1、 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 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 recognized 1985: Interferon first approved for hairy cell leukemia199
2、2: 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 app
3、roved for melanoma 2016: PD-1 inhibitor approved 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 patients:1. autologous stem-cell transpl
4、antation (ASCT). 2. newer treatment regimen + brentuximab vedotin, 3. 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 fr
5、om 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 bl
6、ockade 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 . 病理类型影响PD-L1、2表达86% nodular sclerosis, 11% mixed-cellularity3% not otherwise specied. 病期影响基因扩增、预后Ampl
7、ication of 9p24.1 is more common in patients with advanced stage disease （III/IV） and associated with shorter PFS in this series. 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
8、 . 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 DL
9、BCL 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 lymphom
10、a 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, 201
11、4Feb 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 transplanta
12、tion 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% reducti
13、on, 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-
14、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. http:/www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm501412. htm .
