Elimination of Immature Myeloid Cells

消除未成熟的骨髓细胞

• 批准号: 7145801
• 负责人: Johannes Wolfgang Vieweg
• 金额: $ 17.9万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-19 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7145801
• 关键词: active immunization; antigens; career; immunity; immunosuppression; immunosuppressive; neoplasm /cancer; neoplasm /cancer vaccine; renal cell carcinoma

DESCRIPTION (provided by applicant): With this K24 Career Development Award I am seeking to enhance my opportunities to engage in translational, investigator-initiated research and to mentor physician-scientists entering a career of clinical investigation. I have devoted much of my career to systemically developing immune- and cell-based therapies in the laboratory and in the clinic and have a proven track record as a mentor for residents, fellows and junior faculty pursuing careers in cancer-related clinical investigation. If I should receive this award, I will focus my clinical activities on translational research in patients with advanced renal and prostate malignancies, decrease my patient and administrative responsibilities to one-half day per week, and dedicate my time to the mentoring of new clinical investigators. My immediate research objectives include studies to reverse tumor-mediated immunosuppression and to induce therapeutic antitumor immunity in cancer patients using antigen-loaded dendritic cell vaccines. The first part of this investigation will explore a novel and promising strategy to eliminate immunosuppressive immature myeloid suppressor cells (ImC) in metastatic renal cell carcinoma patients (RCC). In Aim 1, we will develop new technologies enabling us to define, track and monitor ImC in the peripheral blood of RCC patients and develop methods to abrogate their immunosuppressive activity by using differentiation agents. In Aim 2, we will test whether these insights can be translated into clinically relevant human settings by conducting a phase I/I I study in which RCC patients will receive escalating doses of the differentiation agent ATRA, followed by vaccination with antigen-loaded DC. In Aim 3, we will perform thorough immunological and clinical monitoring to determine the biologic and clinical effects of such combinatorial regimen. This novel approach may advance rapidly into phase II clinical trial testing by directly addressing the question of clinical benefit in advanced cancer patients. Alternative strategies to reverse ImC-mediated immunosuppression include inhibition of reactive oxygen species or nitric oxide, possibly acting synergistically with vaccines to enhance immunologic reactivity. I have extensive collaborations with basic and clinical scientists within and outside the Duke Campus through my own NIH- funded research grants and have successfully mentored numerous investigators, including investigators involved with current projects. The projects in this K24 application represent clearly defined paths for young investigators to pursue patient-oriented clinical research under my guidance. These mentoring activities are strongly supported by Duke leadership and represent a unique training opportunity in translational medicine for the next cadre of clinical investigators.

描述（由申请人提供）：通过这个K24职业发展奖，我正在寻求增加我参与转化、研究者发起的研究的机会，并指导进入临床研究职业的医生科学家。我的大部分职业生涯都致力于在实验室和临床上系统地开发免疫和细胞疗法，并作为居民，研究员和初级教师的导师，在癌症相关的临床研究中追求职业生涯。如果我获得这个奖项，我将把我的临床活动集中在晚期肾脏和前列腺恶性肿瘤患者的转化研究上，将我的患者和行政职责减少到每周半天，并将我的时间用于指导新的临床研究者。我的近期研究目标包括研究逆转肿瘤介导的免疫抑制和使用抗原负载的树突状细胞疫苗诱导癌症患者的治疗性抗肿瘤免疫。本研究的第一部分将探索一种新的和有前途的策略，以消除免疫抑制性未成熟髓系抑制细胞（ImC）在转移性肾细胞癌患者（RCC）。在目标1中，我们将开发新技术，使我们能够定义，跟踪和监测RCC患者外周血中的ImC，并开发通过使用分化剂消除其免疫抑制活性的方法。在目标2中，我们将通过进行I/II期研究来测试这些见解是否可以转化为临床相关的人类环境，其中RCC患者将接受递增剂量的分化剂ATRA，然后接种抗原负载的DC。在目标3中，我们将进行全面的免疫学和临床监测，以确定这种组合方案的生物学和临床效果。这种新方法可以通过直接解决晚期癌症患者的临床获益问题，迅速进入II期临床试验测试。逆转IMC介导的免疫抑制的替代策略包括抑制活性氧或一氧化氮，可能与疫苗协同作用以增强免疫反应性。通过我自己的国家卫生研究院资助的研究经费，我与杜克校区内外的基础和临床科学家进行了广泛的合作，并成功地指导了许多研究人员，包括参与当前项目的研究人员。这个K24应用程序中的项目代表了年轻研究人员在我的指导下进行以患者为导向的临床研究的明确定义的路径。这些指导活动得到了杜克领导层的大力支持，并为下一批临床研究人员提供了转化医学方面的独特培训机会。