Immunization Against Melanoma Differentiation Antigens

针对黑色素瘤分化抗原的免疫接种

• 批准号: 8586300
• 负责人: Jedd D. Wolchok
• 金额: $ 29.68万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-06-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8586300
• 关键词: Active Immunotherapy; Adoptive Transfer; Antibodies; Antigens; CD8B1 gene; Cells; Clinical; Clinical Trials; Combined Modality Therapy; Cyclophosphamide; Cytotoxic T-Lymphocytes; DNA Vaccines; Development; Differentiation Antigens; Disease; Evaluation; Genetic; Glucocorticoids; Goals; Grant; Human; Immune; Immune response; Immune system; Immunity; Immunization; Immunologics; Immunotherapeutic agent; Immunotherapy; Incidence; Infusion procedures; Ligation; Malignant Neoplasms; Melanoma Cell; Metastatic Melanoma; Modeling; Mus; Neoplasm Transplantation; Passive Immunotherapy; Pathway interactions; Patients; Preparation; Proteins; Public Health; Regulation; Skin; T-Lymphocyte; Testing; Therapeutic; Translations; Tumor Immunity; Tumor Necrosis Factor Receptor; Vaccines; base; cancer immunotherapy; chemotherapy; clinical application; combinatorial; effective therapy; efficacy testing; immunoregulation; improved; in vivo; melanocyte; melanoma; mouse model; programs; public health relevance; response; tumor

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.

描述（由申请人提供）：黑色素瘤是一个渐进性的公共卫生问题，其发病率不断增加。免疫疗法现已被认为是晚期黑色素瘤的有效治疗方法，尽管它只使一小部分患者受益。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标。我们寻求以几种特定方式在该项目先前取得的成就的基础上开发最有效的免疫治疗计划。该项目的首要目标是研究如何刺激 T 细胞上存在的 GITR 通路，从而刺激效应 T 细胞并抑制抑制性 T 细胞。第二个目标是探索不同的抗体组合，以找到调节不同免疫途径的最佳方法。所有免疫调节抗体都有可用或正在开发的临床级等效抗体。因此，该目标的结果可能具有直接的临床应用价值。最佳的抗体组合将与优化的DNA疫苗相结合，以评估所选择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+（辅助性）和 CD8+（细胞毒性）T 细胞可以对黑色素瘤患者产生治疗效果。确定此类单元的最佳数量和组合将是该项目这一部分的目标。一旦了解了免疫调节抗体和过继转移 T 细胞的最佳组合的细节，就会将这些组合起来，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。第四个目标代表了持续努力在小鼠中生成自发性黑色素瘤的现实模型。人类黑色素瘤中存在的相同遗传畸变被引入皮肤中有黑色素细胞的小鼠体内。这将代表测试综合免疫治疗计划功效的最严格手段。