Developing macrophage reprogramming mRNA nanocarriers for initial clinical testing

项目摘要 肿瘤相关巨噬细胞(TAM)通常表达M2表型，这使它们能够 具有免疫抑制和促肿瘤作用。将这些TAM重新编程为M1表型 可能会挫败他们的亲癌活动并释放抗肿瘤免疫力，但目前实现这一目标的努力 是非特异性的，会引起全身炎症。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，可以传递体外转录的编码M1极化的mRNA 转录因子在不引起全身毒性的情况下对TAMs重新编程。目标是设计第一个 我们建议用这种纳米片治疗化疗耐药的卵巢癌患者的临床试验 将生成IND应用程序所需数据的研究。具体地说，我们将(1)制定一个稳健的 GMP下基因巨噬细胞编程纳米粒的放大生产方案-- 条件，以便它们可以被带入大型灵长类和人类研究，(2)确定潜在的输液 反应风险，参照FDA关于纳米药物的规定，以及(3)确认纳米颗粒的安全性 用于大型动物物种的临床使用。我们预计拟议研究的结果将有助于推动这一进程 探讨晚期卵巢癌治疗的临床实践，为设计提供知识 广泛的纳米疗法曲目，将TAMS基因重新编程为治疗其他肿瘤的策略 类型。

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.