4年年 ipilimumab 治疗后治疗后0 6 12 18 24 28早期进展的患者是否需要时间达到免疫反应? 免疫浸润?12/065/074次盲剂量的 ipilimumab4次剂量为10 mg/kg ipilimumab无治疗大样本临床试验Ipilimumab 与 Tremelimumab非清髓性淋巴细胞删除化疗后输注过继细胞 治疗难治性转移性黑色素瘤Mark E. Dudley, John R. Wunderlich, James C. Yang, Richard M. Sherry, Suzanne L. Topalian, Nicholas P. Res

8、tifo, Richard E. Royal, Udai Kammula, Don E. White, Sharon A. Mavroukakis, Linda J. Rogers, Gerald J. Gracia, Stephanie A. Jones, David P. Mangiameli, Michelle M. Pelletier, Juan Gea-Banacloche, Michael R. Robinson, David M. Berman, Armando C. Filie, Andrea Abati, Steven A. Rosenberg Journal of Clin

9、ical Oncology, Vol 23, No 10 (April 1), 2005: pp. 2346-2357淋巴细胞删除 及T-细胞输注治疗MetastaticpotentialImmortalizationAngiogenesisGrowth signalindependenceLoss of tumorsuppressionBlockedapoptosis(Hanahan & Weinberg, 2000)0501001502002500.01 10Colo205A375p0.01 10D1D3D5NHNHOONNHOCF3Cl4080 nMFLT-3, c-KIT283

10、8 nMp38, PDGFR2040 nMwt B-RAF, V599E B-RAF2 nMC-RAF6-10 nMmVEGFR2, VEGFR3Inactive at 10 mMEGFR, MEK, ERKIC50Kinase assaysOrally available, well-tolerated at 400 mg PO BIDResponse evaluation every 2 cycles (RECIST) After 6 cycles, eligible to continue BAY 43-9006 aloneBAY 43-9006, carboplatin & p

11、aclitaxelResponses in relation to prior therapy and stageResponse rate by # of prior Rx:02348%11933%2-41220%Response rate by stage: M1a771% M1b1030% M1c3732%Response rate by adjuvant IFN:Yes 1937%No3537%NORR%Progression-free survival 6 months = 63% N=54 9 months = 40% N=50 12 months = 22% N=41Flaher

12、ty et al, 2007BAY 43-9006, carboplatin & paclitaxelSummaryBAY 43-9006, carboplatin & paclitaxelPHASE III TRIALSMetastaticpotentialImmortalizationAngiogenesisGrowth signalindependenceLoss of tumorsuppressionBlockedapoptosis(Hanahan & Weinberg, 2000)Phase III Trials in Advanced Melanoma5 r

13、unning/startingPhase III Trials in Advanced Melanoma5 running/startingBcl-2Bcl-2Bcl-2Bcl-2Bcl-2GenasenseTM pretreatment results in decreased Bcl-2 levelsDTIC 1000 mg/m on day 1GenasenseTM 7 mg/kg CIVI x 5 days followed by DTIC 1000 mg/m on day 6RANDOMIZATION1.00.40.20.0020240.80.6481216GM301:overall

14、 survival (ITT) monthsOverall Survival24-Months Minimum Follow-upDTICGenasense/DTICMedian 9.07.8HR 0.87P 0.077MonthsProportion surviving21%improvement38%improvementN = 771Overall SurvivalBaseline LDHProportion survivingProportion surviving1.00.40.20.00.80.6Months02024481216 1.1 x Upper Limit of Norm

15、alMedianHRPGenasense/DTIC4.6DTIC1.110.4124.755%improvementN = 5080.81.12.05.0N2742341577619LDHKaplan-Meier survival curves at 24-month minimum follow-up by LDH category: Study GM301 (overall p 0.0001) Phase III Trials in Advanced Melanoma5 running/startingElesclomol treatment induces ROS - apoptosis

16、elesclomol ROSMitochondriaCytochrome C release, caspase 9 activationAPOPTOSIS0-1 hr: ROS increase1-3 hrs: increase in stress proteins (Hsp70)Hsp703-6 hrs: cardiolipin oxidized in mitochondria6+ hrs: Cytochrome C release, caspase 9, apoptosisNH3CNNNCH3HHSOOS ROSMitochondriaCytochrome C release, caspa

17、se 9 activationAPOPTOSISHsp70Chemotherapeuticagent Elesclomol sensitizes the mitochondria to other cancer drugs, thus facilitating their ability to induce apoptosis without increasing their toxicity to normal cellselesclomolNH3CNNNCH3HHSOOSPhase III Trials in Advanced Melanoma5 running/startingPhase

18、 III Trials in Advanced Melanoma5 running/startingThymosin alpha 1 is an immunomodulatory compound that promotes T cell maturation and upregulates T cell response. T1 showed clinical potential benefit in a previous pilot study in melanoma patients (Rasi et al. Melanoma Research, 2000).STEM CELLNK CE

19、LLThymosin alpha 1: mechanism of actionCANCEROUS CELLCANCEROUS CELLImmunomodulatoryDirect effectson cancer cells MHC I expression of tumor antigens Cancer cell growth T-cell apoptosisCD4+ T-CELLCD8+ T-CELL T-cell production IL-2, IFN- IL-4, IL-10Day 1THYMOSIN 11.6, 3.2 or 6.4 mg/die s.c.THYMOSIN 11.

20、6, 3.2 or 6.4mg/die s.c.Day 8Day 11Day 15Day 18DTIC 800 mg/m2 i.v.IFN 3 MIU s.c.IFN 3 MIU s.c.Day 18Day 11Response n (%)DIT 1.6 (N=97)DIT 3.2 (N=97)DIT 6.4 (N=98)DT 3.2 (N=99)DI (N=97)CR2 (2.1)3 (3.1)2 (2.0)2 (2.0)0PR5 (5.1)7 (7.2)4 (4.1)10 (10.1)4 (4.1)RR (PR+CR)7 (7.2)10* (10.3)6 (6.1)12* (12.1)4

21、(4.1)RR 95% C.I.3.1 ; 14.55.1 ; 18.23.1 ; 15.66.6 ; 20.41.3 ; 10.7By Stratum, nDIT 1.6 DIT 3.2 DIT 6.4DT 3.2DI M1a 1 2 1 4 0M1b 4 4 1 2 2 M1c 2 4 4 6 2 Table 2. RESPONSE RATE, OVERALL AND BY STRATUM*The null hypothesis was rejectedCR=Complete Response; PR=Partial Response; RR=Response Rate; C.I.=Con

22、fidence IntervalOS (months)DIT 1.6DIT 3.2DIT 6.4DT 3.2Tot TDIMedian9.38.510.29.39.46.695% CI7.9 ; 11.06.1; 11.48.2 ; 12.66.7 ; 11.58.3 ; 10.55.2 ; 9.8Survival Distribution Function0.000.250.500.751.00Time (months)0510152025303540STRATA:Treatment=DICensored Treatment=DITreatment=DIT1.6Censored Treatm

23、ent=DIT1.6Treatment=DIT3.2Censored Treatment=DIT3.2Treatment=DIT6.4Censored Treatment=DIT6.4Treatment=DT3.2Censored Treatment=DT3.2Overall Survival in the ITT PopulationSurvival Distribution Function0.000.250.500.751.00Time (months)0510152025303540STRATA:Treatment=DICensored Treatment=DITreatment=DI

24、T1.6Censored Treatment=DIT1.6Treatment=DIT3.2Censored Treatment=DIT3.2Treatment=DIT6.4Censored Treatment=DIT6.4Treatment=DT3.2Censored Treatment=DT3.2time (months)Survival Distribution FunctionSurvival Distribution Function0.000.250.500.751.00Time (months)0510152025303540STRATA:Treatment=DICensored

25、Treatment=DITreatment=TOTAL THYMCensored Treatment=TOTAL THYMOverall Survival in the ITT PopulationSurvival Distribution Function0.000.250.500.751.00Time (months)0.02.55.07.510.012.515.017.520.022.5STRATA:Treatment=DICensored Treatment=DITreatment=TOTAL THYMCensored Treatment=TOTAL THYMSurvival Dist

26、ribution Function0.000.250.500.751.00Time (months)0.02.55.07.510.012.515.017.520.022.5STRATA:Treatment=DICensored Treatment=DITreatment=TOTAL THYMCensored Treatment=TOTAL THYMtime (months)OS (months)DIT 1.6DIT 3.2DIT 6.4DT 3.2Tot TDIMedian12.912.612.814.412.910.895% CI10.3 ; 14.710.1 ; 17.110.8 ; 15

27、.511.7 ; 16.312.1 ; 14.57.4 ; 13.6Survival Distribution Function0.000.250.500.751.00Time (months)0510152025303540STRATA:Treatment=DICensored Treatment=DITreatment=TOTAL THYMCensored Treatment=TOTAL THYMOverall Survival in *Normal LDHSurvival Distribution Function0.000.250.500.751.00Time (months)0.02

28、.55.07.510.012.515.017.520.022.5STRATA:Treatment=DICensored Treatment=DITreatment=TOTAL THYMCensored Treatment=TOTAL THYMSurvival Distribution Function0.000.250.500.751.00Time (months)0.02.55.07.510.012.515.017.520.022.5STRATA:Treatment=DICensored Treatment=DITreatment=TOTAL THYMCensored Treatment=T

29、OTAL THYM*Normal=LDHULNtime (months)Survival Distribution Function0.000.250.500.751.00Time (months)0510152025303540STRATA:Treatment=DICensored Treatment=DITreatment=DIT1.6Censored Treatment=DIT1.6Treatment=DIT3.2Censored Treatment=DIT3.2Treatment=DIT6.4Censored Treatment=DIT6.4Treatment=DT3.2Censore

30、d Treatment=DT3.2Overall Survival in *Normal LDHSurvival Distribution Function0.000.250.500.751.00Time (months)0510152025303540STRATA:Treatment=DICensored Treatment=DITreatment=DIT1.6Censored Treatment=DIT1.6Treatment=DIT3.2Censored Treatment=DIT3.2Treatment=DIT6.4Censored Treatment=DIT6.4Treatment=

31、DT3.2Censored Treatment=DT3.2time (months)*Normal=LDHULNSurvival Distribution Function Thymosin alpha 1 was well tolerated at all doses and regimens Both arms with Thymosin 3.2 mg reached the response rate required to reject the null hypothesis Data on Overall Survival and Progression Free Survival,

32、 particularly in the population with normal LDH level, support the conduction of a phase III program The best candidate regimen for a future phase III trial seems to be DTIC + Thymosin 3.2 mg The role of Interferon alpha in the therapeutic combination is debatablePhase III Trials in Advanced Melanom

33、a5 running/startingPhase III in Advanced Melanoma5 running/starting / 4 . preparing(years)01234560102030405060708090100P=0.05 , HR = 0.77 (99% CI: 0.55 , 1.09) (years)01234560102030405060708090100P=0.006 , HR = 0.59 (99% CI 0.35 , 0.98) UlcerationUlceration & N1:OBSERVATIONPeg-IFN alfa-2bON116 181108 192ON59904596Eggermont(yrs)012345670102030405060708090100TreatmentOBS (N=36)13-month IFN (N=73)25-month IFN (N=59)Stage IIbNO ULCERATIONp=0.81(yrs)0123456701020304050607080