Gene Therapy for Human Malignant Melanoma

描述（由申请人提供）： 黑色素瘤是最恶性的皮肤癌。在美国，黑色素瘤的发病率比任何其他癌症都增长得更快。黑色素瘤是25-30岁女性中最常见的癌症，最近已取代白血病成为美国损失最多工作时间的原因。目前还没有获得批准的治疗方法可以达到超过20%的缓解率。因此，迫切需要更好的治疗恶性黑色素瘤的方法。Introgen Therapeutics正在开发一种新的抗肿瘤基因治疗药物Ad-mda 7，并在与德克萨斯大学医学博士合作进行的I期STTR研究中。安德森癌症中心，已经证明了它的抗肿瘤潜力，在人类黑色素瘤细胞系和动物模型的转移性癌症。Mda 7是一种黑素细胞来源的肿瘤抑制基因，具有白细胞介素特性，最近被命名为IL-24。在我们的其他研究中，初步的I期临床试验测试提供了初步的安全性信息，以及免疫激活的初步数据。在这里，我们提出了验证的原则实验，以评估生物学疗效的Ad-mda 7在黑色素瘤患者的复发性在途疾病。这现在已经导致黑色素瘤患者安全性研究，IND申请和随后的II期STTR中的Ad-mda 7的II期临床试验评价。本提案的主要目的是使用Ad-mda 7进行临床试验（目的1），评价患者生物学材料和反应以确定生物学疗效（目的2），优化人体外模型中的Ad-mda 7联合治疗（目的3），并评估转移性小鼠黑色素瘤模型中全身递送的可能性（目的4）。

DESCRIPTION (provided by applicant): Melanoma is the most malignant of skin cancers. In the USA, the incidence of melanoma is increasing more rapidly than any other cancer. Melanoma is the most frequently occurring cancer in women from the ages of 25-30, and has recently replaced leukemia as responsible for the most lost work hours in the United States. Currently there is no approved therapy that achieves more that a 20% response rate. Therefore, better therapies for malignant melanoma are urgently needed. Introgen Therapeutics is developing a novel anti-tumor gene therapeutic, Ad-mda7, and in the Phase I STTR research studies conducted in collaboration with University of Texas, M.D. Anderson Cancer Center, has demonstrated it's anti-tumor potential in human melanoma cell lines and animal models of metastatic cancer. Mda7 is a melanocyte-derived tumor suppressor gene, with interleukin properties, and has recently been designated IL-24. In our other studies a preliminary Phase I clinical trial testing has provided initial safety information, as well as preliminary data of immune activation. Here, we propose proof-of-principle experiments to evaluate the biological efficacy of Ad-mda7 in melanoma patients with recurrent in transit disease. This has now led to melanoma patient safety studies, IND filing and subsequent Phase II clinical trial evaluation of Ad-mda7 in the Phase II STTR. The primary aims of this proposal are to conduct the clinical trial with Ad-mda7 (Aim 1), evaluate the patient biological material and responses to establish the biologic efficacy (Aim 2), optimize Ad-mda7 combination therapies in human in vitro models (Aim 3), and assess the possibility of systemic delivery in metastatic mouse melanoma models (Aim 4).