The clinical use of Flt3L - an immune adjuvant to potentiate Dendritic Cells

描述（由申请人提供）：本提案描述了一个为期5年的培训计划，用于研究性皮肤病学的学术生涯的发展。主要研究者已完成纽约大学皮肤科住院医师培训，并获得斯坦福大学医学博士/博士学位。她在基础科学研究方面有着良好的记录，并将扩大她在人类临床转化方法，临床试验设计和免疫监测测定方面的科学技能。她曾由已故的拉尔夫·斯坦曼博士指导，在他获得201诺贝尔医学奖之前，她最初与他一起形成了这个应用程序和项目。她现在将受到Michel Nussenzweig博士的密切指导，他是HHMI在适应性免疫方面的杰出研究员。 Flt 3L是一种有效的DC造血细胞生成素，可扩增小鼠中的CD 8交叉呈递树突状细胞（DC）。 研究将集中在Flt 3L作为免疫佐剂的临床开发，以扩大人类DC亚群数量，测试其对人类免疫的影响，并测试其在小鼠中的临床前疗效，当与基于蛋白质的DC靶向免疫相结合时。Flt 3L已在300多名患者中证明了安全性，但由于商业化问题，该药物的开发已停止。FDA最近解除了对Flt 3L的临床控制，因此重新评估该药物的研究可以继续进行。中心假设是Flt 3 L将动员和扩增人中的交叉呈递DC，促进上级T细胞应答。 在Provenge疗法（一种靶向前列腺癌的DC治疗疫苗）中，患者首先经历昂贵且复杂的白细胞去除术程序以获得足够的自体细胞来离体产生DC以用于疫苗接种。使用Flt 3L提供了一种替代方法，在简单注射后在体内产生充足且更生理的DC前体，作为当前白细胞分离步骤的替代。因此，这些实验可以在这种基于DC的抗癌策略中提供实质性的改进，并且还开发了产生佐剂、治疗性DC疫苗和其他组合免疫疗法的创新方法。长期目标是研究克服耐受性和提高皮肤免疫力的机制，重点是生物学方法，以加强这种应用中的特定DC。假设Flt 3L在物种间扩展交叉呈递DC当量，并且可以用作佐剂。 该假设将通过追求2个特定目标进行测试，以（1）用Flt 3L在人体中建立和分析CD 8 β等同物，并比较人DC亚群功能，并评估Flt 3L治疗后从头和回忆免疫应答的变化（2）评估Flt 3L与人用佐剂偶联时是否改善免疫力，以及小鼠中的DC靶向免疫，允许体内靶向而无需白细胞去除。它是创新的，因为使用Flt 3L以增强人交叉呈递DC，目标是DC亚群靶向是新颖的，它使用先进的免疫方法，用申请人实验室开发的基于蛋白质的疫苗靶向DC，目前正在人体中测试。该培训计划旨在确保掌握树突状细胞生物学，应用于免疫治疗和佐剂设计，以改善健康和免疫力。Michel Nussenzweig教授将指导主要研究者的科学发展。Nussenzweig博士是DC开发、靶向和适应性免疫领域的主要领导者。他与斯坦曼博士的合作使人们对耐受性和免疫力的控制有了新的认识。Nussenzweig博士指导了许多初级和高级教师。培训活动将通过在正式的临床转化计划中的高级免疫学和转化生物学的重点教学来加强。一个由杰出的医生科学家组成的科学咨询委员会将提供科学和职业建议。洛克菲勒大学的细胞生理学和免疫学以及分子免疫学实验室是解决临床免疫学复杂领域所需的实验室和转化科学技能强化培训的理想场所。这种环境将为研究性皮肤病学的学术生涯做好准备，在那里她将解决免疫佐剂在提高皮肤免疫力和预防和治疗皮肤癌中的作用。

DESCRIPTION (provided by applicant): This proposal describes a 5-year training program for the development of an academic career in Investigative Dermatology. The principle investigator has completed a residency in Dermatology from New York University and her MD/PhD from Stanford University. She has a strong track record of basic science research and will expand her scientific skills in human clinical translational methods, clinical trial design, and immuno-monitoring assays. She was previously mentored by the late Dr. Ralph Steinman, prior to his receipt of the 201 Nobel Prize in Medicine and with whom she initially formed this application and project. She will now be mentored closely by Dr. Michel Nussenzweig now- an outstanding HHMI investigator in adaptive immunity. Flt3L, a potent DC hematopoietin, expands CD8 cross-presenting dendritic cells (DC) in mice. Research will focus on the clinical development of Flt3L as an immune adjuvant to expand DC subset numbers in humans, testing its impact on immunity in humans and testing its preclinical efficacy in mice, when combined with protein-based DC targeted immunization. Flt3L has demonstrated safety in over 300 patients, but development of this agent was ceased due to commercialization issues. The FDA has recently lifted a clinical hold on Flt3L so studies to re-evaluate this agent can continue. The central hypothesis is that Flt3L will mobilize and expand cross-presenting DCs in humans, promoting superior T cell responses. In Provenge therapy (a DC therapeutic-vaccine targeted against prostate cancer), patients first undergo an expensive and complex leukapheresis procedure to obtain sufficient autologous cells to generate the DCs ex vivo to use for the vaccination. Using Flt3L offers an alternative approach to generate ample and more physiological DC precursors in vivo after simple injection, as a substitute for the current leukapheresis step. Thus these experiments may offer substantial improvement in such a DC-based anti-cancer strategy, and also develop an innovative approach to generating adjuvants, therapeutic DC-vaccines, and other combinatorial immunotherapy. The long-term goal is to investigate mechanisms to overcome tolerance and improve cutaneous immunity, focusing on biologic methods to potentiate particular DC in this application. The hypothesis is that Flt3L expands cross-presenting DC equivalents across species and can be used as an adjuvant. This hypothesis will be tested by pursuing 2 specific aims to (1) establish and profile CD8� equivalents in humans with Flt3L and compare human DC subset functions and assess alterations in de novo and recall immune responses after Flt3L treatment (2) assess whether Flt3L improved immunity when coupled to adjuvants for human use and DC targeted immunization in mice, that allow in vivo targeting without leukophoresis. It is innovative because the use of Flt3L to potentiate human cross-presenting DC with the goal of DC subset targeting is novel~ it uses advanced immunization methods to target DC with protein-based vaccines developed in the applicant's laboratory, and currently being tested in humans. The training program has been designed to ensure a command of dendritic cell biology as applied to immunotherapy and adjuvant design towards improved health and immunity. Prof. Michel Nussenzweig will mentor the principle investigator's scientific development. Dr. Nussenzweig is a key leader of the DC development, targeting, and leads the adaptive immune field. His work with Dr. Steinman has led to a new understanding of the control of tolerance and immunity. Dr. Nussenzweig has mentored numerous junior and senior faculty members. Training activities will be enhanced through focused instruction in advanced immunology and translational biology in a formal clinical translational program. A scientific advisory committee, composed of exceptional physician scientists, will provide scientific and career advice. The Laboratories of Cellular Physiology and Immunology and Molecular Immunology at Rockefeller University are the ideal setting for intensive training in bench and translational science skills required to address a complex area of clinical immunology. This environment will prepare the principle investigator for an academic career in investigative dermatology where she will address a role for immune adjuvants in improving cutaneous immunity and the prevention and treatment of skin cancers.