KLH-pulsed dendritic cells plus TNFerade in Pancreatic Cancer

描述（由申请人提供）：在美国，每年约有30，000人死于胰腺癌。在胃肠道癌症中，它是第三种最常见的恶性肿瘤，也是癌症相关死亡率的第五大原因。这种疾病在早期阶段很难诊断，几乎90%的患者在出现症状时已经患有不治之症。这种疾病的总体5年生存率低于5%，因此死亡率接近发病率。唯一能提供生存优势的治疗方法是手术切除。迄今为止，对于患有不可手术的疾病（局部晚期或转移性胰腺癌）的患者没有有效的治疗方法。这是一项II期临床试验，它结合了两种治疗不可手术胰腺癌患者实体瘤的新疗法--TNFerade诱导细胞凋亡和树突状细胞疗法诱导免疫反应。每种治疗方法都能单独影响胰腺癌的生长和胰腺癌患者的临床结局。这些疗法的组合从未在这种临床环境中提出或执行，但动物模型显示出治疗协同作用，导致肿瘤消退并保护其免受相同肿瘤类型的后续挑战。该项目的长期和广泛的目标是确定在用编码人肿瘤坏死因子-α（TNFerade）的腺病毒载体诱导原发性肿瘤细胞凋亡后，是否可以使用用匙孔血蓝蛋白脉冲的自体树突状细胞在胰腺癌患者中诱导持久的免疫应答。本课题的具体目的如下：1）研究活化的树突状细胞（DC）联合TNFerade瘤内注射治疗局部晚期/转移性胰腺癌的可行性和安全性; 2）研究DC联合TNFerade治疗晚期胰腺癌的免疫学和抗肿瘤作用; 3）确定TNFerade在注射和活化后对局部微环境的影响。将入组无法手术的肿瘤患者接受治疗方案。将评价肿瘤的细胞凋亡程度，并研究患者对肿瘤相关抗原的全身反应。

DESCRIPTION (provided by applicant): In the United States, approximately 30,000 people die of pancreatic cancer each year. Among cancers of the gastrointestinal tract, it is the third most common malignancy and the fifth leading cause of cancer-related mortality overall. The disease is difficult to diagnose in its early stages, and almost 90% of patients have incurable disease by the time they present with symptoms. The overall 5-year survival rate for this disease is less than 5%, so mortality rates approach incidence rates. The only treatment that offers a survival advantage is surgical resection. To date, no effective therapies exist for patients with inoperable disease (locally advanced or metastatic pancreatic cancer). This is a phase II clinical trial that combines two novel therapies for solid tumors in patients with inoperable pancreatic cancer--TNFerade to induce apoptosis and dendritic cell therapy to induce an immunlogic response. Each therapy has been shown to individually affect the growth of pancreatic adenocarcinoma and clinical outcomes in patients with this disease. The combination of these therapies has never been proposed or executed in this clinical setting, but animal models show a therapeutic synergy that leads to tumor regression and protection against subsequent challenge with the same tumor type. The long term and broad objectives of this project are to determine whether a lasting immune response can be induced in patients with pancreatic cancer using autologous dendritic cells pulsed with keyhole limpit hemocyanin after the induction of apoptosis in the primary tumors with an adenoviral vector coding for human tumor necrosis factor-alpha (TNFerade). The specific aims of this project are as follows: 1) To establish the feasability and safety of intratumoral injections of activated dendritic cells combined with TNFerade in the treatment of locally advanced / metastatic pancreatic cancer; 2) To determine the immunologic and anti-tumor effects of DC combined with TNFerade in patients with advanced pancreatic malignancy; 3) To determine the effect of TNFerade on the local microenvironment after injection and activation. Patients with inoperable tumors will be enrolled to receive the treatment protocol. The tumors will be evaluated for the degree of apoptosis, and the patients will be investigated for a systemic response to tumor associated antigens.