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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：
10620636
负责人：
RONALD LEVY
金额：
$ 51.5万
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/10620636
关键词：
Address Adoptive Cell Transfers Amides Amines Animals Antigens Antitumor Response Autologous B-Lymphocytes Biometry Blocking Antibodies Cancer Vaccines Catalysis Cell Culture Techniques Cells Charge Chemical Structure Chemistry Clinic Clinical Research Collaborations Complex Confocal Microscopy Cryoelectron Microscopy Development Drug Delivery Systems Effectiveness Electroporation Engineering Evaluation Family Formulation Gene Expression Genetic Engineering Genetic Transcription Goals Human Hybrids Imaging Techniques Immune response Immune system Immunity Immunoglobulin Idiotypes Immunologist Immunology Immunotherapeutic agent Immunotherapy In Vitro Investigation 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 System T cell response T-Cell Lymphoma T-Cell Receptor T-Lymphocyte Technology Testing Therapeutic Tissues Toxic effect Transfection Translations Tumor-Infiltrating Lymphocytes Vaccinated Vaccination Vaccine Therapy Vaccines Variant Viral Vector animal imaging antigen-specific T cells cancer immunotherapy cancer therapy cancer vaccination cell type chimeric antigen receptor 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，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。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Lysine-Derived Charge-Altering Releasable Transporters: Targeted Delivery of mRNA and siRNA to the Lungs.

赖氨酸衍生的电荷改变可释放转运蛋白：将 mRNA 和 siRNA 定向递送至肺部。

DOI：
10.1021/acs.bioconjchem.3c00019
发表时间：
2023
期刊：
Bioconjugate chemistry
影响因子：
4.7
作者：
Blake,TimothyR;Haabeth,OleAW;Sallets,Adrienne;McClellan,RebeccaL;DelCastillo,TrevorJ;Vilches-Moure,JoseG;Ho,WilsonC;Wender,PaulA;Levy,Ronald;Waymouth,RobertM
通讯作者：
Waymouth,RobertM

Circular RNA vaccine induces potent T cell responses.

DOI：
10.1073/pnas.2302191120
发表时间：
2023-05-16
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
影响因子：
11.1
作者：
Amaya, Laura;Grigoryan, Lilit;Li, Zhijian;Lee, Audrey;Wender, Paul A.;Pulendran, Bali;Chang, Howard Y.
通讯作者：
Chang, Howard Y.

Fingolimod-Conjugated Charge-Altering Releasable Transporters Efficiently and Specifically Deliver mRNA to Lymphocytes In Vivo and In Vitro.

DOI：
10.1021/acs.biomac.2c00469
发表时间：
2022-07-11
期刊：
BIOMACROMOLECULES
影响因子：
6.2
作者：
Testa, Stefano;Haabeth, Ole A. W.;Blake, Timothy R.;Del Castillo, Trevor J.;Czerwinski, Debra K.;Rajapaksa, Ranjani;Wender, Paul A.;Waymouth, Robert M.;Levy, Ronald
通讯作者：
Levy, Ronald