CAREER: Engineering Molecular Adjuvants for Cancer Vaccines

项目编号：1750607疫苗是一种生物物质，代表了不需要的细菌/疾病的非活性形式。当一个人接种了疫苗（通过注射、鼻腔或口腔），身体的免疫系统就会学会如何通过产生适当的抗体来对抗这种无害的疾病。然后，身体就会“记住”细菌，并在下一次攻击发生时需要采取什么措施。为了获得临床效益，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效的“佐剂”，这是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量，从而提高了疫苗的安全性。尽管各种各样的佐剂都是可用的，并且在实验室实验中已被证明可以激活免疫细胞，但只有少数达到了临床阶段。有效性和安全性问题是限制许多佐剂转化为临床环境的主要挑战。为了增强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“理性分子设计”，这是一种基于使用物理模型预测分子结构如何影响其行为的能力来创造具有所需功能的新分子的策略。该项目将构建一系列化学修饰的免疫反应调节剂（IRMs），并定义基于分子结构的设计规则，以控制佐剂-免疫系统在组织、细胞和亚细胞水平上的相互作用。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，并促进下一代癌症疫苗分子佐剂的设计。从这些研究中获得的结果可应用于癌症以外需要辅助效力和安全性的疫苗。此外，该研究将直接整合到教育项目中，包括增强聚合物工程研究生证书课程，以吸引未被充分代表的少数民族在免疫生物工程新兴领域的兴奋和职业机会。本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分子佐剂的重要方面的基本见解，这些佐剂用于治疗性癌症疫苗，既安全又能克服肿瘤相关的免疫抑制。尽管在体外有效，但大多数佐剂不具备激活淋巴结（LNs）中抗原提呈细胞（APCs）所需的物理化学和药代动力学特性，而淋巴结是抗肿瘤免疫启动的解剖部位。一组涉及合成化学和免疫学的综合研究旨在增强两种具有代表性的免疫反应调节剂（IRMs）的辅助功能和安全性。一系列针对淋巴结的irm将被构建并用于定义基于分子结构的设计规则，这些规则控制佐剂-免疫系统在组织、细胞和亚细胞水平上的相互作用。研究目标是：1)合成具有pH敏感连接体的ln靶向免疫应答调节剂（IRMs），并定义基于结构的设计规则，通过“白蛋白搭车”（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控制淋巴结积聚；2)通过结合以ln为靶点的IRMs和以ln为靶点的富含胸腺嘧啶的寡核苷酸来增强T细胞免疫的强度和功能；3)确定这种定位IRMs方法在癌症治疗中的功能和安全性影响。疫苗的预防效果（在注射产生OVA-B16F10细胞的黑色素瘤之前）和治疗效果（在黑色素瘤形成后）将在C57BL/6小鼠中进行评估。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.