Clinical study of GMCI in Pancreatic Cancer

GMCI治疗胰腺癌的临床研究

• 批准号: 7284150
• 负责人: Estuardo Aguilar-Cordova
• 金额: $ 37.67万
• 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 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7284150
• 关键词: Accounting; Acute; Adenovirus Vector; Adjuvant; Aftercare; Antigen-Presenting Cells; Apoptosis; Appendix; Applications Grants; Boston; Cancer Etiology; Cancer Patient; Cancer Vaccines; Cells; Cessation of life; Clinic; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Clinical Trials Data Monitoring Committees; Combined Modality Therapy; Contracts; Data; Diagnosis; Disease; Dose; Evaluation; Excision; Funding; Future; General Hospitals; Genes; Goals; Grant; HSV-Tk Gene; Histologic; Immune; Immunotherapy; Incidence; Infiltration; Inflammatory Response; Injection of therapeutic agent; Institution; Lead; Malignant neoplasm of pancreas; Massachusetts; Measurable; Mediating; Medical Research; Medicine; Modeling; Necrosis; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Palliative Care; Pancreas; Pancreatic Adenocarcinoma; Pathologic; Pathology; Patients; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Population; Process; Prodrugs; Property; Protocols documentation; Radiation; Radiosurgery; Range; Recombinants; Research Ethics Committees; Research Personnel; Resectable; Review Committee; Safety; Site; Specimen; Standards of Weights and Measures; Superantigens; T-Lymphocyte; Technology; Testing; Time; Tissues; Toxic effect; Tumor Antigens; Tumor Immunity; United States National Institutes of Health; Upper arm; Writing; cell killing; chemotherapy; clinical research site; college; cytotoxic; improved; in vivo; neoplastic cell; pancreatic neoplasm; particle; pre-clinical; programs; response; transduction efficiency; tumor; uptake; valacyclovir; vector

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）：胰腺癌是美国癌症死亡的第四大原因；中位生存期不到一年，每年约有 30,000 例确诊和死亡。包括手术、放疗和化疗在内的多学科治疗并未对结果产生重大影响，主要起到姑息治疗的作用。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疗法效果的技术。 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) 与标准疗法结合产生系统性肿瘤疫苗效果的方法。该方法已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功效。 GMCI(tm) 尚未在胰腺癌中进行临床评估。该机制的假设得到了初步研究的支持，涉及 TK 特异性细胞毒性和免疫刺激特性：(1) 局部 TK 介导的肿瘤细胞杀伤适合诱导“危险”微环境，(2) 辐射诱导急性炎症增强抗原呈递细胞对 TK 释放的肿瘤相关抗原的摄取和呈递的反应，以及 (3) 效应 T 细胞刺激通过 TK 分子的超抗原样作用而增强。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着延迟局部进展和转移。胰腺癌提供了评估 GMCI(tm) 的细胞毒性和免疫刺激活性并将其与临床结果相关联的机会。该一期资助将用于支持将该技术应用于胰腺癌的首个一期临床试验（目标 1 和 2），并评估治疗后肿瘤标本的生物活性（目标 3）。该 1 期应用的主要目标是评估 GMCI(tm) 与 AdV-tk 在胰腺癌中的安全性，并评估体内胰腺癌中的载体功能。假设将确定安全且有效的载体剂量，并可在随后的 II 期试验中进行评估。第二阶段试验是本快速通道申请第二阶段部分的主题。

项目成果

Therapeutic endoscopic ultrasonography: intratumoral injection for pancreatic adenocarcinoma.

治疗性内窥镜超声检查：胰腺腺癌的瘤内注射。

• DOI: 10.1155/2013/207129
• 发表时间: 2013
• 期刊: Gastroenterology research and practice
• 影响因子: 2
• 作者: Shirley,LawrenceA;Aguilar,LauraK;Aguilar-Cordova,Estuardo;Bloomston,Mark;Walker,JonP
• 通讯作者: Walker,JonP