Suicide Gene and Radiation Therapy Clinical Trials

项目3的目标是通过基因操纵癌细胞，优先增加对肿瘤组织的固有辐射敏感性，最终目标是改善放射治疗的结果。为了实现这一目标，我们将进行一系列I期和II期临床试验，以验证一般假设，即将复制能力腺病毒介导的双自杀基因治疗与适形放疗相结合可以安全地应用于人类，并且与单独适形放疗相比，将显示出更好的疗效。Specific Aim 1描述了一项I/II期试验，旨在确定复制能力腺病毒介导的双重自杀基因治疗联合常规剂量（72 Gy）调强放疗（IMRT）对新诊断的中高风险前列腺癌患者是否优于单独IMRT。将使用项目1中开发的最好的第二代腺病毒。主要终点将是局部肿瘤控制，由前列腺活检状态在两年内确定。其他终点将是急性和晚期毒性，6个月和1年的早期肿瘤控制，以及没有生化或临床失败。Specific Aim 2描述了一项I/II期试验，旨在确定复制能力腺病毒介导的双重自杀基因治疗联合补救性IMRT治疗局部复发性前列腺癌患者的安全性和有效性。产生了最好的第二代腺病毒

The objective of Project 3 is to genetically manipulate cancer cells to increase intrinsic radiation sensitivity preferentially to tumor tissue with the ultimate goal of improving the outcome of radiation therapy. To achieve this goal, we will conduct a series of Phase I and II clinical trials that will test the general hypothesis that combining replication-competent adenovirus-mediated double suicide gene therapy with conformal radiotherapy can be applied safely in humans and will demonstrate superior efficacy compared to conformal radiotherapy alone. Specific Aim 1 describes a Phase I/II trial to determine whether replication-competent adenovirus-mediated double suicide gene therapy in combination with conventional dose (72 Gy) intensity modulated radiotherapy (IMRT) is superior to IMRT alone in patients with newly diagnosed, intermediate-to-high risk prostate cancer. The best second-generation adenovirus developed in Project 1 will be used. The primary endpoint will be local tumor control as determined by prostate biopsy status at two years. Other endpoints will be acute and late toxicity, early tumor control at six months and one year, and freedom from biochemical or clinical failure. Specific Aim 2 describes a Phase I/II trial to determine the safety and efficacy of replication-competent adenovirus-mediated double suicide gene therapy in combination with salvage IMRT in patients with locally recurrent prostate cancer. The best second-generation adenovirus developed in Project 1 will be used. Three cohorts of three to six patients will receive a single intraprostatic injection of adenovirus (10[12] vp) along with three weeks of 5-FC + vGCV prodrug therapy and an escalating dose (20, 26, 30 Gy) of IMRT. If there are no toxicity concerns at six months, a Phase II trial will be conducted in which patients will receive a single intraprostatic injection of adenovirus (10[12] vp) along with three weeks of 5-FC + vGCV prodrug therapy and the maximum tolerated dose (MTD) of IMRT. The primary endpoint will be local tumor control as determined by prostate biopsy status at two years. Other endpoints will be acute and late toxicity, and freedom from biochemical or clinical failure. Specific Aim 3 describes a Phase I trial that will evaluate the efficiency of therapeutic gene transfer in vivo using an improved vector formulation designed to enhance gene delivery. The efficiency of gene transfer and distribution of vector will be evaluated in patients with localized prostate cancer who are scheduled to undergo prostatectomy. These studies will generate important new knowledge that will provide the scientific basis for which future large-scale human trials will be based and may ultimately lead to better cancer treatments.