Developement of an alphavirus vaccine for melanoma

描述(申请人提供)：2005年，美国估计有59,000人罹患黑色素瘤，导致7,700人死亡，其发病率的上升速度比除肺癌以外的所有其他癌症都快。虽然原发肿瘤可以通过手术切除，但大约一半的患者发展为转移性疾病，几乎没有治疗选择。因此，迫切需要新的治疗方法来对抗恶性黑色素瘤。尽管恶性黑色素瘤对常规化疗有很大的抗药性，但它对免疫疗法却异常敏感。酪氨酸酶(tyrosinase，TYR)是黑素瘤分化抗原的原型，为疫苗治疗提供了一个有吸引力的靶点。表达TYR的DNA疫苗在临床前测试中表现出了希望，最近进入了黑色素瘤治疗的人体测试。在这个新的第一阶段项目中，我们利用一种新的、有效的病毒载体将TYR传递到免疫系统。我们将探索基于甲型病毒委内瑞拉马脑炎病毒的疫苗复制子颗粒(VRP)。VRP平台在各种环境下对不同的抗原产生了强大的细胞和体液免疫反应，该技术采用了分层的安全特征，使其具有在人类身上使用的吸引力。该项目的总体目标是确定我们的新型TYR-VRP疫苗在最佳可用的恶性黑色素瘤临床前模型中是否优于正在研究的TYR-DNA疫苗。这一第一阶段项目的具体目标是：1)确定TYR-VRP给药方案，以最佳地诱导T细胞反应并打破小鼠的免疫耐受；2)在严格的黑色素瘤小鼠模型中比较TYR-VRP和TYR-DNA疫苗对肿瘤的保护作用；以及3)比较TYR-VRP和TYR-DNA疫苗在转基因动物中诱导人类HLA-A2限制性T细胞反应的能力。项目的成功要求TYR-VRP在肿瘤保护和产生HLA-A2限制性反应方面表现出明显优于TYR-DNA。该项目的成功将代表着这一领域的重要进步，并为开发用于人体测试的TYR-VRP提供强大的动力。

DESCRIPTION (provided by applicant): Melanoma will strike an estimated 59,000 individuals and cause 7,700 deaths in the United States in 2005, and its incidence is rising faster than that of all other cancers except lung cancer. While primary tumors can be excised surgically, approximately half of all patients develop metastatic disease for which there are few treatment options. Thus, there is an urgent need for new therapies to combat malignant melanoma. Although largely resistant to conventional chemotherapies, malignant melanoma is unusually susceptible to immune therapies. Tyrosinase (TYR) is the prototype melanosomal differentiation antigen and provides an attractive target for vaccine therapy. DNA plasmid vaccines that express TYR have demonstrated promise in preclinical testing and recently entered human testing for melanoma therapy. In this new Phase I project, we utilize a novel and potent viral vector to deliver TYR to the immune system. We will explore vaccine replicon particles (VRP) based on the alphavirus Venezuelan equine encephalitis virus. The VRP platform has elicited potent cellular and humoral immune responses to diverse antigens in a variety of settings, and the technology incorporates layered safety features that render it attractive for use in humans. The overall goal of this project is to determine if our novel TYR-VRP vaccine is superior to an investigational TYR-DNA vaccine in the best available preclinical models of malignant melanoma. The specific aims of this Phase I project are: 1) Identify TYR-VRP dosing regimens that optimally elicit T-cell responses and break immunological tolerance in mice; 2) Compare TYR-VRP and TYR-DNA vaccines for tumor protection in a stringent mouse model of melanoma; and 3) Compare TYR-VRP and TYR-DNA vaccines for the ability to elicit human HLA-A2 restricted T-cell responses in transgenic animals. Project success requires that TYR-VRP demonstrate clear superiority over TYR-DNA in terms of both tumor protection and the generation of HLA-A2 restricted responses. Success in the project would represent an important advance to this field and provide strong impetus for developing TYR-VRP for human testing.