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。这个多学科的目标 该项目是在临床前提出一种选择性和有效的mRNA递送的新概念， 非常有前途的癌症免疫治疗疫苗接种策略。鉴于癌症疫苗接种的潜力 为了产生针对肿瘤细胞的新的抗原特异性T细胞应答并扩增现有的应答， 癌症疫苗接种本身或与，例如，检查- 封锁点通过化学家、癌症免疫学家和生物统计学家的独特合作， 我建议推进这样一种称为CART-RNA的方法，在初步研究中， 治愈率高达80%的动物与建立肿瘤。 mRNA和所有基于基因的疗法的关键技术挑战是开发 安全、有效、可获得和选择性的mRNA递送载体。这个项目利用了一个独特的类， 电荷改变可释放转运体（CART），其复合、保护和选择性地将mRNA递送至 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 在细胞培养物和活体动物中，它都能介导异常有效的蛋白质翻译。 这三个相互关联的具体目标是针对新型CART的设计和评估， 将mRNA递送到多种细胞类型，引发功能性蛋白质表达，并诱导治疗性细胞因子。 免疫反应。目标1利用了团队的合成专业知识和易于制定 的CART-RNA载体，以评估CART化学结构，配方和 本发明提供了一种用于在培养物和活动物中提高蛋白质表达的效率和选择性的方法。目标二是 目的是评价CART-RNA疫苗接种以引发保护性免疫应答， 用于癌症免疫治疗的有效小鼠模型。目标3侧重于临床前研究，以引出 针对临床相关抗原（特别是B和T细胞淋巴瘤独特型）的保护性免疫， 人类患者的原代细胞 该项目利用了一种跨学科的方法，将材料设计和合成， 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、评估和完善基于新CART的新型疫苗开发战略， RNA平台。将采用细胞和活体动物成像技术来评估 在小鼠中，mRNA递送和表达都是给药方式的函数。这项研究将 确定并阐明设计有效mRNA传递系统的设计标准， 基于mRNA的免疫治疗方法。这个项目是针对新的家庭的上级 用于治疗和治愈癌症的mRNA递送和mRNA疫苗接种的抑制剂。

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.