Overcoming the last barrier to commercialization of virus-specific T cell therapy

克服病毒特异性 T 细胞疗法商业化的最后障碍

• 批准号: 8904289
• 负责人: John Wilson
• 金额: $ 159.96万
• 依托单位: WILSON WOLF MANUFACTURING CORPORATION
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-05 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8904289
• 关键词: Adenoviruses; Adverse effects; Allogenic; Cell Culture Techniques; Clinical; Cytomegalovirus; Cytomegalovirus Infections; Data; Devices; Dose; Evaluation; FDA approved; Genetic Engineering; Health; Human Resources; Immune; Immune system; Immunocompromised Host; Infectious Agent; Medical; Medicine; Methods; Paint; Patients; Pharmaceutical Preparations; Phase; Plant Roots; Process; Production; Protocols documentation; Recording of previous events; Safety; Specific qualifier value; Sterility; T cell therapy; T-Lymphocyte; Therapeutic; Touch sensation; Viral; Viral Load result; Virus; Virus Diseases; Wolves; Work; college; commercialization; fighting; follow-up; killings; manufacturing process; member; novel strategies; programs; standard of care; tool

 DESCRIPTION (provided by applicant): T cell therapy for treatment of viral infections in immune compromised patients holds great promise to be a far superior alternative to conventional anti-viral drugs. After years of work, the last remaining barrier is to eliminate genetic engineering that relies on infectious agents when producing the therapeutic T cell doses. These infectious agents create tremendous complexities and are potentially dangerous to patients. This program will overcome that problem and pave the way for the first off-the-shelf virus-specific T cell therapy in history. At the end of this program the optimal manufacturing specifications for virus specific T cell therapy (VST) directed at adenovirus (AdV), BK, and cytomegalovirus (CMV) infections in immune compromised patients. This will serve an unmet medical need, given there are no FDA approved drugs for AdV and BK, and the only FDA approved drug for CMV is highly toxic and often ineffective. Preliminary data paint a compelling picture of how VST can treats the root cause of viral infection; that is the lack of a functional immune system. Data demonstrate VST can restore the immune system's ability to fight viral infection and has minimal side effects. Preliminary data also show how the manufacturing process that creates VST can be greatly simplified with a novel approaches to virus-specific T cell culture. The specific aims follow up on that data. Aim1 Objective: WWM will construct 6-well "G-Rex" T cell culture devices, which will allow comparison of multiple culture conditions in parallel and facilitate the rapid identification of key variables that support optimal VST production. Aim 1 Deliverable: We will have fully functional, sterile, 6-well G-Rex devices for the VST optimization studies outlined in Aim 2. The construction of this cell culture tool will allow or collaborators from Baylor College of Medicine to rapidly and efficiently assess multiple conditions in parallel. Aim 2 Objective: Find the optimal stimulation protocol to maximize the purity and killing capacity of a therapeutic VST dose. Aim 2 Deliverable: Optimized virus-specific T cell stimulation protocols that maximize purity and killing capacity will be available for evaluation at full scale in Aim 4. Aim 3 Objective: Use the data of Aim 2 to create G-Rex devices of optimal size for use in the verification study of Aim 4. Aim 3 Deliverable: Full scale G-Rex devices will be available for use in Aim 4. Aim 4 Objective: Verify protocols optimized in Aim 2 are repeatable in full scale G-Rex devices. Aim 4 Deliverable: Specifications defining the most efficient manufacturing conditions for maximum VST killing capacity within alloreactivity acceptance criteria, without the need for infectious agents in the manufacturing process, will be available for use in Phase IIb.

 描述（由申请人提供）：用于治疗免疫受损患者的病毒感染的 T 细胞疗法有望成为远优于传统抗病毒药物的替代品。经过多年的努力，剩下的最后一个障碍是消除在生产治疗性 T 细胞剂量时依赖感染因子的基因工程。这些传染源造成了巨大的复杂性，并且对患者有潜在的危险。该计划将克服这个问题，并为历史上第一个现成的病毒特异性 T 细胞疗法铺平道路。在该计划结束时，针对免疫受损患者的腺病毒 (AdV)、BK 和巨细胞病毒 (CMV) 感染的病毒特异性 T 细胞疗法 (VST) 的最佳制造规范。这将满足未满足的医疗需求，因为 FDA 没有批准用于 AdV 和 BK 的药物，并且 FDA 批准的唯一用于 CMV 的药物具有剧毒且通常无效。初步数据描绘了 VST 如何从根本上治疗病毒感染的令人信服的图景；那就是缺乏功能性的免疫系统。数据表明 VST 可以恢复免疫系统抵抗病毒感染的能力，并且副作用最小。初步数据还表明，如何通过病毒特异性 T 细胞培养的新方法大大简化 VST 的制造过程。具体目标是根据这些数据制定的。目标1 目标：WWM 将构建 6 孔“G-Rex”T 细胞培养装置，该装置将允许并行比较多种培养条件，并有助于快速识别支持最佳 VST 生产的关键变量。目标 1 可交付成果：我们将拥有功能齐全、无菌、6 孔 G-Rex 设备，用于 目标 2 中概述了 VST 优化研究。该细胞培养工具的构建将允许贝勒医学院的合作者快速有效地并行评估多种条件。目标 2 目的：找到最佳的刺激方案，以最大限度地提高 VST 治疗剂量的纯度和杀伤能力。目标 2 可交付成果：最大限度提高纯度和杀伤能力的优化病毒特异性 T 细胞刺激方案将可用于目标 4 中的全面评估。目标 3 目标：使用目标 2 的数据创建最佳尺寸的 G-Rex 装置，用于目标 4 的验证研究。目标 3 可交付成果：全尺寸 G-Rex 装置将可用于目标 4。目标 4 目标：验证目标 2 中优化的方案在全面范围内可重复 霸王龙设备。目标 4 可交付成果：在同种异体反应验收标准内定义最有效的制造条件以实现最大 VST 杀灭能力的规范，且在制造过程中不需要感染剂，将可用于 IIb 期。