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

 描述（由申请人提供）：用于治疗免疫受损患者中的病毒感染的T细胞疗法具有成为常规抗病毒药物的远上级替代品的巨大希望。经过多年的工作，最后剩下的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。这些传染性病原体造成了巨大的复杂性，并对患者有潜在的危险。该计划将克服这一问题，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。在该项目结束时，针对免疫受损患者中腺病毒（AdV）、BK和巨细胞病毒（CMV）感染的病毒特异性T细胞疗法（VST）的最佳生产质量标准。这将服务于未满足的医疗需求，因为没有FDA批准的AdV和BK药物，并且唯一FDA批准的CMV药物具有高毒性并且通常无效。初步数据描绘了VST如何治疗病毒感染的根本原因的令人信服的画面;那就是缺乏功能性免疫系统。数据表明，VST可以恢复免疫系统对抗病毒感染的能力，并且副作用最小。初步数据还显示，通过一种新的病毒特异性T细胞培养方法，可以大大简化创建VST的制造过程。具体目标是根据这些数据采取后续行动。目标1：WWM将构建6孔“G-Rex”T细胞培养装置，这将允许平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可实现：我们将拥有功能齐全的无菌6孔G-Rex器械， 目标2中概述的VST优化研究。这种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。目的2目的：寻找最佳刺激方案，以最大限度地提高治疗剂量VST的纯度和杀伤能力。目标2：优化的病毒特异性T细胞刺激方案，最大限度地提高纯度和杀伤能力，将可用于目标4中的全规模评估。目的3目的：使用目的2的数据创建最佳尺寸的G-Rex器械，用于目的4的验证研究。目标3可行：全尺寸G-Rex器械将可用于目标4。目标4目标：验证目标2中优化的方案在全尺寸G-Rex器械中可重复。目标4：在同种异体反应性验收标准范围内定义最大VST杀灭能力的最有效生产条件的质量标准，在生产工艺中不需要感染性因子，将可用于IIb期。

 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.