陳振東—安徽—惡性淋巴瘤免疫治療進展

1、惡性淋巴瘤免疫治療進展,陳振東安徽醫(yī)科大學第二附屬醫(yī)院腫瘤中心,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 immunot

2、herapy and cancer recognized,1985: Interferon first approved for hairy cell leukemia,1992: IL-2 approved for RCC,1997: First mAb for cancer approved, rituximab,2008: First cancer vaccine approved for RCC,2010: Sipuleucel

3、-T approved for prostate cancer,2011: CTLA-4 inhibitor approved for melanoma,2014-2015: PD-1 inhibitors approved for melanoma, squamous NSCLC,,,,2015: First oncolytic virus approved for melanoma,2016: PD-1 inhibitor appr

4、oved for cHLPD-L1 inhibitor approved for UC,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 therapy at all. Such

5、patients:autologous stem-cell transplantation (ASCT). newer treatment regimen + brentuximab vedotin, many patients eventually worsens.,CBT治療HL有效的機制[Roemer MG, Advani RH, Ligon AH, et al: PDL1 and PD-L2 genetic altera

6、tions de?ne classical Hodgkin lymphoma 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,

7、PD-L1 and PD-L2 molecules were found in 97% of the 108 specimens tested response rates to PD-1 inhibitors are higher in classic HL than in any other type of cancer studied to date. CBT，checkpoint blockade ther

8、apy， (免疫)檢查點阻滯治療,CBT治療HL有效的機制[Roemer MG, Advani RH, Ligon AH, et al: PDL1 and PD-L2 genetic alterations de?ne classical Hodgkin lymphoma and predict outcome. J Clin Oncol 34:2690-2697, 2016 ].,病理類型影響PD-L1、2表達 86% n

9、odular sclerosis, 11% mixed-cellularity 3% not otherwise speci?ed. 病期影響基因擴增、預后 Ampli?cation of 9p24.1 is more common in patients with advanced stage disease （III/IV） and associated with shorter PFS in thi

10、s series.,CBT治療HL有效的機制[Roemer MG, Advani RH, Ligon AH, et al: PDL1 and PD-L2 genetic alterations de?ne classical Hodgkin lymphoma and predict outcome. J Clin Oncol 34:2690-2697, 2016 ].,chromosome 9p24.1, resulting in o

11、verexpression of the PD-1 ligands PD-L1 and PD-L2 on the tumour cell surface.JAK2 is also located on chromosome 9p24.1, and alterations in this gene increase JAK–STAT signalling, further inducing PD-L1 overexpression.,P

12、D-1 免疫檢查點抑制劑有效的機制：NHL表達PD-L1、2與cHL不同,25% of DLBCL tumors express PD-1/PD-L1 [Andorsky et  al. 2011]primary mediastinal B-cell lymphoma (PMBL) which, similar to HL，frequently harbors 9p22 amplification leading to o

13、verexpression of PD-L1/PD-L2 [Shi et al. 2014].,R/R cHL-納武單抗Younes A, Santoro A, Shipp M, et al: Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab

14、 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

15、, 2014～Feb 20, 2015, 34 hospitals and academic centres across Europe and North America. primary endpoint was objective response , median follow-up of 8·9 months.,R/R cHL-納武單抗Younes A, Santoro A, Shipp M, et al: Ni

16、volumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: A multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol 17:1283-1294, 2016,lymphoma

17、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 months. Nivolumab

18、 was generally well tolerated. The most common adverse effects of any grade were fatigue, infusion-related reaction, and rash.,R/R cHL-納武單抗Younes A, Santoro A, Shipp M, et al: Nivolumab for classical Hodgkin’s lymphoma

19、after failure of both autologous 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 (

20、neutropenia) and liver enzyme abnormalities (increased lipase), occurred in only 5% of patients. Nivolumab，cHL relapsing or progressing after autologous HSCT and post-transplantation brentuximab vedotin，F(xiàn)DA，May 2016 [US

21、 Food and Drug Administration: Nivolumab (Opdivo) for Hodgkin lymphoma. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm501412. htm] .,R/R cHL- 派姆單抗 KEYNOTE-013: Study Design,Multicenter, multicohort phase

22、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

23、pts with ECOG PS 0/1, 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

24、 toxicity,Discontinuation,,,Armand P, et al. ASH 2015. Abstract 584； Armand P, et al. JCO, 34:3733-3739, 2016.,R/R cHL-派姆單抗 KEYNOTE-013: Baseline Characteristics,Armand P, et al. ASH 2015. Abstract 584； Armand P, et al.

25、 JCO, 34:3733-3739, 2016.,90% of pts had decreases in target lesion burdenincreases circulating numbers of T and NK cells, upregulates TCR/IFN-γ signalingOf 20 pts with CR/PR:Still on treatment: n = 7Discontinued tre

26、atmentCR: n = 1PR switched tx: n = 1AE: n = 1Allogeneic SCT: n = 3PD: n = 7,R/R cHL-派姆單抗，April 2016, FDA, breakthrough therapy designation for treatment of relapsed classic HL.KEYNOTE-013: Efficacy,Armand P, et al.

27、 ASH 2015. Abstract 584. ； Armand P, et al. JCO, 34:3733-3739, 2016,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 pat

28、ients with R/R NHL, an ORR of 11% was observed [Ansell et al. 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, respec

29、tively.,NHL- nivolumab/ pembrolizumab,phase I, nivolumab in various subtypes 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  a

30、l. 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% in peripheral T-cell lymphoma.Similar studies with p

31、embrolizumab in patients with NHL are currently ongoing.,存在的問題-研究本身,single-arm studylong-term follow-up will be required to determine the durability of responsesongoing host immune reactions within tumours might have c

32、ontributed to persistent ¹?F-FDG uptake,存在的問題,PD-L1、2表達程度是否影響療效？治療持續(xù)多長時間最合適？獲得CR后的終止治療，何時開始？CR不是很高，治愈的可能性？PR的意義有多大？比起其他的治療，如放療±其他治療，孰優(yōu)？性價比？,進一步研究,for relapsed as well as newly diagnosed classic HL is under

33、 way. KEYNOTE-204 phase III trial，compare pembrolizumab vs BV in pts with R/R cHL (NCT02684292)nivolumab with brentuximab vedotin and ipilimumab (ClinicalTrials.gov identi?ers: NCT02758717, NCT01896999, and NCT02304458