课件：黑色素瘤及胰腺癌治疗进展 ().ppt

CD40是肿瘤 坏死因子（TNF）超家族的成员之一，它的激活被认为是启动 T细胞依赖的抗肿瘤免疫活性的关键步骤。2011年美国宾 夕法尼亚大学埃布拉姆森癌症中心的肿瘤免疫学家Robert Vonderheide 和同事在《Science》上发表了一篇激动人心的 论文［19］ ，他们开始希望通过激活CD40逆转免疫抑制，驱动 T细胞反应，对21例胰腺癌患者运用吉西他滨联合CD40激 动剂治疗，结果4例病人达到了PR，11例病人为SD，PFS为 5.6个月，OS达到7.4个月，较吉西他滨单药的历史对照延 长了2个月。他们在胰腺癌的老鼠模型中重复以上治疗，得 到了同样的结果。但令人意外的是，这种抗肿瘤作用依赖于 巨噬细胞，而不需要T细胞或吉西他滨。CD40激活的巨噬 细胞快速迁移至肿瘤组织，促使肿瘤基质损耗，引起肿瘤细 胞死亡。这一研究再次显示了肿瘤微环境对胰腺癌的重要 性，通过靶向肿瘤基质的治疗，也能达到抗肿瘤的目的，这也 提示我们胰腺癌作为一种特殊的肿瘤，肿瘤细胞周围存在大 量基质，与血管距离较远，药物不易进入肿瘤细胞，既往大量 药物被证明对胰腺癌无效，实际上可能是药物无法有效到达 肿瘤细胞中。 Twenty-two patients with chemotherapy-na?ve advanced PDA were treated with 1,000 mg/m(2) gemcitabine once weekly for three weeks with infusion of CP-870,893 at 0.1 or 0.2 mg/kg on day three of each 28-day cycle. Four patients achieved a partial response (PR). (FDG-PET/CT) showed more than 25% decrease in FDG uptake within primary pancreatic lesions in six of eight patients however, responses observed in metastatic lesions were heterogeneous, with some lesions responding with complete loss of FDG uptake, whereas other lesions in the same patient failed to respond. Improved overall survival correlated with a decrease in FDG uptake in hepatic lesions (R = -0.929; P = 0.007). 两种疫苗联用可刺激产生胰抗腺肿瘤细胞免疫应答，GVAX先诱导抗多种肿瘤蛋白的广泛应答，之后CRS-207刺激产生抗间皮素蛋白免疫应答。从本质上讲，这种疫苗联合接种法可增强患者的天然免疫系统，并使其识别和攻击胰腺肿瘤。 ASCO 2014 Gastrointestinal Cancer Symposium: Abstract 177. Background: Immunotherapy for pancreatic ductal adenocarcinoma (PDA) is likely to require synergistic combinations. One approach is to use heterologous prime boost vaccinations to capitalize on immunostimulatory features of distinct vectors. GVAX is irradiated, GM-CSF-secreting allogeneic pancreatic cell lines given intradermally to elicit a broad antigenic response. Low-dose cyclophosphamide (CY) is given prior to GVAX to inhibit regulatory T-cells. CRS-207 is live-attenuated Listeria monocytogenes (Lm) which expresses mesothelin and stimulates innate and adaptive immunity. In mouse tumor models, Lm/GVAX vaccines are synergist