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1、恶性淋巴瘤免疫治疗进展,精选ppt,1,恶性淋巴瘤免疫治疗进展 精选ppt1,History of Immunotherapy,Elert E. Nature. 2013;504:S2-S3.,1796: First use of immunotherapy, Jenner smallpox vaccine,1976: BCG vaccine for bladder cancer,1863: Connection between immunotherapy and cancer recognized,1985: Interferon first approved for hairy cell
2、leukemia,1992: IL-2 approved for RCC,1997: First mAb for cancer approved, rituximab,2008: First cancer vaccine approved for RCC,2010: Sipuleucel-T approved for prostate cancer,2011: CTLA-4 inhibitor approved for melanoma,2014-2015: PD-1 inhibitors approved for melanoma, squamous NSCLC,2015: First on
3、colytic virus approved for melanoma,2016: PD-1 inhibitor approved for cHLPD-L1 inhibitor approved for UC,精选ppt,2,History of ImmunotherapyElert,霍奇金淋巴瘤：背景,HL, Classic type, 95% past 40 years, 86% will live 5 years after diagnosis. 20% to 30% relapse after initial treatment or will not respond to thera
4、py at all. Such patients:autologous stem-cell transplantation (ASCT). newer treatment regimen + brentuximab vedotin, many patients eventually worsens.,精选ppt,3,霍奇金淋巴瘤：背景HL, Classic type, 95%,CBT治疗HL有效的机制Roemer MG, Advani RH, Ligon AH, et al: PDL1 and PD-L2 genetic alterations dene classical Hodgkin l
5、ymphoma and predict outcome. J Clin Oncol 34:2690-2697, 2016 .,Reed-Sternberg cells from genetic changes. Which result in an abundance of immune checkpoint molecules PD-L1 and PD-L2.cHL, PD-L1 and PD-L2 molecules were found in 97% of the 108 specimens tested response rates to PD-1 inhibitors are hig
6、her in classic HL than in any other type of cancer studied to date. CBT，checkpoint blockade therapy， (免疫)检查点阻滞治疗,精选ppt,4,CBT治疗HL有效的机制Roemer MG, Advan,CBT治疗HL有效的机制Roemer MG, Advani RH, Ligon AH, et al: PDL1 and PD-L2 genetic alterations dene classical Hodgkin lymphoma and predict outcome. J Clin Onco
7、l 34:2690-2697, 2016 .,病理类型影响PD-L1、2表达 86% nodular sclerosis, 11% mixed-cellularity 3% not otherwise specied. 病期影响基因扩增、预后 Amplication of 9p24.1 is more common in patients with advanced stage disease （III/IV） and associated with shorter PFS in this series.,精选ppt,5,CBT治疗HL有效的机制Roemer MG, Advan,CBT治疗HL
8、有效的机制Roemer MG, Advani RH, Ligon AH, et al: PDL1 and PD-L2 genetic alterations dene classical Hodgkin lymphoma and predict outcome. J Clin Oncol 34:2690-2697, 2016 .,chromosome 9p24.1, resulting in overexpression of the PD-1 ligands PD-L1 and PD-L2 on the tumour cell surface.JAK2 is also located on
9、chromosome 9p24.1, and alterations in this gene increase JAKSTAT signalling, further inducing PD-L1 overexpression.,精选ppt,6,CBT治疗HL有效的机制Roemer MG, Advan,PD-1 免疫检查点抑制剂有效的机制：NHL表达PD-L1、2与cHL不同,25% of DLBCL tumors express PD-1/PD-L1 Andorsky et al. 2011primary mediastinal B-cell lymphoma (PMBL) which,
10、similar to HL，frequently harbors 9p22 amplification leading to overexpression of PD-L1/PD-L2 Shi etal. 2014.,精选ppt,7,PD-1 免疫检查点抑制剂有效的机制：NHL表达PD-L1,R/R cHL-纳武单抗Younes A, Santoro A, Shipp M, et al: Nivolumab for classical Hodgkins lymphoma after failure of both autologous stem-cell transplantation and
11、 brentuximab vedotin: A multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol 17:1283-1294, 2016,single-arm phase 2 study ECOG 0 or 1, nivolumab intravenously over 60 min at 3 mg/kg every 2 weeks until progressionAug 26, 2014Feb 20, 2015, 34 hospitals and academic centres across Europe an
12、d North America. primary endpoint was objective response , median follow-up of 89 months.,精选ppt,8,R/R cHL-纳武单抗Younes A, Santoro,R/R cHL-纳武单抗Younes A, Santoro A, Shipp M, et al: Nivolumab for classical Hodgkins lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedoti
13、n: A multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol 17:1283-1294, 2016,lymphoma went into remission in 53 (66%) of 80 patients and disappeared entirely in seven. Nearly all patients with classic HL who responded to the treatment had at least a 50% reduction, and responses lasted 8
14、months. Nivolumab was generally well tolerated. The most common adverse effects of any grade were fatigue, infusion-related reaction, and rash.,精选ppt,9,R/R cHL-纳武单抗Younes A, Santoro,R/R cHL-纳武单抗Younes A, Santoro A, Shipp M, et al: Nivolumab for classical Hodgkins lymphoma after failure of both autol
15、ogous stem-cell transplantation and brentuximab vedotin: A multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol 17:1283-1294, 2016,Severe adverse effects, such as low blood counts (neutropenia) and liver enzyme abnormalities (increased lipase), occurred in only 5% of patients. Nivolumab，
16、cHL relapsing or progressing after autologous HSCT and post-transplantation brentuximab vedotin，FDA，May 2016 US Food and Drug Administration: Nivolumab (Opdivo) for Hodgkin lymphoma. http:/www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm501412. htm .,精选ppt,10,R/R cHL-纳武单抗Younes A, Santoro,R/R
17、cHL- 派姆单抗 KEYNOTE-013: Study Design,Multicenter, multicohort phase Ib trial, open-label, December 2013 to September 2014. Primary endpoints: safety, CRSecondary endpoints: OR, DoR, PFS, OS, biomarkersResponse to treatment was assessed at week 12 and every 8 weeks thereafter.,cHL pts with ECOG PS 0/1
18、, previous brentuximab vedotin failure, ASCT failure or ineligibility (N = 31),Discontinuation permitted 24 wks,Pembrolizumab 10 mg/kg IV Q2W,CR,PR or SD,PD,Tx to 24 mos orPD or intolerable toxicity,Discontinuation,Armand P, et al. ASH 2015. Abstract 584； Armand P, et al. JCO, 34:3733-3739, 2016.,精选
19、ppt,11,R/R cHL- 派姆单抗 KEYNOTE-013: St,R/R cHL-派姆单抗 KEYNOTE-013: Baseline Characteristics,Armand P, et al. ASH 2015. Abstract 584； Armand P, et al. JCO, 34:3733-3739, 2016.,精选ppt,12,R/R cHL-派姆单抗 KEYNOTE-013: Bas,90% of pts had decreases in target lesion burdenincreases circulating numbers of T and NK
20、cells, upregulates TCR/IFN- signalingOf 20 pts with CR/PR:Still on treatment: n = 7Discontinued treatmentCR: n = 1PR switched tx: n = 1AE: n = 1Allogeneic SCT: n = 3PD: n = 7,R/R cHL-派姆单抗，April 2016, FDA, breakthrough therapy designation for treatment of relapsed classic HL.KEYNOTE-013: Efficacy,Arm
21、and P, et al. ASH 2015. Abstract 584. ； Armand P, et al. JCO, 34:3733-3739, 2016,精选ppt,13,90% of pts had decreases in ta,NHL- CTLA4 antibody ipilimumab,the ORR to checkpoint blockade in NHL is generally lower compared with HL and PMBL.phase I trial of ipilimumab in 18 patients with R/R NHL, an ORR o
22、f 11% was observed Ansell etal. 2009. Notably, responses, although low, were quite durable with an ongoing CR lasting more than 31 and 19 months in one DLBCL and one FL patient, respectively.,精选ppt,14,NHL- CTLA4 antibody ipilimumab,NHL- nivolumab/ pembrolizumab,phase I, nivolumab in various subtypes
23、 of NHL (n = 54) revealed the highest rate of ORR was achieved in patients with FL at 40%, closely followed by DLBCL at 36% Lesokhin et al. 2016. Patients with T-cell lymphomas (n = 23) were also included, but did not fare as well with variable responses: 15% ORR (all PR) in mycosis fungoides and 40
24、% in peripheral T-cell lymphoma.Similar studies with pembrolizumab in patients with NHL are currently ongoing.,精选ppt,15,NHL- nivolumab/ pembrolizumabp,存在的问题-研究本身,single-arm studylong-term follow-up will be required to determine the durability of responsesongoing host immune reactions within tumours
25、might have contributed to persistent F-FDG uptake,精选ppt,16,存在的问题-研究本身single-arm study精选pp,存在的问题,PD-L1、2表达程度是否影响疗效？治疗持续多长时间最合适？获得CR后的终止治疗，何时开始？CR不是很高，治愈的可能性？PR的意义有多大？比起其他的治疗，如放疗其他治疗，孰优？性价比？,精选ppt,17,存在的问题PD-L1、2表达程度是否影响疗效？精选ppt17,进一步研究,for relapsed as well as newly diagnosed classic HL is under way.
26、KEYNOTE-204 phase III trial，compare pembrolizumab vs BV in pts with R/R cHL (NCT02684292)nivolumab with brentuximab vedotin and ipilimumab (ClinicalTrials.gov identiers: NCT02758717, NCT01896999, and NCT02304458). other hematologic malignancies, as well as in multiple myeloma (ClinicalTrial.gov identier: NCT01953692).,精选ppt,18,进一步研究for relapsed as well as n,谢谢聆听!,精选ppt,19,谢谢聆听!精选ppt19,
