Immunization Against Melanoma Differentiation Antigens

描述(申请人提供)：黑色素瘤是一个进行性的公共卫生问题，因为它的发病率持续增加。免疫疗法现在被认为是治疗晚期黑色素瘤的有效方法，尽管它只对一小部分患者有利。这笔赠款的总体目标是开发更有效的策略，利用免疫系统识别黑色素瘤细胞上存在的特定靶点。我们寻求在这个项目以前的成就的基础上，以几种具体的方式来开发最有效的免疫治疗计划。该项目的第一个目标是研究如何刺激T细胞上存在的一种称为GITR的途径，作为一种刺激效应性T细胞和抑制抑制性T细胞的方法。在第二个目标中，将探索不同的抗体组合，以找到调节不同免疫途径的最佳方式。所有的免疫调节抗体都有临床级别的等效物可用或正在开发中。因此，这一目的的结果可能立即具有临床适用性。最佳抗体组合将与优化的DNA疫苗结合，以评估所选的免疫调节方案是否增强了疫苗的效果。第三个目标是研究抗原特异性T细胞作为治疗黑色素瘤的方法。已知，同时输注CD4+(辅助性)和CD8+(细胞毒性)T细胞对黑色素瘤患者有治疗益处。确定这类电池的最佳数量和组合将是该项目这一部分的目标。一旦免疫调节抗体和过继转移的T细胞的最佳组合的细节被知道，这些将被结合起来，试图开发一个全面的免疫治疗计划。这将首先在小鼠的移植肿瘤中进行评估。第四个目标是继续努力在老鼠身上建立一个真实的自发性黑色素瘤模型。人类黑色素瘤中存在的同样的基因变异也被引入到皮肤中有黑素细胞的小鼠身上。这将是测试综合免疫疗法计划有效性的最严格手段。 公共卫生相关性：黑色素瘤是一种进行性公共卫生问题，其发病率持续上升。免疫疗法现在被认为是治疗晚期黑色素瘤的有效方法，尽管它只对一小部分患者有利。这笔赠款的总体目标是开发更有效的策略，利用免疫系统识别黑色素瘤细胞上存在的特定靶点。

DESCRIPTION (provided by applicant): Melanoma is a progressive public health problem as its incidence continues to increase. Immunotherapy is now recognized to be an effective treatment for advanced melanoma, although it only benefits a small proportion of patients. The overall goal of this grant is to develop more effective strategies to use the immune system to recognize specific targets present on melanoma cells. We seek to build on prior accomplishments of this project in several specific ways to develop the most potent immunotherapeutic program. The first aim of the project is focused on investigating ways to stimulate a pathway known as GITR, present on T cells, as a way to stimulate effector T cells and inhibit suppressive T cells. In the second aim, different combinations of antibodies will be explored to find the optimal way to modulate different immunologic pathways. All of the immunomodulatory antibodies have clinical grade equivalents available or in development. Therefore, the results of this aim may have immediate clinical applicability. The best combination of antibodies will be combined with optimized DNA vaccine to assess if the chosen immune modulation program enhances the effect of the vaccine. The third aim will investigate the use of antigen specific T cells as a therapy for melanoma. It is known that infusions of both CD4+ (helper) and CD8+ (cytotoxic) T cells can have therapeutic benefit in melanoma patients. Determination of the optimal number and combination of such cells will be the goal of this part of the project. Once the details of the best combination of immunomodulating antibodies and adoptively transferred T cells are known, these will be combined in an attempt to develop a comprehensive immunotherapeutic program. This will be evaluated first in a transplanted tumor in mice. The fourth aim represents a continuing effort to generate a realistic model of spontaneous melanoma in mice. The same genetic aberrations present in human melanoma are being introduced into mice with melanocytes in the skin. This will represent the most stringent means to test the efficacy of the comprehensive immunotherapy program. PUBLIC HEALTH RELEVANCE: Melanoma is a progressive public health problem as its incidence continues to increase. Immunotherapy is now recognized to be an effective treatment for advanced melanoma, although it only benefits a small proportion of patients. The overall goal of this grant is to develop more effective strategies to use the immune system to recognize specific targets present on melanoma cells.