惡性淋巴瘤免疫治療進(jìn)展課件

1、惡性淋巴瘤免疫治療進(jìn)展 精選ppt1惡性淋巴瘤免疫治療進(jìn)展 精選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 leukemia

2、1992: IL-2 approved for RCC1997: 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

3、approved for melanoma 2016: PD-1 inhibitor approved for cHLPD-L1 inhibitor approved for UC精選ppt2History 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 therapy at all. Such pa

4、tients:autologous stem-cell transplantation (ASCT). newer treatment regimen + brentuximab vedotin, many patients eventually worsens. 精選ppt3霍奇金淋巴瘤：背景HL, Classic type, 95%CBT治療HL有效的機(jī)制Roemer MG, Advani RH, Ligon AH, et al: PDL1 and PD-L2 genetic alterations dene classical Hodgkin lymphoma and predict o

5、utcome. 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 higher in classic HL than

6、 in any other type of cancer studied to date. CBT，checkpoint blockade therapy， (免疫)檢查點(diǎn)阻滯治療精選ppt4CBT治療HL有效的機(jī)制Roemer MG, AdvanCBT治療HL有效的機(jī)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 .病理類型

7、影響PD-L1、2表達(dá) 86% nodular sclerosis, 11% mixed-cellularity 3% not otherwise specied. 病期影響基因擴(kuò)增、預(yù)后 Amplication of 9p24.1 is more common in patients with advanced stage disease （III/IV） and associated with shorter PFS in this series. 精選ppt5CBT治療HL有效的機(jī)制Roemer MG, AdvanCBT治療HL有效的機(jī)制Roemer MG, Advani RH, Lig

8、on 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 chromosome 9p24.1, and alterati

9、ons in this gene increase JAKSTAT signalling, further inducing PD-L1 overexpression.精選ppt6CBT治療HL有效的機(jī)制Roemer MG, AdvanPD-1 免疫檢查點(diǎn)抑制劑有效的機(jī)制：NHL表達(dá)PD-L1、2與cHL不同25% of DLBCL tumors express PD-1/PD-L1 Andorsky et al. 2011primary mediastinal B-cell lymphoma (PMBL) which, similar to HL，frequently harbors 9p2

10、2 amplification leading to overexpression of PD-L1/PD-L2 Shi etal. 2014. 精選ppt7PD-1 免疫檢查點(diǎn)抑制劑有效的機(jī)制：NHL表達(dá)PD-L1R/R cHL-納武單抗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, mu

11、lticohort, 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 North America. primary endpoint was o

12、bjective response , median follow-up of 89 months. 精選ppt8R/R cHL-納武單抗Younes A, SantoroR/R cHL-納武單抗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

13、phase 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 tolera

14、ted. The most common adverse effects of any grade were fatigue, infusion-related reaction, and rash. 精選ppt9R/R cHL-納武單抗Younes A, SantoroR/R cHL-納武單抗Younes A, Santoro A, Shipp M, et al: Nivolumab for classical Hodgkins lymphoma after failure of both autologous stem-cell transplantation and brentuxima

15、b vedotin: A multicentre, multicohort, single-arm phase 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 H

16、SCT and post-transplantation brentuximab vedotin，F(xiàn)DA，May 2016 US Food and Drug Administration: Nivolumab (Opdivo) for Hodgkin lymphoma. /Drugs/InformationOnDrugs/ApprovedDrugs/ucm501412. htm .精選ppt10R/R cHL-納武單抗Younes A, SantoroR/R cHL- 派姆單抗 KEYNOTE-013: Study DesignMulticenter, multicohort phase Ib

17、 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, previous brentuximab vedotin failure, ASCT failure or ineligibility

18、(N = 31) Discontinuation permitted 24 wksPembrolizumab 10 mg/kg IV Q2WCRPR or SDPDTx to 24 mos orPD or intolerable toxicityDiscontinuationArmand P, et al. ASH 2015. Abstract 584； Armand P, et al. JCO, 34:3733-3739, 2016. 精選ppt11R/R cHL- 派姆單抗 KEYNOTE-013: StR/R cHL-派姆單抗 KEYNOTE-013: Baseline Characte

19、risticsCharacteristicPembrolizumab(N = 31)Median age, yrs (range)32 (20-67)Pathology, n (%)Nodular sclerosisMixed 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 (%)FailureIne

20、ligibility/refusal22 (71)9 (29)Armand P, et al. ASH 2015. Abstract 584； Armand P, et al. JCO, 34:3733-3739, 2016. 精選ppt12R/R cHL-派姆單抗 KEYNOTE-013: Bas90% of pts had decreases in target lesion burdenincreases circulating numbers of T and NK cells, upregulates TCR/IFN- signalingOf 20 pts with CR/PR:St

21、ill on treatment: n = 7Discontinued treatmentCR: n = 1PR switched tx: n = 1AE: n = 1Allogeneic SCT: n = 3PD: n = 7R/R cHL-派姆單抗，April 2016, FDA, breakthrough therapy designation for treatment of relapsed classic HL.KEYNOTE-013: EfficacyEndpoint, %Total (N = 31)Transplant Failure(n = 22)Transplant Ine

22、ligibility/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精選ppt1390% of pts had decreases in taNHL- CTLA4 antibody ipilimumab the ORR to checkpoint blo

23、ckade 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 and 19 months in one DLBCL and one FL patient,

24、 respectively. 精選ppt14NHL- CTLA4 antibody ipilimumabNHL- 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 = 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 pembrolizumab in patients with NHL are currently ongoing.精選ppt15NHL- ni