课件：恶性淋巴瘤免疫治疗进展.ppt

恶性淋巴瘤免疫治疗进展,陈振东 安徽医科大学第二附属医院肿瘤中心,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 immunotherapy 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-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 approved for cHL PD-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 patients: autologous stem-cell transplantation (ASCT). newer treatment regimen + brentuximab vedotin, many patients eventually worsens.,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 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 in any other type of cancer studied to date. CBT，checkpoint blockade therapy， (免疫)检查点阻滞治疗,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 Oncol 34:2690-2697, 2016 .,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 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 alterations in this gene increase JAKSTAT signalling, further inducing PD-L1 overexpression.,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. 2011 primary mediastinal B-cell lymphoma (PMBL) which, similar to HL，frequently harbors 9p22 amplification leading to overexpression of PD-L1/PD-L2 Shi et al. 2014.,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 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 progression Aug 26, 2014Feb 20, 2015, 34 hospitals and academic centres across Europe and North America. primary endpoint was objective response , median follow-up of 89 months.,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 vedotin: 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 months. Nivolumab was generally well tolerated. The most common adverse effects of any grade were fatigue, infusion-related reaction, and rash.,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 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，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. /Drugs/InformationOnDrugs/ApprovedDrugs/ucm501412. htm .,R/R cHL- 派姆单抗 KEYNOTE-013: Study Design,Multicenter, multicohort phase Ib trial, open-label, December 2013 to September 2014. Primary endpoints: safety, CR Secondary endpoints: OR, DoR, PFS, OS, biomarkers Response 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 wks,Pembrolizumab 10 mg/kg IV Q2W,CR,PR or SD,PD,Tx to 24 mos or PD or intolerable toxicity,Discontinuation,Armand P, et al. ASH 2015. Abstract 584； Armand P, et al. JCO, 34:3733-3739, 2016.,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.,90% of pts had decreases in target lesion burden increases circulating numbers of T and NK cells, upregulates TCR/IFN- signaling Of 20 pts with CR/PR: Still on treatment: n = 7 Discontinued treatment CR: n = 1 PR switched tx: n = 1 AE: n = 1 Allogeneic SCT: n = 3 PD: n = 7,R/R cHL-派姆单抗，April 2016, FDA, breakthrough therapy designation for treatment of relapsed classic HL. KEYNOTE-013: Efficacy,Armand P, et al. 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 patients 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, respectively.,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 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.,存在的