肿瘤免疫治疗讲座课件

,*,Click to edit Master title style,Click to edit Master text styles,Second Level,Third Level,Fourth Level,Fifth Level,*,Click to edit Master title style,Click to edit Master text styles,Second Level,Third Level,Fourth Level,Fifth Level,1,肿 瘤 免 疫 治 疗,1,.,1 肿 瘤 免 疫 治 疗 1.,2,2,.,22.,3,肿瘤免疫治疗,肿瘤免疫治疗是通过激发或调动机体的免疫系统，增强肿瘤微环境抗肿瘤免疫力，从而控制和杀伤肿瘤细胞的一种肿瘤治疗模式，属于肿瘤生物治疗范畴。,3,.,3肿瘤免疫治疗 肿瘤免疫治疗是通过激发或调动机体的免疫系,4,肿瘤免疫治疗研究的历史背景：,1891,年,:,纽约一名外科医生,William Coley,用细菌来治疗肿瘤的试验开始，经历了漫长的探索，遭遇重大挫折。,1940-50,年代：,TSTA,（肿瘤特异性移植抗原）的提出。,1970,年代：,IL-2,、细胞及体液免疫抗肿瘤研究。,1980,年代：,Steven. Rosenberg. LAK. TIL,治疗黑色素瘤等肿瘤,1984,年，美国国立癌症研究院史蒂夫,罗森伯格,(Steve Rosenberg),团队成功地用高剂量白细胞介素,2(IL-2),治愈第一例病人，给肿瘤免疫治疗带来一线曙光。,1985,年：生物治疗概念的提出,4,.,4 肿瘤免疫治疗研究的历史背景：,5,Steven Rosenberg says his,30-year push for an immune-based assault,on melanoma is working at last,5,.,5Steven Rosenberg says his5.,6,2010年 Dendreon公司经历15年开发，花费十亿美元的治疗性肿瘤疫苗-Provenge(sipuleucelT) 将成为首个在美国获准的治疗性肿瘤疫苗，用于治疗转移型激素难治性晚期前列腺肿瘤。,6,.,6 2010年 Dendreon公司经历15年开发，花,7,7,.,77.,8,How can we harness the immune response?,Tumour cell present,Broken up to release antigens,APC,APC recruits T cells able to recognise tumour antigens,T,T,T,h,CTL,CTL recognise and destroy other tumour cells,CTL,T,h,cells educate other T/B cells,B,Ab / ADCC / cytokine attack,8,.,8How can we harness the immune,9,9,.,99.,10,被动免疫治疗,单克隆抗体抗肿瘤作用机制：,Apoptosis induction,Complement-mediated cytotoxicity,ADCC,NK,M,Conjugated to toxin / isotope,10,.,10 被动免疫治疗单克隆抗体抗,11,Antibody-based immunotherapy,Name,Malignancy,Target,Rituxan,B cell lymphoma,CD20,Herceptin,Breast, lymphoma,Her-2/neu,Campath,B-CLL,CD52,Erbitux,Colo-rectal,EGFR,Avastin,Colo-rectal,VEGF,Name,Malignancy,Target,Mylotarg,AML,CD33,(calicheamicin),Bexxar,B cell lymphoma,CD20,(,131,In /,90,Y),11,.,11Antibody-based immunotherapy,12,主动免疫治疗,疫苗策略,-,：,多肽/蛋白质疫苗,核酸疫苗,DC疫苗,细胞治疗,：肿瘤特异性,CTL,肿瘤诱导的,APC,12,.,12 主动免疫治疗12.,13,Complete regression of a large liver metastasis from kidney cancer in a patient treated with IL-2.,Regression is ongoing seven years later,Rosenberg (2001) Nature, 411;381-4,13,.,13Complete regression of a lar,14,Effectiveness of multiple antigen vaccines,Patient with multiple metastatic melanomas treated with tyrosinase / gp100 / MART vaccine,14,.,14Effectiveness of multiple an,15,15,.,1515.,16,16,.,1616.,17,17,转移性恶性黑色素瘤的免疫治疗,17,.,1717转移性恶性黑色素瘤的免疫治疗 17.,18,18,白细胞素介-2 (IL-2),1. IL-2治疗作用?,2. 治疗方案如何?,3.IL-2相关毒性？,18,.,1818白细胞素介-2 (IL-2)18.,19,19,IL-2 600,000 or720,000 IU/kg 静滴15 分钟， q8h ，共14 次,休息6 -9 天后，继续同样治疗,J Clin Oncol 1999; 17: 21052116,19,.,1919J Clin Oncol 1999; 17: 210,20,20,20,.,202020.,21,21,21,.,212121.,22,22,ORR: 16%,CR: 6%,4% 获得持久完全缓解.,1998年，IL-2 被 FDA 批准治疗转移性黑色素瘤。,22,.,2222ORR: 16% 22.,23,23,IFN-a,85 例晚期黑色素瘤病人随机 IL-2 4.5 X 10,6,U/m2 + IFN-alpha 3 X 10,6,U/m2 对比IL-2 4.5 X 10,6,U/m2,PR: 5% vs 10% receiving IL-2 alone vs IL-2/IFN-alpha (P = .30).,IL-2(10.2 months) vs IL-2/IFN-alpha (9.7 months).,J Clin Oncol 1993; 11:19691977.,23,.,2323IFN-aJ Clin Oncol 1993; 11,24,24,24,.,242424.,25,25,In summary, IFN-a improves response rates but not OS and cannot be recommended for treatment of metastatic malignant melanoma.,25,.,252525.,26,26,Anti-CTL-A4 (anti-CD152),ipilimumab (MDX-010),tremelimumab (CP-675,206),26,.,2626Anti-CTL-A4 (anti-CD152)ip,27,27,27,.,272727.,28,28,Improved Survival with Ipilimumab in Patients with Metastatic Melanoma,N Engl J Med 2010,28,.,2828Improved Survival with Ipi,29,29,29,.,292929.,30,30,30,.,303030.,31,31,Ipilimumab +Dacarbazine for Previously Untreated Metastatic Melanoma,31,.,3131Ipilimumab +Dacarbazine fo,32,32,32,.,323232.,33,33,33,.,333333.,34,34,Mar. 25, 2011 The U.S. Food and Drug Administration (FDA)announced today its approval of a new treatment for advanced melanoma.-ipilimumab,34,.,3434Mar. 25, 2011 The U.S. F,35,2008年，Naomi N. Hunder9单独使用免疫疗法成功治愈晚期皮肤黑色素瘤。他们采用体外激活的自体NY-ESO-1抗原特异性CD4+T细胞回输使黑色素瘤的肺部及腹腔转移灶完全消失，随访26个月未见复发。令人惊奇的是：NY-ESO-1特异性 CD4+ T细胞输注治疗还可诱导自身T淋巴细胞产生针对黑色素瘤其它抗原MAGE-3 和MART-1的免疫反应。,35,.,3535.,36,Chimeric Antigen Receptor (CAR)-Engineered Lymphocytes for Cancer Therapy,36,.,36Chimeric Antigen Receptor (C,37,肺癌免疫治疗系列临床研究介绍,37,.,37肺癌免疫治疗系列临床研究介绍 37.,38,过继免疫治疗,1. 特异性细胞过继免疫治疗,一项随机对照临床研究（n=113）TIL联合rIL-2 治疗IIa，IIIa及IIIb NSCLC 3年生存率明显提高（p0.05) , mOS (22.4m vs 14.1m),Cancer.1996,78:244251,38,.,38过继免疫治疗1. 特异性细胞过继免疫治疗Cancer.1,39,39,.,3939.,40,40,.,4040.,41,41,.,4141.,42,42,.,4242.,43,43,.,4343.,44,44,.,4444.,45,抗程序性死亡-1(PD-1)*治疗晚期NSCLC的临床活性与安全性：CA209-003,Gettinger S, et al.,2012 ESMO Abstract 1237PD.,*BMS-936558/MDX-1106/ONO-4538,45,.,45抗程序性死亡-1(PD-1)*治疗晚期NSCLC的临床活,46,CA209-003：研究背景,PD-1,抗体：完全人源化,IgG4,抗人体,PD-1,阻断抗体,对,PD-1,具有高亲和力；阻断,PD-L1(B7-H1),和/或,PD-L2(B7-DC),的结合,阻断,PD-1/PD-L1,的相互作用使得抗肿瘤效果得以持续,Gettinger S, et al. 2012 ESMO Abstract 1237PD.,Ribas et al. NEJM 2012; 366:2517-2519.,46,.,46CA209-003：研究背景PD-1抗体：完全人源化Ig,47,CA209-003研究背景 抗-PD1抗体的I期临床研究,Topalian et al, NEJM 2012; 366;2443-2454.,总人群,可评价疗效人群,有效人群（%）,黑色素瘤,104,94,26（28）,NSCLC,122,76,14（18）,肾癌,34,33,9（27）,抗PD-1,所有治疗相关不良事件,70%,3/4级治疗相关不良事件,14%,肺,1%,腹泻,1%,自身免疫,1%,因不良事件中止治疗,5%,5级不良事件 (肺),N=3,47,.,47CA209-003研究背景 抗-PD1抗体的I期临,48,48,.,4848.,49,49,.,4949.,50,50,.,5050.,51,51,.,5151.,52,52,.,5252.,53,anti-CD152 单抗,ipilimumab (MDX-010),53,.,53anti-CD152 单抗ipilimumab (MDX,54,54,.,5454.,55,Phase II trial of ipilimumab (IPI) and paclitaxel/carboplatin (P/C) in first-line stage IIIb/IV non-small cell lung cancer (NSCLC).,IPI + P/C P/C,OS,CON (n = 70) SEQ (n = 68) PBO (n = 66),Median mo,11.01 11.56 9.99,p value,0.429 0.104,J Clin Oncol 28:15s, 2010 (suppl; abstr 7531),55,.,55Phase II trial of ipilimumab,56,肺癌疫苗,蛋白疫苗：,a. MAGE-A3 蛋白疫苗,30-50% NSCLC表达MAGE-A3抗原。,JCO报道一项随机，双盲，多中心对照研究（n=182），结果显示：MAGE-A3阳性的Ib及II期NSCLC术后每周一次计次MAGE-A3蛋白疫苗治疗，随访个月，复发率明显降低（30.3vs 41.7%),J Clin Oncol (Meeting Abstracts),2007;25:7554.,56,.,56肺癌疫苗蛋白疫苗：J Clin Oncol (Meeti,57,57,.,5757.,58,58,.,5858.,59,59,.,5959.,60,MAGRIT是一项随机、双盲、安慰剂对照研究，旨在评估MAGE-A3癌症免疫疗法用于IB期、II期和IIA期完全切除的MAGE-A3阳性非小细胞肺癌（NSCLC）患者的疗效和安全性。,该项研究在MAGE-A3阳性非小细胞肺癌（NSCLC）患者中开展，数据表明，与安慰剂相比，MAGE-A3未能显著延长整个MAGE-A3阳性群体（首个共同主要终点）和未接受化疗的MAGE-A3阳性患者群体（第二个共同主要终点）无病生存期（DFS），未能达到研究的首个和第二个共同主要终点。,继续推进DERMA研究，以便确定出可能从MAGE-A3癌症免疫疗法中获益的一个黑色素瘤亚组群体,60,.,60MAGRIT是一项随机、双盲、安慰剂对照研究，旨在评估M,61,EGF 疫苗：,50 例IIIb期及 30例IV期患者接受疫苗治疗，结果年龄小于岁较大于岁的明显延长（15 m vs 7.4m,p0.001),61,.,61EGF 疫苗：61.,62,2. 肽疫苗：,a. Mucin-1 疫苗（,Stimuvax,）,IIb/IV期NSCLC一线化疗获益者,L-BLP25 疫苗II期随机，对照研究,（n=171）,J Clin Oncol,2005;23:66746681,62,.,622. 肽疫苗：J Clin Oncol 2005;23:,63,63,.,6363.,64,64,.,6464.,65,65,.,6565.,66,66,.,6666.,67,67,.,6767.,68,68,.,6868.,69,初步分析,1239,例患者，中位年龄,61,岁，,65%,的患者接受过同步放化疗，,35%,的患者接受了序贯放化疗。次要终点分析至疾病进展时间（,TTP,）和至症状进展时间（,TSP,）提示,HR,分别为,0.87,（,P=0.053,）和,0.85,（,P=0.023,），,L-BLP25,组略有优势。,在同步放化疗亚组（,806,例）分析中，,L-BLP25,组中位,OS,优于安慰剂组（,30.8,个月对,24.6,个月，,HR=1.12,，,P=0.38,）,.,然而在序贯放化疗亚组中，实验组却劣于安慰剂组（,19.4,个月对,24.6,个月，,HR=1.09,，,P=0.663,）。,L-BLP25,耐受性及安全性均佳，无免疫相关不良反应的报告。,上述结果提示，,L-BLP25,在,期,NSCLC,中维持治疗的耐受性及安全性可，但并未达到主要终点。然而，同步放化疗亚组中试验组的生存临床获益却带来一线希望，提示了该药物在特定患者中可有一定的临床应用前景。,69,.,69初步分析1239例患者，中位年龄61岁，65%,70,b. hTERT 肽疫苗,GV1001：hTERT（611-626）及HR2822： hTERT（540-548）II 期临床研究（n=26），,GV1001有1例完全缓解。,另一项研究：TERT572Y,（,n=22），其中，16/22（76.2%)产生免疫反应。较未产生免疫反应者中位生存期明显延长（30.0月vs 4.1月）。,JOURNAL OF CLINICAL ONCOLOGY,，,2007,，,25,（,19,）：,2728-2734,70,.,70b. hTERT 肽疫苗JOURNAL OF CLIN,71,71,.,7171.,72,3. 肿瘤细胞疫苗：,a. TGF-,2,反义基因修饰的同种异基因瘤苗（Lucanix）,Phase II Study of Belagenpumatucel-L, a Transforming Growth Factor Beta-2 Antisense Gene-Modified Allogeneic Tumor Cell Vaccine in NonSmall-Cell Lung Cancer,J Clin Oncol,2006;24:47214730,72,.,723. 肿瘤细胞疫苗：72.,73,73,.,7373.,74,74,.,7474.,75,Phase III Lucanix Vaccine Therapy in Advanced Non-small Cell Lung Cancer (NSCLC) Following Front-line Chemotherapy,Description,：,Purpose: This randomized phase III trial is studying vaccine therapy to see how well it works compared with a placebo as maintenance therapy in treating subjects with stage III or stage IV non-small cell lung cancer,75,.,75Phase III Lucanix Vaccine T,76,b. GM-CSF 基因修饰的肿瘤瘤苗,GVAX：,一项II期研究结果（n=43，早期10例，晚期33例）：GVAX可延长晚期及早期NSCLC患者生存期。,76,.,76b. GM-CSF 基因修饰的肿瘤瘤苗76.,77,Survival in a Randomized Phase III Trial in Patients With Limited Disease (LD) Small Cell Lung Cancer Vaccinated With Adjuvant BEC2 and BCG,Bec2 is an anti-idiotypic antibody that mimics GD3,J Clin Oncol (2005) 23: 6854-64.,77,.,77Survival in a Randomized Pha,78,78,.,7878.,79,79,.,7979.,80,谢 谢！,主动特异性免疫治疗将成为防治肿瘤复发和转移的主要手段之一。,癌症治疗新时代的曙光已经初露,!,80,.,80谢 谢！主动特异性免疫治疗将成为防治肿瘤复发和转移的主要,