CAREER: Engineering Molecular Adjuvants for Cancer Vaccines

职业：工程癌症疫苗分子佐剂

• 批准号: 1750607
• 负责人: Haipeng Liu
• 金额: $ 53.94万
• 依托单位: Wayne State University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1750607&HistoricalAwards=false
• 关键词: CAREER; Engineering; Molecular; Adjuvants; Cancer

PI: Liu, HaipengProposal #: 1750607Vaccines are biological substances that represent inactive forms of unwanted germs/diseases. When a person is inoculated with a vaccine (by injection, nose or mouth) the body's immune system learns how to confront the harmless version of the disease by creating appropriate antibodies. The body then "remembers" the germ and what is required should another attack occur. To achieve clinical benefits, since tumors use many strategies to suppress the body's immune system, therapeutic cancer vaccines must include strong "adjuvants," which are substances that are added to vaccines to improve the body's immune response to the vaccine. The use of adjuvants decreases the amount of vaccine needed to overcome the tumor-related immune suppression, which improves vaccine safety. Though a wide variety of adjuvants are available and have been shown to activate immune cells in laboratory experiments, only a few have reached the clinical stage. Effectiveness and safety concerns are the major challenges that have limited the translation of many adjuvants to the clinical setting. To amplify the effectiveness and safety of two representative molecular adjuvants, this project uses "rational molecular design," which is a strategy for creating new molecules with a desired functionality, based upon having the ability to use physical models to predict how the molecule's structure will affect its behavior. The PI will construct a series of chemically modified immune response modifiers (IRMs) and define the molecular structure-based design rules governing the adjuvant-immune system interactions at the tissue, cellular, and subcellular levels. The knowledge gained through these efforts will bridge the gap between synthetic chemistry and immunology, and give rise to the design of the next generation of molecular adjuvants for cancer vaccines. The results obtained from these studies can be applied to vaccines other than cancer, where adjuvant efficacy and safety are needed. In addition, the research will be directly integrated into educational programs, including enhancement of the Graduate Certificate Program in Polymer Engineering, with the goal of attracting underrepresented minorities to the excitement and career opportunities in the emerging field of immunobioengineering.This project focuses on integrating molecular engineering and immunology to gain fundamental insight into important aspects of how to rationally design molecular adjuvants for therapeutic cancer vaccines that are safe and can overcome tumor related immune suppression. Although potent in vitro, most adjuvants do not have the desired physiochemical and pharmacokinetic properties to activate antigen presenting cells (APCs) in lymph nodes (LNs), the anatomical sites where the anti-tumor immunity is initiated. A comprehensive set of studies involving synthetic chemistry and immunology has been designed to amplify the adjuvant function and safety of two representative immune response modifiers (IRMs). A series of lymph node targeting IRMs will be constructed and used to define the molecular structure-based design rules governing the adjuvants-immune system interactions at the tissue, cellular, and subcellular levels. The research objectives are: 1) To synthesize LN-targeting immune response modifiers (IRMs) with a pH sensitive linker and define the structure-based design rules that govern lymph node accumulation via "albumin-hitchhiking" (adjuvants bind to endogenous albumin protein and transport to lymph nodes), immune cell uptake and activation; 2) To amplify the magnitude and function of the T cell immunity by combining LN-targeting IRMs and an LN-targeting, thymidine-rich oligonucleotide and 3) To establish the functional and safety impact of this localized IRMs approach in therapeutic treatment of cancer. Vaccine efficacy, both prophylactic (prior to injection of melanoma producing OVA-B16F10 cells) and therapeutic (after melanoma establishment), will be evaluated in C57BL/6 mice.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

PI：刘，海鹏提案#：1750607疫苗是代表有害细菌/疾病的非活性形式的生物物质。当一个人接种疫苗(通过注射、鼻子或口腔)时，身体的免疫系统会学习如何通过产生适当的抗体来对抗无害的疾病。然后，身体会“记住”细菌，并在再次发作时需要做些什么。为了达到临床效果，由于肿瘤使用许多策略来抑制人体的免疫系统，治疗性癌症疫苗必须包括强大的“佐剂”，即添加到疫苗中的物质，以提高人体对疫苗的免疫反应。佐剂的使用减少了克服肿瘤相关免疫抑制所需的疫苗数量，从而提高了疫苗的安全性。尽管有各种各样的佐剂可用，并且在实验室实验中被证明可以激活免疫细胞，但只有少数几种佐剂已经进入临床阶段。有效性和安全性问题是限制许多佐剂转化到临床环境的主要挑战。为了扩大两种具有代表性的分子佐剂的有效性和安全性，该项目使用了“合理的分子设计”，这是一种创造具有所需功能的新分子的策略，其基础是能够使用物理模型来预测分子结构将如何影响其行为。PI将构建一系列化学修饰的免疫反应修饰物(IRMS)，并定义基于分子结构的设计规则，控制组织、细胞和亚细胞水平上的佐剂-免疫系统相互作用。通过这些努力获得的知识将弥合合成化学和免疫学之间的差距，并产生下一代癌症疫苗分子佐剂的设计。这些研究的结果可以应用于癌症以外的疫苗，因为这些疫苗需要佐剂的有效性和安全性。此外，这项研究将被直接整合到教育项目中，包括增强聚合物工程研究生证书计划，目标是吸引未被充分代表的少数群体对新兴免疫生物工程领域的兴奋和职业机会感兴趣。该项目专注于整合分子工程和免疫学，以获得关于如何合理设计安全且能够克服肿瘤相关免疫抑制的治疗性癌症疫苗的分子佐剂的重要方面的基本见解。虽然在体外有效，但大多数佐剂并不具有所需的物理化学和药代动力学特性来激活淋巴(LNS)中的抗原提呈细胞(APC)，LNS是启动抗肿瘤免疫的解剖部位。一系列涉及合成化学和免疫学的综合研究已被设计用于放大两种具有代表性的免疫反应修饰剂(IRMS)的佐剂功能和安全性。将构建一系列以淋巴结为靶向的IRMS，并用于定义基于分子结构的设计规则，该规则在组织、细胞和亚细胞水平上控制佐剂-免疫系统的相互作用。研究的目标是：1)合成具有pH敏感连接子的LN靶向免疫反应修饰物(IRMS)，并确定基于结构的设计规则，这些设计规则通过“白蛋白搭便车”(佐剂与内源性白蛋白蛋白结合并运输到淋巴结)、免疫细胞摄取和激活来调控淋巴结聚集；2)通过将LN靶向IRMS与LN靶向、胸腺嘧啶核苷丰富的寡核苷酸相结合，放大T细胞免疫的大小和功能；3)建立这种局部IRMS方法在癌症治疗中的功能和安全性影响。疫苗的效力，无论是预防性的(在注射产生黑色素瘤的OVA-B16F10细胞之前)和治疗性的(在黑色素瘤建立后)，都将在C57BL/6小鼠中进行评估。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Long-Circulating Amphiphilic Doxorubicin for Tumor Mitochondria-Specific Targeting

• DOI: 10.1021/acsami.8b17399
• 发表时间: 2018-12-19
• 期刊: ACS APPLIED MATERIALS & INTERFACES
• 影响因子: 9.5
• 作者: Xi, Jingchao;Li, Meng;Liu, Haipeng
• 通讯作者: Liu, Haipeng