Efficient automated processing for gene-engineered autologous cell therapies

基因工程自体细胞疗法的高效自动化处理

• 批准号: 10323695
• 负责人: Philip Henry Coelho
• 金额: $ 25.35万
• 依托单位: THERMOGENESIS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-08 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323695
• 关键词: Address; Antibodies; Autologous; Automation; Biological Sciences; Blood; Blood Cells; CD3 Antigens; CD34 gene; Capital; Cell Separation; Cell Therapy; Cell physiology; Cells; Centrifugation; Characteristics; Clinical; Cost Savings; Data Collection; Decentralization; Devices; Disease; Dose; Engineered Gene; Engineering; Equipment; Erythrocytes; Failure; Ficoll; Formulation; Gases; Goals; Harvest; Hematologic Neoplasms; Hematopoietic stem cells; Hereditary Disease; Hospitals; Individual; Industry; Injections; Lead; Legal patent; Lentivirus Vector; Leukapheresis; Magnetism; Methods; Microbubbles; Microprocessor; Molds; Molecular; Mononuclear; Outcome; Partner in relationship; Patients; Performance; Phase; Positioning Attribute; Price; Process; Production; Quality Control; Reagent; Recovery; Sampling; Savings; Series; Small Business Innovation Research Grant; Source; Sterility; System; T-Lymphocyte; Techniques; Technology; Thalassemia; Therapeutic; Time; Transgenes; Translating; Validation; base; cellular engineering; cellular transduction; chimeric antigen receptor T cells; cost; design; expectation; experience; feeding; improved; innovation; instrument; magnetic cell separation; manufacturing process; meetings; new technology; operation; peripheral blood; point of care; polycarbonate; prototype; success

ABSTRACT Gene-engineered autologous cell (GEAC) therapies for hematologic cancers and inherited disorders are earning growing numbers of FDA approvals, but manufacturing inefficiencies (90+% scrap rates) contribute to long workflows and high costs. Current automation efforts do not offer a solution, because the cell processing techniques they automate – like Ficoll-based cell enrichment, magnetic cell sorting (MACS), expansion and cell washing – are themselves inefficient (in terms of cell recoveries). This Phase 1 SBIR will validate the suitability of significantly more efficient cell handling processes (enabled by applicant’s functionally closed X-Series cell processing cartridge and X-BACS buoyancy-based cell isolation reagents, distributed by Corning Life Sciences) for integration into a ‘one-pot’ GEAC manufacturing workflow lending itself to full automation in the simple, compact, moderately priced Quintessence instrument (the subject of a follow-on Phase 2 SBIR proposal). X-Series cartridges are proven to enrich mononuclear cells from blood with target cell recovery efficiencies of 90-100% (for T cells and hematopoietic stem cells), and to wash or volume-reduce cells with equal recovery efficiency. Similarly, X-BACS reagents used in X-Series cartridges prove 50% more efficient than conventional MACS at target cell isolation at very high purity. Combined, these innovations can offer at least a 6-fold improvement in cell yield relative to conventional techniques. Target blood cells thus prepared have been shown to be transduced with lentiviral vectors as readily as are conventionally produced target cells. This proposal’s Specific Aims are: (1) to prototype and manufacture in small quantities an enhanced X-Series cartridge with additional features required to support the subsequent Aim; and (2) to validate and optimize the performance of all the steps of GEAC manufacturing (from blood to transduced, expanded and washed cells comprising a typical therapeutic dose) in a single such cartridge (‘one-pot’ workflow), the milestone for application for a Phase 2 SBIR to design and validate the Quintessence instrument that will fully automate that workflow. Success in delivering low-cost, high-efficiency, fully automated GEAC manufacturing technology may substantially improve patient experiences and outcomes by enabling the industry to (1) make these therapies more affordable; (2) reduce GEAC’s high manufacturing failure rate (failure to produce a full clinical dose); (3) reduce lead times from Rx to treatment; (4) produce more robust cells by minimizing ex vivo cell expansion; (5) switch from leukapheresis to peripheral blood as the manufacturing input; and (6) decentralize manufacturing to the point of care (hospitals).

摘要 基因工程自体细胞(GEAC)治疗血液病和遗传性疾病的成果 FDA批准的数量不断增加，但制造效率低下(90%以上的废品率)导致 工作流程和高成本。目前的自动化工作没有提供解决方案，因为细胞处理 他们自动化的技术-如基于Ficoll的细胞浓缩、磁性细胞分选(MAC)、扩增和细胞 洗涤--本身就是低效的(就细胞回收而言)。此阶段1 SBIR将验证是否适合 更高效的电池处理过程(由申请人的功能封闭的X系列电池实现 处理盒和X-BACS浮力细胞分离剂，由康宁生命科学公司分销) 集成到一个‘一刀切’的Geac制造工作流程中， 紧凑、价格适中的QuintEssence仪器(第二阶段SBIR后续提案的主题)。 X系列试剂盒已被证明可以从血液中浓缩单个核细胞，目标细胞回收率为 90-100%(对于T细胞和造血干细胞)，并以相同的回收率洗涤或减容细胞 效率。同样，X系列墨盒中使用的X-BACS试剂的效率也比传统试剂高50% MACs以非常高的纯度分离靶细胞。加在一起，这些创新可以提供至少6倍的 与传统技术相比，提高了细胞产量。已经展示了如此制备的靶血细胞 以慢病毒载体转导，就像传统生产的靶细胞一样容易。 该计划的具体目标是：(1)小批量制造增强型X系列 具有支持后续目标所需的附加功能的墨盒；以及(2)验证和优化 Geac制造的所有步骤(从输血到转换、扩增和洗涤细胞)的性能 包括典型的治疗剂量)在单个这样的墨盒中(‘一锅’工作流程)，这是应用的里程碑 对于第二阶段SBIR，设计和验证QuintEssence仪器将完全自动化该工作流程。 成功提供低成本、高效率、全自动化的Geac制造技术可能会 通过使行业能够(1)进行这些治疗，显著改善患者体验和结果 更实惠；(2)降低Geac的高制造不合格率(不能生产全部临床剂量)；(3) 减少从处方到治疗的领先时间；(4)通过最大限度地减少体外细胞扩张，生产更强大的细胞；(5) 从白细胞分离转向外周血作为生产投入；以及(6)分散生产以 看护点(医院)。