New Materials to Deliver mRNA: Applications in Cancer Immunotherapy

项目概述：癌症是全球主要的死亡原因。这一多学科的目标是 项目是在临床前提出一种选择性和高效的信使核糖核酸传递的新概念，使 非常有希望的癌症免疫治疗的疫苗接种策略。考虑到癌症疫苗接种的潜力 为了既产生新的针对肿瘤细胞的抗原特异性T细胞反应，又放大现有的反应， 癌症疫苗接种本身或与检查相结合，可能是一种特别有效的治疗方法。 点封锁。通过化学家、癌症免疫学家和生物统计学家的独特合作，我们 提出了一种称为CART-RNA的方法，该方法在初步研究中已经产生了 在已有肿瘤的动物身上，治愈率高达80%。 对于mRNA和所有基于基因的疗法来说，关键的技术挑战是开发 安全、有效、可获得和选择性的信使核糖核酸载体。该项目利用了一类独特的 电荷可变的可释放转运体(CART)，它复杂、保护并选择性地将mRNA输送到 靶向细胞/器官，然后通过前所未有的电荷改变在细胞内释放mRNA 机制，在细胞培养和活体动物中非常有效地调节蛋白质的翻译。 这三个相互关联的具体目标针对的是设计和评估 将信使核糖核酸传递给各种类型的细胞，诱导功能性蛋白表达，并诱导治疗性 免疫反应。AIM 1利用团队的综合专业知识和易于制定 评估CART-RNA载体的化学结构、配方和 对培养和活体动物中蛋白质表达的效率和选择性进行管理。目标2是 目的评价CART-RNA疫苗诱导小鼠保护性免疫应答的效果 用于癌症免疫治疗的有效的小鼠模型。目标3侧重于临床前研究，以引发 对临床相关抗原(特别是B细胞和T细胞淋巴瘤独特型)的保护性免疫 来自人类病人的原代人类细胞。 这个项目采用了一种整合了材料设计和合成的跨学科方法， 化学、微生物学、非侵入性细胞和活体动物成像、免疫学和生物统计学 开发、评估和改进基于新CART的新型疫苗开发战略-- RNA平台。将使用细胞和活体动物成像技术来评估 在小鼠中，信使核糖核酸的传递和表达作为给药方式的函数。这项研究将 确定并阐明工程上有效的信使核糖核酸传递系统的设计标准和有效性 以信使核糖核酸为基础的免疫治疗方法。这个项目是针对新的上级家庭的 用于治疗和治疗癌症的信使核糖核酸载体和信使核糖核酸疫苗。

Project Summary: Cancer is a leading global cause of mortality. The goal of this multi-disciplinary project is to pre-clinically advance a novel concept for selective and efficient mRNA delivery that enables a highly promising vaccination strategy for cancer immunotherapy. Given the potential of cancer vaccination to both generate new antigen-specific T cell responses against tumor cells and amplify existing responses, cancer vaccination could be an especially effective therapy on its own or in combination with, e.g., check- point blockade. Through a unique collaboration of chemists, cancer immunologists and biostatisticians we propose to advance just such a method called CART-RNA which in preliminary studies has produced cures of up to 80% in animals with established tumors. The critical technological challenge for mRNA and all gene-based therapies is the development of safe, effective, accessible and selective mRNA delivery vectors. This project exploits a unique class of charge-altering releasable transporters (CARTs) that complex, protect and selectively deliver mRNA to target cells/organs and then release mRNA intracellularly through an unprecedented charge-altering mechanism, mediating exceptionally effective translation to proteins both in cell culture and in live animals. The three interrelated specific aims are directed at the design and evaluation of novel CARTs that deliver mRNA to a variety of cell types, elicit functional protein expression, and induce a therapeutic immunological response. Aim 1 leverages the synthetic expertise of the team and the ease of formulation of CART-RNA vectors to assess the relationship of CART chemical structure, formulation and administration to the efficiency and selectivity of protein expression in culture and in live animals. Aim 2 is directed at the evaluation of CART-RNA vaccination to elicit protective immunological responses in validated mouse models for cancer immunotherapy. Aim 3 focuses on pre-clinical investigations to elicit protective immunity against clinically-relevant antigens (specifically B- and T-cell lymphoma idiotypes) in primary human cells from human patients. This project exploits an interdisciplinary approach that integrates materials design and synthesis, chemistry, microbiology, non-invasive cellular and live animal imaging, immunology and biostatistics to develop, evaluate and refine strategies for the development of novel vaccines based on the new CART- RNA platform. Cellular and live animal imaging techniques will be employed to assess the efficiency of both mRNA delivery and expression as a function of mode of administration in mice. This research will identify and clarify design criteria for engineering effective mRNA delivery systems and the effectiveness of mRNA-based approaches for immunotherapy. This project is directed at new families of superior transfecting agents for mRNA delivery and mRNA vaccination for treating and curing cancer.