Clinical study of GMCI in Pancreatic Cancer

描述(申请人提供)：胰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30,000例诊断和死亡。包括手术、放疗和化疗在内的多种治疗方法并未对预后产生重大影响，主要起到了缓解作用。因此，迫切需要新的治疗方法来治疗胰腺癌。Advantagene一直在开发可能改善这些标准疗法结果的技术。Advantagene的领先技术平台，基因介导的细胞毒免疫疗法(GMCI(Tm))，是一种通过局部递送表达HSV-tk(Tk)的腺病毒载体(ADV-tk)与标准疗法相结合而产生全身肿瘤疫苗效应的方法。这种方法已经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的有效性。GMCI(Tm)尚未被用于胰腺癌的临床评估。这一机制的假说得到了初步研究的支持，涉及TK特异性的细胞毒和免疫刺激特性：(1)局部TK介导的肿瘤细胞杀伤适合于诱导一个“危险”的微环境，(2)辐射诱导急性炎症反应，促进抗原提呈细胞摄取和呈递TK释放的肿瘤相关抗原，以及(3)效应T细胞刺激被TK分子的超抗原样效应增强。临床假说是，由此产生的抗肿瘤免疫将降低胰腺癌患者的发病率或显着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，并将其与临床结果相关联。这一阶段的拨款是为了支持第一阶段的临床试验，将这项技术应用于胰腺癌(目标1和目标2)，并在治疗后评估肿瘤标本的生物活性(目标3)。这一阶段应用的主要目标是评估GMCI(Tm)和Adv-tk在胰腺癌中的安全性，并在体内评估胰腺癌中的载体功能。假设将确定一个安全和有效的媒介剂量，可以在随后的第二阶段试验中进行评估。第二阶段试验是此Fast-Track应用程序第二阶段部分的主题。

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.