Establishing the POROS Intracellular Delivery System as a Platform for Cellular Therapeutics

建立 POROS 细胞内输送系统作为细胞治疗平台

• 批准号: 10495192
• 负责人: Michael M Binkley
• 金额: $ 118.02万
• 依托单位: OPENCELL TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-10 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10495192
• 关键词: Acoustics; Address; Allogenic; Area; Autologous; B lymphoid malignancy; B-Lymphocyte Subsets; Biological Sciences; Biophysics; Buffers; CAR T cell therapy; CD19 gene; CD7 gene; CRISPR/Cas technology; Cell Survival; Cell Therapy; Cells; Cellular Membrane; Characteristics; Complex; Consumption; Contracts; DNA; Development; Device or Instrument Development; Devices; Electrophoresis; Electroporation; Engineering; Event; FDA approved; Fibroblasts; Frequencies; Generations; Genes; Genetic Engineering; Goals; Health; Human; Hybrids; Immune; Jurkat Cells; Knock-in; Laws; Legal patent; Malignant Neoplasms; Manufacturer Name; Mediating; Medical Device; Methods; Modification; Outcome; Patients; Pharmacologic Substance; Phase; Physiologic pulse; Production; Proteins; RNA; Recovery; Regenerative Medicine; Reporter; Reproducibility; Research; Sales; Sample Size; Small Business Innovation Research Grant; Sterility; System; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Technology; Therapeutic; Therapy Clinical Trials; Time; Transfection; Validation; base; cancer therapy; case-by-case basis; cell injury; cell type; cellular engineering; chimeric antigen receptor T cells; cost; cost effective; design; electric field; experimental study; fighting; genome editing; instrument; interest; macromolecule; manufacturing process; neoplastic cell; new technology; next generation; novel; novel strategies; nuclease; nucleic acid delivery; operation; parallelization; personalized medicine; programs; prototype; research and development; two-dimensional; uptake

Abstract CAR-T therapy is a rapidly emerging therapy for the treatment of cancer, with two companies receiving FDA approval for their first CAR-T therapies in 2017. These therapies use immune cells called T cells, either from the patient themselves, or a healthy donor, and genetically engineer them to kill the tumor cells. The genetic engineering involves direct delivery of nucleic acids to these cells, which is challenging as current delivery methods either lack efficiency, are very damaging to cells, or both. This engineering is performed on a case- by-case basis and the methods are costly and time-consuming. Next generation CAR-T therapies will include more complex genetic engineering, with two or more editing events required. This is currently being done in a sequential fashion, which increases the time-to-patient of the final product. In order to make CAR-T therapies available to more patients in a cost-effective, safe and timely manner, new approaches need to be developed. Current research is addressing this need by developing new technologies for cell treatment that allow faster recovery and expansion time of the treated cells, allow delivery of multiple molecules in one shot and that can be integrated into a closed, manufacturing-ready system. Another focus of research is engineering healthy donor T cells to be used in CAR-T therapy, which would allow for an off-the-shelf cellular therapeutic. For this type of product to be realized, high capacity treatment methods need to be developed capable of treating > 1010 cells while also maintaining high cell viability and delivery efficiency. OpenCell Technologies has developed a proprietary technology, POROS, to deliver macromolecules such as DNA, RNA and protein to a wide variety of cell types. POROS uses an acoustic drive to push cells through an array of nozzles one cell at a time, thus creating shear force that porates the cells. In this SBIR program, OpenCell is expanding the capabilities of its POROS platform by developing higher capacity POROS devices. Approach: In this Phase II project, OpenCell will develop a high capacity version of POROS, capable of treating a larger number of cells to enable CAR-T development. We will develop a prototype POROS device, capable of treating 1-5 × 108 cells in under 10 minutes, and demonstrate gene editing in T cells as a proof-of- concept experiment. The POROS device development will pave the way for development of a large, all-in-one, GMP-compliant POROS-giga device, for manufacturing of off-the-shelf cellular therapeutics. Additionally, the POROS unit developed in this Phase II project will also be a salable unit of its own with anticipated applications in research and development, personalized medicine and small batch production of cells for autologous cell therapies and for clinical trials.

抽象的 CAR-T疗法是一种快速新兴的癌症治疗疗法，两家公司接受FDA 批准了2017年的第一种CAR-T疗法。这些疗法使用称为T细胞的免疫细胞 患者本身或健康的供体，并在基因上设计它们以杀死肿瘤细胞。遗传 工程涉及将核酸直接递送到这些细胞，这是当前交付的挑战 方法要么缺乏效率，要么对细胞非常损害，要么两者兼而有之。该工程是在案例上进行的 旁观者和方法是昂贵且耗时的。下一代CAR-T疗法将包括 更复杂的基因工程，需要两个或多个编辑事件。目前正在 顺序时尚，增加了最终产品的患者时间。为了进行CAR-T疗法 需要开发出具有成本效益，安全和及时的方式的更多患者，需要开发新的方法。 当前的研究是通过开发用于细胞处理的新技术来解决这一需求，以更快地 处理过的细胞的恢复和膨胀时间，允许一次镜头递送多个分子，这可以 集成到一个封闭的，可以制造的系统中。研究的另一个重点是工程健康 供体T细胞用于CAR-T治疗，这将允许进行现成的细胞治疗。为了这 要实现的产品类型，需要开发高容量治疗方法能够治疗> 1010个细胞，同时还保持高细胞活力和递送效率。 Opencell Technologies开发了一种专有技术Poros，以提供大分子，例如 DNA，RNA和蛋白质到多种细胞类型。 Poros使用声学驱动来推动细胞通过 一系列喷嘴一次一个单元，从而产生剪切力使细胞捕捉细胞。在这个SBIR计划中， Opencell通过开发更高容量的Poros设备来扩展其Poros平台的功能。 方法：在此II阶段项目中，Opencell将开发高容量版本的Poros，能够 处理大量细胞以实现CAR-T发育。我们将开发一个原型的poros设备， 能够在10分钟内治疗1-5×108个细胞，并在T细胞中证明基因编辑作为一种证明 概念实验。 Poros设备的开发将为开发大型，多合一的开发铺平道路 符合GMP的Poros-Giga设备，用于制造现成的细胞疗法。另外， 在此II阶段项目中开发的Poros单位也将是其本身的可售出单位，并具有预期的应用 在研发中，个性化医学和自体细胞细胞的小批量产生 治疗和临床试验。