Immunotherapy via engineered therapeutic programs in tumors using RNA

使用 RNA 通过工程化治疗方案进行肿瘤免疫治疗

基本信息

批准号：
10330085
负责人：
Yizhou Dong
金额：
$ 65.35万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
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：
2021-09-20 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10330085
关键词：
Beds CAR T cell therapy Cancer Etiology Cancer Model Cell Death Cells Cessation of life Cues Data Disseminated Malignant Neoplasm Distal Engineering Event Evolution FDA approved Formulation Gene Expression Genes Human Immune Immune signaling Immune system Immunotherapy In Vitro Injections KRASG12D Link Lung Lung Adenocarcinoma Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Minority Modeling Oral Patients Pharmaceutical Preparations Publishing RNA Replicon Safety Series Signal Pathway Solid Neoplasm Synthetic Genes T-Lymphocyte TP53 gene Technology Testing Therapeutic Transfection Treatment Efficacy Tumor Immunity Ultrasonography anti-cancer therapeutic anti-tumor immune response base cancer cell cancer immunotherapy cell type design immune checkpoint blockade immunogenic in vivo interest lipid nanoparticle lung cancer cell mouse model neoplastic cell next generation nucleic acid delivery programs promoter recruit response small molecule synthetic biology therapeutic evaluation tumor tumor microenvironment tumor-immune system interactions

项目摘要

Immunotherapy treatments such as checkpoint blockade and chimeric antigen receptor T cell therapy have demonstrated the power of the immune system to eradicate metastatic cancer, but the efficacy of immunotherapies in solid tumors remains confined to a minority of patients. A series of interlinked events are needed for efficacy – including induction of immunogenic tumor cell death, recruitment of immune cells to the tumor bed, and reversion of immunosuppressive cues in the tumor microenvironment (TME). We have developed a therapeutic approach using intratumorally-administered synthetic lipid nanoparticles (LNPs) to deliver self-replicating (replicon) RNAs to tumors that activate innate immune signaling pathways and potently express therapeutic payloads. As shown in our recently published preliminary data, this approach elicited profound anti-tumor immune responses in several tumor models, and enabled tumor regression of both injected and distal non-injected tumors. Here we bring together a strong interdisciplinary team to build on these initial findings and apply a synthetic biology toolkit to create next-generation LNP-replicon therapeutics, which combine multiple features to increase the safety and efficacy of this approach, including: (1) cell classifier circuits that allow replicon expression only in target cancer cells or immune cells, (2) optimized multi- subgenomic promoter replicons that encode multiple payload genes expressed at tunable predefined expression levels, and (3) small molecule-regulated replicons that allow two-stage therapeutic programs to be implemented following a single intratumoral injection. These engineered RNAs will be combined with optimized LNP formulations that promote efficient transfection of desired target cell types in the TME. We will apply this technology to treat the leading cause of cancer death, lung cancer, and assess its impact using a syngeneic mouse model of local intratumoral therapy in orthotopic and autochthonous lung cancer models that recapitulate the TME of human lung cancers. Our specific aims are: (1) Develop formulations for cell type- specific expression in cancer cells and T cells, (2) Create small molecule-regulated RNA circuits for cancer cells and T cells for programmable immunogenic cancer cell death and specifically expression in T cells. (3) Therapeutic testing of optimized replicon circuits in orthotopic lung cancer models alone and in combination. Altogether, this proposal brings together a highly interdisciplinary team, marrying cutting edge concepts from synthetic biology and cancer immunotherapy to achieve a more effective, safe, and scalable form of immunotherapy.

检查点阻断和嵌合抗原受体 T 细胞疗法等免疫疗法免疫系统消灭转移性癌症的力量，但其功效实体瘤的免疫疗法仍然局限于少数患者。功效所需的——包括诱导免疫原性肿瘤细胞死亡、招募免疫细胞到肿瘤床，以及肿瘤微环境（TME）中免疫抑制信号的逆转。开发了一种使用肿瘤内施用合成纳米脂质颗粒（LNP）的治疗方法向肿瘤递送自我复制（复制子）RNA，激活先天免疫信号通路并有效正如我们最近发布的初步数据所示，这种方法引发了。在多种肿瘤模型中产生广泛的抗肿瘤免疫反应，并使肿瘤消退在这里，我们聚集了一个强大的跨学科团队来发展这些肿瘤。初步发现并应用合成生物学工具包来创建下一代 LNP 复制子疗法，结合多种功能来提高该方法的安全性和有效性，包括：（1）细胞分类器允许复制子仅在目标癌细胞或免疫细胞中表达的电路，（2）优化的多编码多个有效负载基因的亚基因组启动子复制子，这些有效负载基因以可调节的预定义表达表达水平，以及（3）小分子调节的复制子，允许两阶段治疗方案这些工程化的RNA将与优化的RNA相结合后进行单次瘤内注射。 LNP 制剂可促进 TME 中所需靶细胞类型的有效转染。治疗癌症死亡主要原因肺癌的技术，并使用同基因评估其影响原位和本土肺癌模型中局部瘤内治疗的小鼠模型概括人类肺癌的 TME 是：(1) 开发针对细胞类型的制剂。在癌细胞和T细胞中特异性表达，（2）创建针对癌症的小分子调节RNA回路细胞和 T 细胞用于可编程免疫原性癌细胞死亡以及 T 细胞中的特异性表达 (3)。单独和组合原位肺癌模型中优化复制子电路的治疗测试。总而言之，该提案汇集了一个高度跨学科的团队，结合了来自合成生物学和癌症免疫疗法，以实现更有效、安全和可扩展的形式免疫疗法。