Safety and Survival With GVAX Pancreas Prime and Listeria Monocytogenes-Expressing Mesothelin (CRS-207) Boost Vaccines for Metastatic Pancreatic Cancer
Safety and Survival With GVAX Pancreas Prime and Listeria Monocytogenes-Expressing Mesothelin (CRS-207) Boost Vaccines for Metastatic Pancreatic Cancer
复制标题
DOI：
10.1200/jco.2014.57.4244
复制
发表时间：
2015-04-20
影响因子：
45.3
通讯作者：
Jaffee, Elizabeth M.
中科院分区：
文献类型：
--
作者：
Le, Dung T.;Wang-Gillam, Andrea;Jaffee, Elizabeth M.
目的GVAX胰腺癌细胞是分泌粒细胞-巨噬细胞集落刺激因子的同种异体胰腺肿瘤细胞，诱导T细胞对包括间皮素在内的癌抗原的免疫。GVAX与低剂量环磷酰胺（Cy）一起施用以抑制调节性T细胞。CRS-207，表达间皮素的减毒活单核细胞增生李斯特菌，诱导先天性和适应性免疫。临床前协同作用的基础上，我们测试了总理/加强疫苗接种GVAX和CRS-207在pancreaticadenocarcino.Patients和MethodsPreviously治疗的转移性胰腺癌患者被随机分配的比例为2：1的两个剂量的Cy/GVAX，然后由四个剂量的CRS-207（A组）或六个剂量的Cy/GVAX（臂B）每3周。稳定的患者提供额外的课程。主要终点是两组间的总生存期（OS）。次要终点是安全性和临床respons.ResultsA共90例患者进行了治疗（A组，n = 61;臂B，n = 29）; 97%接受过既往化疗; 51%接受过两种方案的转移性疾病。A组和B组的平均给药次数（标准差）分别为5.5 +/- 4.5和3.7 +/- 2.2。最常见的3 - 4级相关毒性为一过性发热、淋巴细胞减少、肝酶升高和疲乏。A组的OS为6.1个月，而B组为3.9个月（风险比[HR]，0.59; P = .02）。在对接受至少三剂（两剂Cy/GVAX加一剂CRS-207或三剂Cy/GVAX）的患者进行的预先规定的符合方案分析中，OS为9.7个月对4.6个月（A组对B组; HR，0.53; P = 0.02）。增强的间皮素特异性CD 8 T细胞反应与较长的OS相关，无论治疗arm. ConclusionHeteroimmune总理/加强与Cy/GVAX和CRS-207延长胰腺癌患者的生存期，毒性最小。(C)2015年美国临床肿瘤学会
PurposeGVAX pancreas, granulocyte-macrophage colony-stimulating factor-secreting allogeneic pancreatic tumor cells, induces T-cell immunity to cancer antigens, including mesothelin. GVAX is administered with low-dose cyclophosphamide (Cy) to inhibit regulatory T cells. CRS-207, live-attenuated Listeria monocytogenes-expressing mesothelin, induces innate and adaptive immunity. On the basis of preclinical synergy, we tested prime/boost vaccination with GVAX and CRS-207 in pancreatic adenocarcinoma.Patients and MethodsPreviously treated patients with metastatic pancreatic adenocarcinoma were randomly assigned at a ratio of 2:1 to two doses of Cy/GVAX followed by four doses of CRS-207 (arm A) or six doses of Cy/GVAX (arm B) every 3 weeks. Stable patients were offered additional courses. The primary end point was overall survival (OS) between arms. Secondary end points were safety and clinical response.ResultsA total of 90 patients were treated (arm A, n = 61; arm B, n = 29); 97% had received prior chemotherapy; 51% had received two regimens for metastatic disease. Mean number of doses ( standard deviation) administered in arms A and B were 5.5 +/- 4.5 and 3.7 +/- 2.2, respectively. The most frequent grade 3 to 4 related toxicities were transient fevers, lymphopenia, elevated liver enzymes, and fatigue. OS was 6.1 months in arm A versus 3.9 months in arm B (hazard ratio [HR], 0.59; P = .02). In a prespecified per-protocol analysis of patients who received at least three doses (two doses of Cy/GVAX plus one of CRS-207 or three of Cy/GVAX), OS was 9.7 versus 4.6 months (arm A v B; HR, 0.53; P = .02). Enhanced mesothelin-specific CD8 T-cell responses were associated with longer OS, regardless of treatment arm.ConclusionHeterologous prime/boost with Cy/GVAX and CRS-207 extended survival for patients with pancreatic cancer, with minimal toxicity. (C) 2015 by American Society of Clinical Oncology