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

描述（由申请人提供）：癌症影响着全世界数千万人，是美国公众健康的主要威胁。免疫治疗作为新一代的癌症治疗方法，近十年来取得了重大进展，包括成功利用过继T细胞疗法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进入了一个新时代，并为其快速发展奠定了基础。在候选的免疫治疗药物中，不变性自然杀伤T （iNKT）细胞特别有吸引力，因为它们对刺激的反应迅速而有效，并且它们能够独立于肿瘤抗原限制靶向各种类型的癌症。然而，iNKT细胞在人体中的低频率和高变异性（血液中约0.001-1%）极大地阻碍了基于iNKT细胞的治疗的应用。因此，迫切需要能够克服这些限制的创新方法。该项目旨在开发一种新的iNKT细胞治疗癌症，克服目前的局限性，通过基因工程造血干细胞（hsc）产生靶向癌症的iNKT细胞。由于造血干细胞的寿命和自我更新，这种新疗法有可能为患者提供终身治疗水平的工程iNKT细胞。为了证明这种新疗法，将使用传统的小鼠模型进行原理验证研究，以分析其针对同基因小鼠黑色素瘤的可行性和效率。为了便于将该疗法应用于人类，研究人员将利用一种包含人类免疫系统的特殊小鼠模型来研究人类造血干细胞工程iNKT细胞对人类黑色素瘤的治疗潜力。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在富有成效的转化研究方面的良好记录也将确保这种新疗法从实验室成功过渡到床边。一旦确立，这种新疗法可以很容易地用于治疗黑色素瘤以外的癌症。此外，尽管这个项目的重点是癌症，iNKT细胞已经被认为可以调节许多其他人类疾病，包括感染，如肺结核，过敏，如哮喘，以及自身免疫性疾病，如I型糖尿病和多发性硬化症。因此，该项目的成功将使干细胞工程iNKT细胞疗法在未来的应用能够治疗许多疾病，并对公共卫生产生重大影响。

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.