CAREER: Engineering Molecular Adjuvants for Cancer Vaccines

PI：Liu，Haipeng提案编号：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，鼻或口）时，身体的免疫系统通过产生适当的抗体来学习如何对抗疾病的无害版本。 然后身体“记住”细菌，以及如果发生另一次攻击所需要的东西。 为了获得临床效益，由于肿瘤使用许多策略来抑制人体免疫系统，治疗性癌症疫苗必须包含强“佐剂”，即添加到疫苗中以提高人体对疫苗免疫反应的物质。 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。虽然有各种各样的佐剂可供使用，并已在实验室实验中显示出激活免疫细胞，但只有少数已经达到临床阶段。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。为了增强两种代表性分子佐剂的有效性和安全性，该项目使用“理性分子设计”，这是一种创造具有所需功能的新分子的策略，基于使用物理模型预测分子结构如何影响其行为的能力。PI将构建一系列化学修饰的免疫反应调节剂（IRM），并定义基于分子结构的设计规则，在组织、细胞和亚细胞水平上控制免疫系统相互作用。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。从这些研究中获得的结果可以应用于癌症以外的疫苗，其中需要佐剂功效和安全性。此外，该研究将直接融入教育计划，包括加强高分子工程研究生证书课程，该项目的目标是吸引未被充分代表的少数民族在新兴的免疫生物工程领域的兴奋和职业机会。该项目的重点是整合分子工程和免疫学，以获得如何合理设计分子佐剂的重要方面的基本见解，治疗性癌症疫苗是安全的，可以克服肿瘤相关的免疫抑制。 尽管在体外是有效的，但大多数佐剂不具有所需的生理化学和药代动力学特性来激活淋巴结（LN）中的抗原呈递细胞（APC），淋巴结是抗肿瘤免疫起始的解剖部位。一系列涉及合成化学和免疫学的综合研究旨在增强两种代表性免疫应答调节剂（IRMs）的佐剂功能和安全性。将构建一系列淋巴结靶向IRM，并用于定义基于分子结构的设计规则，这些规则在组织、细胞和亚细胞水平上控制免疫剂-免疫系统相互作用。研究目标是：1）合成具有pH敏感性接头的LN靶向免疫应答调节剂（IRMs），并定义基于结构的设计规则，其通过“白蛋白搭便车”控制淋巴结积聚。（佐剂与内源性白蛋白结合并转运至淋巴结）、免疫细胞摄取和活化; 2）通过将LN靶向的IRM和LN靶向的IRM组合来放大T细胞免疫的大小和功能，3）确定这种局部IRMs方法在癌症治疗性治疗中的功能和安全性影响。 将在C57 BL/6小鼠中评估疫苗的预防性（在注射产生黑色素瘤的OVA-B16 F10细胞之前）和治疗性（在黑色素瘤建立之后）效力。该奖项反映了NSF的法定使命，并被认为值得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来支持。

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.