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：
10394950
负责人：
RONALD LEVY
金额：
$ 51.24万
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/10394950
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 RNA vaccination 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 delivery vehicle 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：癌症是全球主要的死亡原因。这一多学科的目标该项目的目的是在临床前推进一种选择性和高效 mRNA 递送的新概念，使癌症免疫治疗的非常有前途的疫苗接种策略。鉴于癌症疫苗接种的潜力产生针对肿瘤细胞的新抗原特异性 T 细胞反应并放大现有反应，癌症疫苗接种可能是一种特别有效的治疗方法，单独使用或与其他方法结合使用，例如：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，我们建议推进一种称为 CART-RNA 的方法，该方法在初步研究中已产生对于患有已形成肿瘤的动物，治愈率高达 80%。 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、可获取和选择性的 mRNA 递送载体。该项目利用了一类独特的电荷改变可释放转运蛋白 (CART)，可复合、保护并选择性地将 mRNA 递送至靶细胞/器官，然后通过前所未有的电荷改变在细胞内释放 mRNA 机制，在细胞培养物和活体动物中介导异常有效的蛋白质翻译。这三个相互关联的具体目标旨在设计和评估新颖的 CART，将 mRNA 递送至多种细胞类型，引发功能性蛋白表达，并诱导治疗免疫反应。目标 1 利用团队的综合专业知识和配方的简易性 CART-RNA 载体，以评估 CART 化学结构、配方和管理对培养物和活体动物中蛋白质表达的效率和选择性的影响。目标 2 是旨在评估 CART-RNA 疫苗接种以引发保护性免疫反应验证了癌症免疫治疗的小鼠模型。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 细胞和 T 细胞淋巴瘤独特型）的保护性免疫来自人类患者的原代人类细胞。该项目采用跨学科方法，整合材料设计和合成，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制定、评估和完善基于新 CART- 的新型疫苗开发策略 RNA平台。将采用细胞和活体动物成像技术来评估效率 mRNA 递送和表达均作为小鼠给药模式的函数。这项研究将确定并阐明设计有效 mRNA 传递系统的设计标准及其有效性基于 mRNA 的免疫治疗方法。该项目针对的是新的优越家庭用于治疗和治愈癌症的 mRNA 递送和 mRNA 疫苗接种的转染剂。