Immunization Against Melanoma Differentiation Antigens

描述（由申请人提供）：黑色素瘤是一个进行性公共卫生问题，其发病率持续增加。免疫疗法现在被认为是晚期黑色素瘤的有效治疗方法，尽管它只对一小部分患者有益。这项拨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的特定靶点。我们寻求在这个项目之前的成就的基础上，以几种具体的方式来开发最有效的免疫治疗方案。该项目的第一个目标是研究刺激T细胞上被称为GITR的途径的方法，作为刺激效应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可用的或正在开发的临床级等效抗体。因此，这一目标的结果可能具有直接的临床适用性。将最佳抗体组合与优化后的DNA疫苗组合，以评估所选择的免疫调节程序是否能增强疫苗的效果。第三个目标是研究使用抗原特异性T细胞治疗黑色素瘤。众所周知，输注CD4+（辅助）和CD8+（细胞毒性）T细胞对黑色素瘤患者有治疗效果。确定这些细胞的最佳数量和组合将是这部分项目的目标。一旦了解了免疫调节抗体和过继性转移T细胞最佳组合的细节，这些将被结合起来，试图开发一个全面的免疫治疗方案。这将首先在小鼠移植肿瘤中进行评估。第四个目标是继续努力在小鼠身上产生一个真实的自发黑色素瘤模型。人类黑色素瘤中存在的相同基因畸变正被引入皮肤中有黑色素细胞的小鼠。这将是检验综合免疫治疗方案疗效的最严格手段。

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.