Developement of an alphavirus vaccine for melanoma

描述（由申请人提供）：2005年，美国估计有59,000人罹患黑色素瘤，导致7,700人死亡，其发病率上升速度超过除肺癌以外的所有其他癌症。虽然原发肿瘤可以手术切除，但大约一半的患者会发展为转移性疾病，而治疗选择很少。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（TYR）是黑素体分化抗原的原型，为疫苗治疗提供了一个有吸引力的靶点。表达TYR的DNA质粒疫苗已在临床前测试中显示出前景，最近进入黑色素瘤治疗的人体测试。在这个新的I期项目中，我们利用一种新的有效的病毒载体将TYR传递到免疫系统。我们将探索基于委内瑞拉马脑炎病毒甲病毒的疫苗复制子颗粒（VRP）。VRP平台在各种环境下对各种抗原引发了有效的细胞和体液免疫反应，该技术结合了分层安全特征，使其对人类具有吸引力。该项目的总体目标是确定我们的新型tyrr - vrp疫苗在最佳的恶性黑色素瘤临床前模型中是否优于研究性tyrr - dna疫苗。该I期项目的具体目标是：1)确定最佳引发t细胞反应并打破小鼠免疫耐受的TYR-VRP给药方案；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；3)比较TYR-VRP和TYR-DNA疫苗在转基因动物中引发人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HLA-A2限制性反应的产生方面都比TYR-DNA有明显的优势。该项目的成功将代表这一领域的重要进展，并为开发tyrr - vrp进行人体试验提供强大动力。

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.