Kinetic Assembly of Polymer-mRNA Nanoparticles Targets Circulating Monocytes to Enhance Cancer Immunotherapy

聚合物-mRNA纳米颗粒的动力学组装靶向循环单核细胞以增强癌症免疫治疗

基本信息

批准号：
10681055
负责人：
Jordan Green
金额：
$ 56.1万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-23 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10681055
关键词：
Adjuvant Advanced Malignant Neoplasm Animal Model Antigen-Presenting Cells Antigens Antitumor Response Biodistribution Bone Marrow COVID-19 Cancer Vaccines Cells Chemical Structure Chemistry Circulation Deposition Disseminated Malignant Neoplasm Dose Drug Kinetics Engineering Esters Formulation Freeze Drying Generations Homing Immune Immune checkpoint inhibitor Immune response Immune system Immunologic Adjuvants Immunotherapeutic agent Immunotherapy Infiltration Kinetics Ligands Mediating Messenger RNA Methodology Methods Modeling Mus Patients Peripheral Polymers Population Procedures Production Property RNA vaccine Reporter Role STING agonists Safety Solid Neoplasm Spleen Standardization Structure-Activity Relationship Surface T-Cell Activation Testing Time Tissues Training Transfection Treatment Efficacy Tumor Antigens Tumor Tissue Vaccines anti-tumor immune response biomaterial compatibility cancer immunotherapy combinatorial design efficacy validation experience gene therapy immune activation improved in vivo innovation intravenous injection lymph nodes mRNA delivery manufacturing scale-up melanoma monocyte mouse model nanomedicine nanoparticle nanoparticle delivery neoantigens plasmid DNA polycation programs rational design response secondary lymphoid organ success targeted delivery therapeutic target trafficking tumor tumor growth tumor microenvironment vaccine platform

项目摘要

PROJECT SUMMARY Cancer vaccines have significantly advanced cancer immunotherapy; and recent successes of mRNA vaccines have raised prospect of generating potent anti-tumor response by specifically delivering mRNAs encoding tumor-associated antigens to antigen presenting cells (APCs). However, APC activation elicited by nanoparticles containing antigen mRNAs is rather limited. Circulating monocytes offer a promising cell target as an abundant APC precursor that can be deposited to spleen, lymph nodes, and tumor tissue following polarization and activation. The overall objective of this study is to engineer kinetically assembled poly(beta- amino ester) (PBAE) /mRNA nanoparticles (KaNPs) that can specifically deliver mRNAs encoding tumor antigens and immunoadjuvants into circulating monocytes in vivo and demonstrate the safety and efficacy of this new mRNA cancer vaccine platform. This study is built on the preliminary results showing biodegradable PBAE/mRNA KaNPs with an optimized size of 400 nm mediated preferential transfection of circulating monocytes following intravenous (i.v.) injection, leading to more effective transfection and deposition of circulating monocytes and a higher level of tumor-killing activity compared to the standard small size PBAE/mRNA nanoparticles. In this proposed study, we plan to pursue four specific aims: (1) optimize the composition, size, and surface functionality of PBAE/mRNA KaNPs to improve targeted mRNA delivery efficiency into circulating monocytes in vivo, (2) characterize pharmacokinetic profile of PBAE/mRNA KaNPs and define functions of transfected circulating monocytes in vivo, (3) assess the immunotherapeutic efficacy of PBAE/mRNA KaNPs in suppressing tumor growth in combination with TLR9 and STING agonists in mouse tumor models, and (4) develop an GMP-compliant, shelf-stable, lyophilized PBAE/mRNA KaNP formulation and validate the efficacy in a mouse model. If successful, this study will uncover structure-function relationships in a previously inaccessible size range (200–1000 nm) for gene therapy carriers, demonstrate circulating monocytes as a potent mRNA therapeutic target and the role of KaNP-transfected circulating monocytes in potentiating antitumor immune responses, and inspire rational design of new mRNA-based immunotherapies for treatment of solid tumors and metastatic cancers.

项目摘要癌症疫苗具有明显的晚期癌症免疫疗法；以及mRNA的最新成功疫苗通过特异性传递mRNA来提高了产生潜在抗肿瘤反应的前景编码肿瘤相关的抗原与抗原呈递细胞（APC）。但是，APC激活引起含有抗原mRNA的纳米颗粒相当有限。循环单核细胞提供了一个承诺细胞目标可以沉积到脾脏，淋巴结和肿瘤组织的丰富APC前体极化和激活。这项研究的总体目标是工程师动力组装的聚（β-）氨基酯）（PBAE） /mRNA纳米颗粒（KANPS），可以特异性地递送编码肿瘤抗原的mRNA 并在体内进入循环的单核细胞，并证明了这种新的安全性和效率 mRNA癌症疫苗平台。这项研究建立在显示可生物降解的初步结果的基础上 PBAE/mRNA KANP，优化尺寸为400 nm介导的循环的优先转染静脉注射（i.v.）注射后的单核细胞，导致更有效的翻译和沉积与标准小尺寸相比，循环单核细胞和更高水平的肿瘤活性 PBAE/mRNA纳米颗粒。在这项拟议的研究中，我们计划追求四个具体目标：（1）优化 PBAE/mRNA KANP的组成，大小和表面功能，以提高目标mRNA递送效率在体内循环单核细胞中，（2）表征PBAE/mRNA kanps的药代动力学特征并定义体内翻译的循环单核细胞的功能，（3）评估PBAE/mRNA的免疫治疗效率 KANP抑制肿瘤与TLR9和小鼠肿瘤模型中的刺激激动剂的肿瘤生长，以及（4）开发一个符合GMP符合GMP稳定的，冻干的PBAE/mRNA KANP公式并验证效率在鼠标模型中。如果成功，这项研究将发现以前的结构功能关系无法访问的尺寸范围（200-1000 nm）用于基因治疗载体，以循环单核细胞为有效 mRNA热靶和KANP转染的循环单核细胞在增强抗杀菌剂中的作用免疫调查，并激发新的基于mRNA的免疫疗法的理性设计用于治疗固体肿瘤和转移性癌症。