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Stem Cell-Engineered Invariant Natural Killer T Cells for Cancer Therapy

用于癌症治疗的干细胞工程恒定自然杀伤 T 细胞

基本信息

批准号：
8758635
负责人：
Lili Yang
金额：
$ 231万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-23 至 2019-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Cancer affects tens of millions of people worldwide and is a leading threat to public health in the United States. As the new generation of cancer therapy, immunotherapy has undergone significant progress in this decade, including the successful utilization of adoptive T cell therapy and immune- modulatory drugs to treat melanoma, kidney cancer, lung cancer and leukemia. These breakthroughs mark a new era for cancer immunotherapy and set the stage for its fast expansion. Among the candidate immunotherapy agents, invariant natural killer T (iNKT) cells are especially attractive due to thei immediate and potent responses to stimulations and their capacity to target various types of cancer independent of tumor antigen restriction. However, the application of iNKT cell-based therapies has been greatly hindered by the low frequency and high variability of iNKT cells in humans (~0.001-1% in blood). Innovative approaches that can overcome these limitations are therefore desperately needed. This project aims to develop a novel iNKT cell therapy for cancer that overcomes the current limitations by genetically engineering hematopoietic stem cells (HSCs) to produce iNKT cells targeting cancer. Because of the longevity and self-renewal of HSCs, this new therapy has the potential to provide patients with therapeutic levels of engineered iNKT cells for a lifetime. In order to demonstrate this novel therapy, a proof-of-principle study using a conventional mouse model will be performed to analyze its feasibility and efficiency in targeting syngeneic mouse melanoma. To facilitate the translation of the therapy to humans, a specialized mouse model harboring the human immune system will be employed to investigate the therapeutic potential of human HSC-engineered iNKT cells against human melanoma. At the heart of this project is the concept known as SEI (stem cell- engineered immunotherapy). As the inventor of SEI and multiple other innovative immunotherapy approaches, the PI is uniquely suited to accomplish this project. The PI's demonstrated track record of productive translational research will also ensure the successful transition of this nove therapy from bench to bedside. Once established, this new therapy can be readily adapted to treat cancers other than melanoma. Moreover, although this project focuses on cancer, iNKT cells have been suggested to regulate many other human diseases, including infections such as tuberculosis, allergies such as asthma, and autoimmune diseases such as Type I diabetes and multiple sclerosis. The success of this project will thus enable the future application of stem cel-engineered iNKT cell therapy for treating many diseases and have a substantial impact on public health.

描述（由申请人提供）：癌症影响全球数千万人，是美国公共卫生的主要威胁。免疫治疗作为新一代的肿瘤治疗方法，在近十年来取得了重大进展，包括成功利用过继性T细胞治疗和免疫调节药物治疗黑色素瘤、肾癌、肺癌和白血病。这些突破标志着癌症免疫治疗的新时代，并为其快速扩展奠定了基础。在候选的免疫治疗剂中，不变的自然杀伤T（iNKT）细胞由于其对刺激的立即和有效的反应以及其不依赖于肿瘤抗原限制的靶向各种类型的癌症的能力而特别有吸引力。然而，基于iNKT细胞的疗法的应用由于iNKT细胞在人体中的低频率和高变异性（血液中约0.001-1%）而受到极大阻碍。因此，迫切需要能够克服这些限制的创新办法。该项目旨在开发一种新的iNKT细胞治疗癌症的方法，通过遗传工程改造造血干细胞（HSC）以产生靶向癌症的iNKT细胞来克服目前的局限性。由于HSC的寿命和自我更新，这种新疗法有可能为患者提供终身治疗水平的工程化iNKT细胞。为了证明这种新疗法，将使用常规小鼠模型进行原理验证研究，以分析其靶向同基因小鼠黑色素瘤的可行性和效率。为了促进将治疗转化为人类，将采用携带人类免疫系统的专门小鼠模型来研究人类HSC工程化的iNKT细胞对人类黑素瘤的治疗潜力。这个项目的核心是被称为SEI（干细胞工程免疫疗法）的概念。作为SEI和其他多种创新免疫治疗方法的发明者，PI非常适合完成这个项目。PI在生产性转化研究方面的良好记录也将确保这种新疗法从实验室到临床的成功过渡。一旦建立，这种新疗法可以很容易地适应于治疗黑色素瘤以外的癌症。此外，虽然该项目的重点是癌症，但iNKT细胞已被建议调节许多其他人类疾病，包括结核病等感染，哮喘等过敏，以及I型糖尿病和多发性硬化症等自身免疫性疾病。因此，该项目的成功将使干细胞工程iNKT细胞疗法在未来应用于治疗许多疾病，并对公共卫生产生重大影响。