Elimination of Immature Myeloid Cells

描述(由申请者提供)：通过这个K24职业发展奖，我寻求增加我从事翻译性的、由研究人员发起的研究的机会，并指导进入临床研究职业生涯的医生-科学家。我职业生涯的大部分时间都致力于在实验室和诊所系统地开发基于免疫和细胞的疗法，并作为住院医生、研究员和初级教职员工在癌症相关临床研究领域寻求职业生涯的导师，有着良好的记录。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癌患者的转译研究上，将我的患者和管理职责减少到每周半天，并将我的时间奉献给指导新的临床研究人员。我目前的研究目标包括逆转肿瘤介导的免疫抑制，以及使用负载抗原的树突状细胞疫苗在癌症患者中诱导治疗性抗肿瘤免疫。这项研究的第一部分将探索一种新的和有希望的策略来消除转移性肾癌患者(RCC)中免疫抑制的未成熟髓系抑制细胞(IMC)。在目标1中，我们将开发新的技术，使我们能够定义、跟踪和监测肾癌患者外周血中的IMC，并开发通过使用分化药物来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/I I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，在I/I I期研究中，肾癌患者将接受递增剂量的分化试剂ATRA，然后接种抗原负载的DC疫苗。在目标3中，我们将进行彻底的免疫学和临床监测，以确定这种联合方案的生物学和临床效果。通过直接解决晚期癌症患者的临床益处问题，这一新方法可能会迅速进入第二阶段临床试验测试。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NIH资助的研究拨款，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调查人员，包括参与当前项目的调查人员。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路径。这些指导活动得到了杜克大学领导层的大力支持，为下一批临床研究人员提供了一个独特的转化医学培训机会。

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.