Engineering Nanomaterials to Prime Immunity

摘要 开发具有治疗效果的癌症疫苗技术一直是一个难以实现的目标。 常规佐剂诱导弱水平的细胞毒性CD8+T淋巴细胞(CTL)反应，而 越来越多的证据表明，需要同时进行CTL和抗体(Ab)反应才能有效 心理治疗。因此，迫切需要能够实现强大抗肿瘤作用的替代方法。 免疫反应。我们的长期研究目标是开发新的基于材料的策略，以实现 免疫刺激，对癌症有强大的治疗效果。我们在此R01应用程序中的目标是 描述设计有效纳米疫苗的关键纳米材料标准，并利用所获得的知识 从这些研究中开发出治疗原发和转移性肿瘤的强大疫苗技术 黑色素瘤。为此，我们开发了一种新的纳米疫苗系统，它可以(A)有效地运送 抗原(Ag)与树突状细胞(DC)；(B)促进T细胞的抗原交叉提呈和交叉激发；(C) 与基于DC的传统疫苗相比，产生明显更强的抗原特异性CD8+T细胞反应， 其他纳米制剂和临床试验中的实验佐剂；(D)加强抗肿瘤药物的积累 肿瘤微环境中的T细胞；以及(E)诱导针对原发和转移的抗肿瘤免疫 黑色素瘤，以生物相容和安全的方式。在本应用程序中，我们建议解决以下问题 问：我们的纳米疫苗有什么独特的特点，可以激发如此强大的抗肿瘤免疫力， 与其他传统癌症疫苗相比？我们能否反过来调节这些参数以进一步 优化我们的纳米疫苗技术，放大抗肿瘤免疫？我们将评估我们的 局部和全身播散性黑色素瘤小鼠模型的策略。我们的创新方法 利用材料科学、生物工程和免疫学的跨学科原理将导致一种新的 疫苗纳米技术，可消除原发和转移性黑色素瘤并改善癌症 免疫疗法。

Abstract Development of vaccine technologies with therapeutic efficacy against cancer has been an elusive goal. Conventional adjuvants induce weak levels of cytotoxic CD8+ T lymphocyte (CTL) responses, while accumulating evidence suggests that simultaneous CTL and antibody (Ab) responses are needed for effective therapy. Therefore, there is a critical need for alternative approaches that can achieve strong anti-tumor immune responses. Our long-term research goal is to develop new material-based strategies that can achieve immune stimulation with potent therapeutic efficacy against cancer. Our objective in this R01 application is to delineate the key nanomaterial criteria for designing effective nano-vaccines and to utilize knowledge gained from these studies to develop a powerful vaccine technology for treatment of primary and metastatic melanomas. To that end, we have developed a novel nano-vaccine system that can (a) efficiently transport antigen (Ag) to dendritic cells (DCs); (b) promote Ag cross-presentation and cross-priming of T-cells; (c) generate significantly stronger Ag-specific CD8+ T-cell responses than conventional vaccines based on DCs, other nano-formulations, and experimental adjuvants in clinical trials; (d) enhance accumulation of anti-tumor T-cells in tumor microenvironment; and (e) induce anti-tumor immunity against primary and metastatic melanomas, in a biocompatible and safe manner. In this application, we propose to address the following questions: what are unique characteristics of our nano-vaccines that evoke such strong anti-tumor immunity, compared with other traditional cancer vaccines? Can we in turn modulate these parameters to further optimize our nano-vaccine technology and amplify anti-tumor immunity? We will evaluate outcomes of our strategy in murine models of locally and systemically disseminated melanomas. Our innovative approach employing interdisciplinary principles of materials science, bioengineering, and immunology will lead to a new vaccine nanotechnology that may eliminate primary and metastatic melanomas and improve cancer immunotherapy.