Suicide Gene and Radiation Therapy Clinical Trials

项目3的目的是通过基因操作癌细胞，以提高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，我们将进行一系列的I期和II期临床试验，以检验以下基本假设：将复制型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，并将证明与单独的适形放疗相比具有上级疗效。具体目标1描述了一项I/II期试验，以确定在新诊断的中高危前列腺癌患者中，复制能力腺病毒介导的双自杀基因治疗与常规剂量（72戈伊）调强放疗（IMRT）联合是否上级单独的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，由第2年的前列腺活检状态确定。其他终点将是急性和晚期毒性，6个月和1年时的早期肿瘤控制，以及无生化或临床失败。具体目标2描述了一项I/II期试验，以确定复制能力腺病毒介导的双自杀基因治疗与补救性调强放疗联合治疗局部复发性前列腺癌患者的安全性和有效性。最好的第二代腺病毒开发 项目1将使用。3 - 6例患者的3个队列将接受腺病毒（10[12] vp）单次前列腺内注射沿着3周的5-FC + vGCV前药治疗和递增剂量（20、26、30戈伊）的IMRT。如果在6个月时没有毒性问题，将进行II期试验，患者将接受腺病毒（10[12] vp）单次前列腺内注射沿着3周的5-FC + vGCV前药治疗和最大耐受剂量（MTD）的IMRT。主要终点将是局部肿瘤控制，由第2年的前列腺活检状态确定。其他终点将是急性和晚期毒性，以及无生化或临床失败。具体目标3描述了I期试验 这将评估使用设计用于增强基因递送的改进载体制剂的体内治疗性基因转移的效率。将在计划接受前列腺切除术的局限性前列腺癌患者中评价基因转移和载体分布的效率。这些研究将产生重要的新知识，为未来的大规模人体试验提供科学依据，并可能最终导致更好的癌症治疗。

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.