Developing macrophage reprogramming mRNA nanocarriers for initial clinical testing

开发用于初始临床测试的巨噬细胞重编程 mRNA 纳米载体

基本信息

批准号：
10292408
负责人：
Matthias Stephan
金额：
$ 16.91万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10292408
关键词：
Acute Animals Antibodies Autopsy Biological Assay Blood Chemical Analysis Cancer Patient Catheters Cells Chemoresistance Clinic Clinical Clinical Trials Coagulation Process Collaborations Communication Complement Complement Activation DNA Dangerousness Data Dose Ensure Filtration Fred Hutchinson Cancer Research Center Funding Genes Genetic Glioblastoma Goals Hour Human Immune Immunological Models In Vitro Inflammatory Infusion procedures Injectable Interferons Interleukin-12 Interleukin-2 Intervention Investigational Drugs Investigational New Drug Application Knowledge Laboratories Late Effects Macaca fascicularis Malignant Neoplasms Malignant neoplasm of ovary Measurement Medical Messenger RNA Methods Microfluidics Modeling Mus Nanotechnology Nature Outcome PTTG1 gene Pharmaceutical Preparations Phase I Clinical Trials Phenotype Phosphotransferases Physicians Platelet aggregation Polymers Primates Production Protocols documentation Reaction Regulation Research Research Personnel Risk Rivers Safety Schedule Sterility System Technology Testing Therapeutic Toxic effect Toxicity Tests Translating Tumor Immunity Tumor-associated macrophages Work anticancer research clinical practice cytokine design experimental study immunosuppressive macrophages immunotoxicity in vitro Assay in vivo interest interleukin-23 macrophage meetings monocyte nanocarrier nanodrug nanoformulation nanomedicine nanoparticle nanotherapeutic neoplastic cell new therapeutic target novel novel strategies porcine model pre-clinical programs research clinical testing scale up side effect small molecule success systemic inflammatory response systemic toxicity transcription factor tumor

项目摘要

Project Summary Tumor-associated macrophages (TAMs) usually express an M2 phenotype which enables them to perform immunosuppressive and tumor-promoting functions. Reprogramming these TAMs toward an M1 phenotype could thwart their pro-cancer activities and unleash anti-tumor immunity, but current efforts to accomplish this are nonspecific and elicit systemic inflammation. Our group at Fred Hutchinson Cancer Research Center has developed a targeted nanocarrier that can deliver in vitro-transcribed mRNA encoding M1-polarizing transcription factors to reprogram TAMs without causing systemic toxicity. With the goal of designing the first clinical trial for treating chemotherapy-resistant ovarian cancer patients with this nanodrug, we propose here research that will generate the data required for an IND application. Specifically, we will (1) develop a robust protocol for the scaled-up production of genetic macrophage-programming nanoparticles under GMP- conditions so they can be carried forward into large primate and human studies, (2) identify potential infusion reaction risks, with reference to FDA regulations for nanomedicines, and (3) confirm safety of the nanoparticles for clinical use in a large-animal species. We expect the outcome of the proposed research will help propel this approach into clinical practice for the treatment of advanced ovarian cancer, and provide knowledge to design a broad repertoire of nanotherapeutics that genetically reprogram TAMs as a strategy to treat other tumor types.

项目概要肿瘤相关巨噬细胞 (TAM) 通常表达 M2 表型，这使得它们能够执行免疫抑制和肿瘤促进功能。将这些 TAM 重新编程为 M1 表型可以阻止它们的促癌活动并释放抗肿瘤免疫力，但目前为实现这一目标所做的努力是非特异性的并引起全身炎症。我们弗雷德·哈钦森癌症研究中心的团队开发了一种靶向纳米载体，可以传递编码 M1 极化的体外转录 mRNA 转录因子重新编程 TAM，而不引起全身毒性。以设计第一个为目标我们在此提出用这种纳米药物治疗化疗耐药性卵巢癌患者的临床试验将生成 IND 申请所需数据的研究。具体来说，我们将 (1) 开发一个强大的在 GMP 下扩大生产遗传巨噬细胞编程纳米颗粒的方案条件，以便将它们进行大型灵长类动物和人类研究，（2）确定潜在的输注反应风险，参考 FDA 对纳米药物的规定，以及 (3) 确认纳米颗粒的安全性用于大型动物物种的临床应用。我们预计拟议研究的结果将有助于推动这一目标方法进入晚期卵巢癌治疗的临床实践，并提供设计知识一系列广泛的纳米疗法，通过对 TAM 进行基因重编程作为治疗其他肿瘤的策略类型。