New Materials to Deliver mRNA: Applications in Cancer Immunotherapy

传递 mRNA 的新材料：在癌症免疫治疗中的应用

基本信息

批准号：
10237935
负责人：
RONALD LEVY
金额：
$ 52.25万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-13 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10237935
关键词：
Address Adoptive Cell Transfers Amides Amines Animals Antigens Antitumor Response Autologous B-Lymphocytes Biometry Blocking Antibodies Cancer Model Cancer Vaccines Catalysis Cations Cell Culture Techniques Cells Charge Chemical Structure Clinic Clinical Research Collaborations Complex Confocal Microscopy Cryoelectron Microscopy Development Drug Delivery Systems Effectiveness Electroporation Engineering Evaluation Family Formulation Gene Expression Genetic Engineering Goals Human Hybrids Imaging Techniques Immune response Immune system Immunity Immunoglobulin Idiotypes Immunologist Immunology Immunotherapeutic agent Immunotherapy In Vitro Lactams Length Lipids Lymphocyte Lymphoma Malignant Neoplasms Mediating Messenger RNA Methods Microbiology Modeling Molecular Biology Molecular Immunology Morbidity - disease rate Mus Neomycin resistance gene Non-Viral Vector Organ Patients Pharmaceutical Chemistry Pre-Clinical Model Procedures Proteins RNA Research Signal Pathway Specificity Structure Synthesis Chemistry System T cell response T-Cell Lymphoma T-Cell Receptor T-Lymphocyte Technology Testing Therapeutic Tissues Toxic effect Translations Tumor-Derived Tumor-Infiltrating Lymphocytes Vaccinated Vaccination Vaccine Therapy Vaccines Variant Viral Vector animal imaging antigen-specific T cells base cancer immunotherapy cancer therapy cancer vaccination cell type chimeric antigen receptor clinical investigation clinically relevant combinatorial cytotoxicity density design disorder prevention effective therapy effectiveness evaluation effector T cell gene therapy immune checkpoint blockade immunogenicity improved in vivo interdisciplinary approach iterative design lipid nanoparticle mRNA Expression mRNA delivery mortality mouse model multidisciplinary neoantigens neoplastic cell novel novel vaccines patient population pre-clinical protein expression response tumor uptake vaccination strategy vector zeta potential

项目摘要

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.

项目摘要：癌症是全球死亡率的主要原因。这个多学科的目标项目是在链式前推进一个新颖的概念，以进行选择性和高效的mRNA传递，以实现癌症免疫疗法的高度有希望的疫苗接种策略。鉴于癌症疫苗接种的潜力两者都会产生针对肿瘤细胞的新抗原特异性T细胞反应，并扩大现有反应，癌症疫苗接种可能是一种特别有效的治疗，或者与检查点封锁。通过化学家，癌症免疫学家和生物统计学家的独特合作，我们提议仅推进这种称为Cart-RNA的方法，该方法在初步研究中产生了在患有已建立肿瘤的动物中，疗法多达80％。 mRNA和所有基于基因的疗法的关键技术挑战是发展安全，有效，可访问和选择性mRNA递送向量。这个项目利用了独特的类别改变电荷的可释放转运蛋白（手推车），将mRNA和选择性地传递到靶细胞/器官，然后细胞内通过前所未有的电荷释放机制，在细胞培养和活体动物中介导对蛋白质的异常有效翻译。这三个相互关联的特定目标是针对新型购物车的设计和评估将mRNA传递到多种细胞类型，引起功能蛋白表达并诱导治疗性免疫反应。 AIM 1利用团队的合成专业知识和配方的便利性 CART-RNA载体的评估CART化学结构，配方和配方的关系给予蛋白质表达在培养和活体动物中的效率和选择性。 AIM 2是致力于评估Cart-RNA疫苗接种以引起保护性免疫反应经过验证的癌症免疫疗法的小鼠模型。 AIM 3专注于临床前调查以引发在临床上与临床相关的抗原（特异性B-和T细胞淋巴瘤偶像）中的保护性免疫力来自人类患者的原代人细胞。该项目利用了一种整合材料设计和合成的跨学科方法，化学，微生物学，非侵入性细胞和活动物成像，免疫学和生物统计学根据新的推车开发，评估和完善策略来开发新型疫苗的新疫苗 RNA平台。将采用细胞和活动物成像技术来评估 mRNA递送和表达是小鼠给药方式的函数。这项研究会确定并阐明工程有效mRNA输送系统的设计标准和有效性基于mRNA的免疫疗法的方法。该项目针对上级的新家庭用于mRNA递送和mRNA疫苗接种的转染剂治疗和治愈癌症。