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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：
10491263
负责人：
Yizhou Dong
金额：
$ 62.69万
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/10491263
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 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 ultrasound

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.

免疫疗法如检查点阻断和嵌合抗原受体T细胞疗法