1、恶性淋巴瘤免疫治疗进展 精选ppt1History of ImmunotherapyElert E.Nature.2013;504:S2-S3.1796:First use of immunotherapy,Jenner smallpox vaccine1976:BCG vaccine for bladder cancer1863:Connection between immunotherapy and cancer recognized1985:Interferon first approved for hairy cell leukemia1992:IL-2 approved for RC
2、C1997:First mAb for cancer approved,rituximab2008:First cancer vaccine approved for RCC2010:Sipuleucel-T approved for prostate cancer2011:CTLA-4 inhibitor approved for melanoma 2014-2015:PD-1 inhibitors approved for melanoma,squamous NSCLC2015:First oncolytic virus approved for melanoma 2016:PD-1 in
3、hibitor approved for cHLPD-L1 inhibitor approved for UC精选ppt2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 patients:1.autologous stem-cell transplantation(ASCT).2.newer treatment regi
4、men+brentuximab vedotin,3.many patients eventually worsens.精选ppt3CBT治疗HL有效的机制Roemer MG,Advani RH,Ligon AH,et al:PDL1 and PD-L2 genetic alterations define classical Hodgkin lymphoma and predict outcome.J Clin Oncol 34:2690-2697,2016.Reed-Sternberg cells from genetic changes.Which result in an abundan
5、ce 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 higher 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ppt4CBT治疗HL有效的机制Roemer
6、 MG,Advani RH,Ligon AH,et al:PDL1 and PD-L2 genetic alterations define classical Hodgkin lymphoma and predict outcome.J Clin Oncol 34:2690-2697,2016.病理类型影响PD-L1、2表达 86%nodular sclerosis,11%mixed-cellularity 3%not otherwise specified.病期影响基因扩增、预后 Amplification of 9p24.1 is more common in patients with
7、 advanced stage disease（III/IV）and associated with shorter PFS in this series.精选ppt5CBT治疗HL有效的机制Roemer MG,Advani RH,Ligon AH,et al:PDL1 and PD-L2 genetic alterations define classical Hodgkin lymphoma and predict outcome.J Clin Oncol 34:2690-2697,2016.chromosome 9p24.1,resulting in overexpression of
8、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 JAKSTAT signalling,further inducing PD-L1 overexpression.精选ppt6PD-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.2011pri
9、mary mediastinal B-cell lymphoma(PMBL)which,similar to HL，frequently harbors 9p22 amplification leading to overexpression of PD-L1/PD-L2 Shi etal.2014.精选ppt7R/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 transplantati
10、on and 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 and N
11、orth America.primary endpoint was objective response,median follow-up of 89 months.精选ppt8R/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 vedotin:A multicentre,multicohort,single-arm phas
12、e 2 trial.Lancet Oncol 17:1283-1294,2016lymphoma 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 was generally well tolerated.The most
13、 common adverse effects of any grade were fatigue,infusion-related reaction,and rash.精选ppt9R/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 vedotin:A multicentre,multicohort,single-arm ph
14、ase 2 trial.Lancet Oncol 17:1283-1294,2016Severe adverse effects,such as low blood counts(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，FDA，May 2016
15、 US Food and Drug Administration:Nivolumab(Opdivo)for Hodgkin lymphoma.http:/www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm501412.htm.精选ppt10R/R cHL-派姆单抗 KEYNOTE-013:Study DesignMulticenter,multicohort phase Ib trial,open-label,December 2013 to September 2014.Primary endpoints:safety,CRSecon
16、dary 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,previous brentuximab vedotin failure,ASCT failure or ineligibility(N=31)Discontinuation permitted 24 wksPembrolizumab 10 mg/kg IV Q2WCRPR or SDPDTx to 24 mos orP
17、D or intolerable toxicityDiscontinuationArmand P,et al.ASH 2015.Abstract 584；Armand P,et al.JCO,34:3733-3739,2016.精选ppt11R/R cHL-派姆单抗 KEYNOTE-013:Baseline CharacteristicsCharacteristicCharacteristicPembrolizumabPembrolizumab(N=31)(N=31)Median age,yrs(range)32(20-67)Pathology,n(%)Nodular sclerosisMix
18、ed cellularity30(97)1(3)Previous radiation therapy,n(%)10(32)Previous systemic therapy,n(%)2-4 514(45)17(55)Previous brentuximab vedotin failure,n(%)31(100)ASCT,n(%)FailureIneligibility/refusal22(71)9(29)Armand P,et al.ASH 2015.Abstract 584；Armand P,et al.JCO,34:3733-3739,2016.精选ppt1290%of pts had d
19、ecreases in 90%of pts had decreases in target lesion burdentarget lesion burdenincreases circulating numbers increases circulating numbers of T and NK cells,of T and NK cells,upregulates TCR/IFN-upregulates TCR/IFN-signalingsignalingOf 20 pts with CR/PR:Of 20 pts with CR/PR:Still on treatment:n=7Sti
20、ll on treatment:n=7Discontinued treatmentDiscontinued treatmentCRCR:n=1:n=1PR switched tx:n=1PR switched tx:n=1AE:n=1AE:n=1Allogeneic SCT:n=3Allogeneic SCT:n=3PD:n=7PD:n=7R/R cHL-派姆单抗，April 2016,FDA,breakthrough therapy designation for treatment of relapsed classic HL.KEYNOTE-013:EfficacyEndpoint,%E
21、ndpoint,%Total Total(N=(N=31)31)Transplant Transplant FailureFailure(n=22)(n=22)Transplant Ineligibility/Refusal(n=9)ORRCRPR651648731459442222SD231833PD13922DoR 24 wksResponses occurring by 12 wks7180PFS at 24 wks69Armand P,et al.ASH 2015.Abstract 584.；Armand P,et al.JCO,34:3733-3739,2016精选ppt13NHL-
22、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 of 11%was observed Ansell etal.2009.Notably,responses,although low,were quite durable with an ongoing CR lasting more than 31 an
23、d 19 months in one DLBCL and one FL patient,respectively.精选ppt14NHL-nivolumab/pembrolizumabphase 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 al.2016.Patients with T-cell lymphomas(n=2
24、3)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 pembrolizumab in patients with NHL are currently ongoing.精选ppt15存在的问题-研究本身1.single-arm study2.long-term follow-up will be required to det
25、ermine the durability of responses3.ongoing host immune reactions within tumours might have contributed to persistent F-FDG uptake 精选ppt16存在的问题1.PD-L1、2表达程度是否影响疗效？2.治疗持续多长时间最合适？3.获得CR后的终止治疗，何时开始？4.CR不是很高，治愈的可能性？5.PR的意义有多大？6.比起其他的治疗，如放疗其他治疗，孰优？性价比？精选ppt17进一步研究for relapsed as well as for relapsed as w
26、ell as newly diagnosednewly diagnosed classic HL is classic HL is under way.under way.KEYNOTE-204 phase III trialKEYNOTE-204 phase III trial，compare pembrolizumab vs compare pembrolizumab vs BV in pts with R/R cHL(NCT02684292)BV in pts with R/R cHL(NCT02684292)nivolumab with brentuximab vedotin and
27、ipilimumab nivolumab with brentuximab vedotin and ipilimumab(ClinicalTrials.gov identi(ClinicalTrials.gov identifiers:NCT02758717,ers:NCT02758717,NCT01896999,and NCT02304458).NCT01896999,and NCT02304458).other hematologic malignancies,as well as in other hematologic malignancies,as well as in multiple myeloma(ClinicalTrial.gov identimultiple myeloma(ClinicalTrial.gov identifier:er:NCT01953692).NCT01953692).精选ppt18 谢谢聆听!精选ppt19
