Path to Commercialization of the first “off the shelf” T cell product

摘要 病毒特异性T细胞过继转移在病毒性肝炎患者中的临床效果显著 疾病。然而，这种疗法的广泛应用受到了(I)令人望而却步的生产的限制 成本，(2)制造的复杂性，(3)准备和产品发布的时间延长，以及(4) 对个性化的、针对患者的产品的要求。在过去的6年里，我们系统地 解决了这些问题：我们简化和改进了我们的制造技术，消除了生物危害 组件，并采用了使用透气培养装置的新的细胞扩张平台，该装置 在符合GMP的封闭系统中促进大量细胞的增殖和存活 技术人员干预。最后，我们已经确定了部分输注的临床益处。 人类白细胞抗原与预期产生并储存的病毒特异性T细胞相匹配，使它们可用于 立即“现成”使用。 因此，为了超越高度专业化的学术中心，我们成立了贝勒 医学院附属的一家名为ViraCyte的公司的目标是将“现成”的病毒商业化-- 特定的T细胞。我们的产品Viralym-B是一组对BK病毒具有特异性的T细胞系，在 包括儿童在内的免疫功能低下的人，会导致严重的临床症状，如 出血性膀胱炎和肾病，可导致明显的发病率和住院时间延长。我们的 治疗的目的是治疗耐药感染/疾病，这种情况不会像 在美国有20万人，而且没有照顾的标准。因此，在当前 我们将测试Viralym-B在异基因造血系统中的安全性和抗病毒活性 干细胞移植接受者。此外，我们将进一步降低将这项技术转让给私人公司的风险 部门合同制造组织(CMO)通过将我们的单元生产从开放式过渡到 完全封闭的系统，并验证我们的放大制造协议。这项申请的成功将为 为第二阶段研究奠定基础，以确认“现成”病毒B细胞的疗效并促进市场 批准，从而将BK病毒的T细胞疗法纳入公共领域，作为护理的标准。

ABSTRACT The adoptive transfer of virus-specific T cells has produced remarkable clinical results in patients with viral disease. However, broader implementation of this therapy has been limited by the (i) prohibitive production costs, (ii) complexity of manufacture, (iii) prolonged time for preparation and product release, and (iv) the requirement for individualized, patient-specific products. Over the past 6 years we have systematically addressed these problems: we simplified and refined our manufacturing technology, removed biohazardous components and employed a new cell expansion platform using a gas permeable culture device which promotes the proliferation and survival of large cell numbers in a GMP-compliant closed system with minimal technician intervention. Finally, we have established the clinical benefit associated with the infusion of partially HLA matched virus-specific T cells that are prospectively generated and banked, making them available for immediate “off the shelf” use. Thus, with the purpose of moving beyond highly specialized academic centers we established a Baylor College of Medicine-affiliated company called ViraCyte with the goal of commercializing “off the shelf” virus- specific T cells. Our product - Viralym-B - is a bank of T cell lines with specificity for BK virus, which, in immunocompromised individuals including children, is responsible for severe clinical syndromes like hemorragic cystitis and nephropathy that can lead to significant morbidity and prolonged hospital stay. Our therapy is intended for the treatment of drug-resistant infections/disease, a condition that afflicts less than 200,000 persons in the United States and for which there is no standard of care. Thus, in the current application we will test the safety and potential for anti-viral activity of Viralym-B in allogeneic hematopoietic stem cell transplant recipients. In addition, we will further de-risk the transfer of this technology to a private sector contract manufacturing organization (CMO) by transitioning our cell production from an open to an entirely closed system and validating our scale-up manufacture protocol. Success of this application will lay the foundation for a Phase IIb study to confirm the efficacy of “off the shelf” Viralym-B cells and facilitate market approval, thereby moving T cell therapy for BK virus into the public domain as a standard of care.