Elimination of Immature Myeloid Cells

描述（由申请人提供）：凭借这个K24职业发展奖，我正在寻求增加我从事转化研究的机会，研究者发起的研究，并指导进入临床研究职业的内科科学家。我的大部分职业生涯都致力于在实验室和临床中系统地开发基于免疫和细胞的疗法，并且作为住院医生、研究员和从事癌症相关临床研究的初级教师的导师，我有着良好的业绩记录。如果我应该获得这个奖项，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，将我的病人和行政责任减少到每周半天，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，并使用抗原负载树突状细胞疫苗在癌症患者中诱导治疗性抗肿瘤免疫。本研究的第一部分将探索一种新的有前途的策略来消除转移性肾癌患者（RCC）中免疫抑制的未成熟髓样抑制细胞（ImC）。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来消除其免疫抑制活性的方法。在Aim 2中，我们将通过进行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，在该研究中，RCC患者将接受递增剂量的分化剂ATRA，然后接种抗原负载DC。在Aim 3中，我们将进行彻底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。这种新方法通过直接解决晚期癌症患者的临床获益问题，可能迅速进入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NIH资助的研究经费，我与杜克大学校园内外的基础和临床科学家有广泛的合作，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。本次K24申请中的项目为年轻研究者在我的指导下进行以患者为导向的临床研究提供了清晰的路径。这些指导活动得到了杜克大学领导层的大力支持，并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.