Clinical study of GMCI in Pancreatic Cancer

GMCI治疗胰腺癌的临床研究

• 批准号: 7056254
• 负责人: Estuardo Aguilar-Cordova
• 金额: $ 37.07万
• 依托单位: ADVANTAGENE, INC
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-04 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7056254
• 关键词: arm; clinical research; clinical trial phase I; clinical trial phase II; literature survey; neoplasm /cancer; pancreas neoplasms; prodrugs; surgery

DESCRIPTION (provided by applicant): Pancreatic adenocarcinoma is the fourth leading cause of cancer deaths in the US; with less than one-year median survival, it accounts for approximately 30,000 diagnoses and deaths per year. Multimodality therapy, including surgery, radiation and chemotherapy, have not made a significant impact on the outcome and serve mostly as palliation. Thus, new treatment approaches are desperately needed for pancreatic cancer. Advantagene has been developing technologies that may improve the outcome of these standard therapies. Advantagene's lead technology platform, Gene Mediated Cytotoxic Immunotherapy (GMCI(tm)), is an approach which generates a systemic tumor vaccine effect through local delivery of an adenoviral vector (AdV-tk) expressing HSV-tk (TK) when combined with standard therapies. This approach has shown activity in many preclinical tumor models and demonstrated safety with potential efficacy in Phase I and Phase II clinical trials. GMCI(tm) has not been clinically evaluated in pancreatic cancer. The hypothesis for the mechanism, supported by preliminary studies, involves TK-specific cytotoxic and immune-stimulatory properties: (1) local TK-mediated tumor cell killing is appropriate to induce a "danger" microenvironment, (2) radiation induces an acute inflammatory response that potentiates uptake and presentation of TK-released tumor associated antigens by antigen presenting cells, and (3) effector T cell stimulation is potentiated by a superantigen-like effect of the TK molecule. The clinical hypothesis is that the resultant anti-tumor immunity will decrease the incidence or significantly delay local progression and metastases in pancreatic cancer patients. Pancreatic cancer provides an opportunity to evaluate the cytotoxic and immunostimulatory activity of GMCI(tm) and correlate this with clinical outcome. This Phase 1 grant is to support the first Phase I clinical trial to apply this technology in pancreatic cancer (Aim 1 and 2) and evaluate biologic activity in tumor specimens after treatment (Aim 3). The primary goal of this Phase 1 application is to evaluate the safety of GMCI(tm) with AdV-tk in pancreatic cancer and to evaluate vector function in pancreatic cancer in vivo. The hypothesis is that a safe and active vector dose will be identified that can be evaluated in a subsequent Phase II trial. The Phase II trial is the subject of the Phase 2 portion of this Fast-track application.

描述（由申请人提供）：胰腺腺癌是美国癌症死亡的第四大原因；它的中位生存期不到一年，每年约有3万例诊断和死亡。包括手术、放疗和化疗在内的多模式治疗对预后没有显著影响，主要起到缓解作用。因此，胰腺癌迫切需要新的治疗方法。Advantagene一直在开发可以改善这些标准治疗结果的技术。Advantagene的领先技术平台，基因介导的细胞毒性免疫疗法（GMCI(tm)），是一种通过局部递送表达HSV-tk （TK）的腺病毒载体（AdV-tk），与标准疗法联合，产生全身肿瘤疫苗效果的方法。该方法在许多临床前肿瘤模型中显示出活性，并在I期和II期临床试验中证明了安全性和潜在疗效。GMCI（tm）尚未在胰腺癌中进行临床评估。初步研究支持的机制假说涉及TK特异性细胞毒性和免疫刺激特性：(1)TK介导的局部肿瘤细胞杀伤适合诱导“危险”微环境；(2)辐射诱导急性炎症反应，增强了抗原呈递细胞对TK释放的肿瘤相关抗原的摄取和呈递；(3)TK分子的超抗原样作用增强了效应T细胞刺激。临床假设是由此产生的抗肿瘤免疫将降低胰腺癌患者的发病率或显著延缓局部进展和转移。胰腺癌提供了一个评估GMCI（tm）的细胞毒性和免疫刺激活性的机会，并将其与临床结果联系起来。这项I期资助是为了支持第一个I期临床试验，将该技术应用于胰腺癌（Aim 1和2），并评估治疗后肿瘤标本的生物活性（Aim 3）。该i期申请的主要目标是评估GMCI（tm）与AdV-tk在胰腺癌中的安全性，并评估胰腺癌体内的载体功能。假设将确定一种安全有效的载体剂量，可在随后的II期试验中进行评估。二期试验是该快速通道申请二期部分的主题。