Development of E1A Gene Therapy in Ovarian Cancer

在上一个资助期间，我们确定了与E1 A基因相关的多种抗肿瘤活性 表达，并建立了适当的动物模型，以评估E1脂质体的抗卵巢癌活性 复杂.一项使用E1 A-脂质体复合物靶向乳腺癌和卵巢癌的I期研究， 在上一个资助期内完成并报告（附录1-J. Clin. Oncol. 19：3422-3433，2001）。 基于这一经验，我们启动了腹腔内单药E1 A基因治疗的II期试验， 2001年复发性卵巢癌患者。由于符合资格的患者数量很少， 根据要求，我们终止了II期试验，并启动了一项新的I/II期试验， E1 A基因治疗，并有更合适的资格要求。该I/II期试验已 开放，并已开始积累病人。在竞争性更新中，我们将继续进行两项临床前研究 和临床试验，以确保开发有效的卵巢癌治疗方法， 利用基因疗法。为了实现这一目标，我们提出以下三个具体目标：具体目标1： 完成E1 A基因治疗联合化疗的I/II期试验。用一个新奇的试验 设计，我们将进行一项随机l/ll期试验，其中一组接受每周静脉注射紫杉醇（以 为异质性患者组建立并行对照组），另一组每周接受 在不同剂量水平下i. v.紫杉醇与i. p.脂质体E1 A基因治疗。这项研究将确定毒性， 紫杉醇每周一次联合化疗的最大耐受剂量（MTD）、临床缓解率和无进展生存期 E1 A-\\p\d复合治疗。将获得活检以监测细胞水平的治疗。具体目标 2、建立卵巢癌特异性基因转移系统及表达载体。两种方法 将用于改善E1 A基因治疗的全身静脉内靶向，以治疗卵巢癌异种移植物：1） 卵巢癌特异性启动子元件的开发和2）脂质体与靶向 肽、叶酸配体和抗叶酸受体抗体。具体目标3：制定有效的 在临床前卵巢癌模型中E1 A基因治疗与其他药物的组合。使用 卵巢癌异种移植瘤，我们将测试E1 A基因治疗与 用于治疗卵巢癌患者的细胞毒性药物以及新型生物制剂（TNF α和TRAIL）。 初步数据表明，这些药物可以发挥协同抗肿瘤活性在亚毒性剂量。的 目标1的临床数据和目标2和3的临床前见解可以在未来结合起来设计 新的和潜在的甚至更有效的治疗策略。

During the previous funding period, we defined multiple antitumor activities associated with E1A gene expression and established an appropriate animal model to evaluate the anti-ovarian cancer activity of an E1Aliposome complex. A phase I study using ElA-liposome complex targeting of breast and ovarian cancers was completed and reported during the previous funding period (Appendix 1-J. Clin. Oncol. 19:3422-3433, 2001). Based on this experience, we initiated a phase II trial of intraperitoneal single-agent E1A gene therapy in patients with recurrent ovarian cancer in 2001. Because of the small number of patients who met the eligibility requirements, we terminated the phase II trial and initiated a new phase l/ll trial that combines chemotherapy with E1A gene therapy and that has more appropriate eligibility requirements. This phase l/ll trial has been opened and has begun to accrue patients. In the competitive renewal, we will continue both preclinical studies and clinical trials to ensure the development of an effective therapeutic approach for ovarian cancer that utilizes gene therapy. To achieve this goal, we propose the following three Specific Aims: Specific Aim 1: To complete the phase l/ll trial of E1A gene therapy combined with chemotherapy. Using a novel trial design, we will perform a randomized phase l/ll trial in which one arm receives weekly i.v. paclitaxel (to establish a concurrent control group for a heterogeneous group of patients) and the other arm receives weekly i.v. paclitaxel with i.p. liposomal E1A gene therapy at different does levels. This study will define the toxicity, maximum tolerated dose (MTD), clinical response rate, and progression-free survival of weekly paclitaxel plus E1A-\\p\d complex treatment. Biopsies will be obtained to monitor therapy at the cellular level. Specific Aim 2: To develop an ovarian cancer-specific gene delivery system and expression vector. Two approaches will be used to improve systemic i.v. targeting of E1A gene therapy to treat ovarian cancer xenografts: 1) development of ovarian cancer-specific promoter elements and 2) conjugation of liposomes with targeting peptides, folate ligand, and anti¿folate receptor antibodies. Specific Aim 3: To develop an effective combination of E1A gene therapy with other agents in a preclinical ovarian cancer model. Using ovarian cancer xenografts, we will test the efficacy and toxicity of E1A gene therapy in combination with cytotoxic drugs used to treat ovarian cancer patients as well as novel biologic agents (TNFa and TRAIL). Preliminary data suggest that these agents may exert synergistic antitumor activity at subtoxic doses. The clinical data from Aim 1 and preclinical insights from Aims 2 and 3 can be combined in the future to design novel and potentially even more effective therapeutic strategies.