Molecular mechanisms of antibody-mediated immunotherapies

抗体介导的免疫疗法的分子机制

• 批准号: 9888968
• 负责人: JEFFREY Victor RAVETCH
• 金额: $ 101.7万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9888968
• 关键词: Antibodies; Antibody Therapy; Clinical; Disease; Generations; Goals; Immune Targeting; Immune response; Immune system; Immunotherapeutic agent; Immunotherapy; Lead; Malignant Neoplasms; Mediating; Memory; Modality; Molecular; Pathway interactions; Recurrence; Refractory; Therapeutic; Therapeutic Agents; Therapeutic Effect; Tumor Antibodies; cancer vaccination; fighting; immunoregulation; improved; long term memory; neoplasm immunotherapy; neoplastic cell; public health relevance; response; tumor; tumor microenvironment

 DESCRIPTION (provided by applicant): Our studies over the past two decades have focused on clarifying the mechanisms by which anti-tumor immunotherapies elicit their therapeutic effects. As a result of our studies, the importance of Fc-FcγR mediated effector pathways for the elimination of tumors has been elucidated, resulting in the optimization of these interactions in second-generation anti-tumor immunotherapeutics with improved clinical activity. While these strategies have resulted in more effective anti-tumor antibodies (Abs) with significantly improved survival, the long-term goal of immunotherapy is to develop therapeutic strategies that will elicit memory responses that will effectively eliminate recurrences and thus result in long-term survival. This current proposal aims to mechanistically investigate general strategies to accomplish this goal by focusing on 1) inducing tumor vaccination using anti-tumor monoclonal Abs (mAbs), 2) define the mechanisms by which agonistic and antagonistic immunomodulatory mAbs enhance anti-tumor vaccination, and 3) explore how the tumor microenvironment may be manipulated in order to augment these immunotherapeutic strategies. Our preliminary results have indicated that anti-tumor Abs can elicit long-term cellular memory responses when appropriate Fc-FcγR interactions are integrated into these Abs. Manipulating both the cellular effector responses and the tumor microenvironment through the use of Fc-optimized immunomodulatory Abs can augment these pathways to result in long-term memory responses.