Fernanda Agostini Rocha , Caio Raony Farina Silveira , Ancély Ferreira dos Santos , Ana Carolina Buzzo Stefanini , Nelson Hamerschlak , Luciana Cavalheiro Marti
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引用次数: 0
摘要
目前,异体造血干细胞受者在移植后仍受到反复感染的困扰。据报道,移植后输注病毒特异性 T 细胞(VST)可抵抗多种病毒,但不会增加新发移植物抗宿主疾病的风险。本研究以巨细胞病毒(CMV)为目标,开发了一种创新方法,用于按照《药品生产质量管理规范》(GMP)指南生成特异性极强的 VST 产品。我们使用无菌一次性隔室(名为 "白细胞减少系统室",Leukoreduction System Chamber,LRS-chamber)作为起始材料,该隔室已证明含有大量 T 细胞。利用 IL-2 和 IL-7 的组合,我们可以改善 CMV 特异性 T 细胞的扩增。此外,通过开发和建立新的产品方案,我们能够刺激 VST 增殖,并有利于 T 细胞效应记忆特征。扩增后的 VST 在一个封闭的自动化系统中富集,形成了高纯度的抗 CMV 产品,该产品在体外进行了特异性临床前测试,在体内使用 NOD scid 小鼠进行了持久性、生物分布和毒性测试。我们的结果表明,VST 具有很强的特异性,只有在细胞受到人类 CMV 株(AD169)感染的情况下才能分泌大量干扰素,而且对部分 HLA 相容但未感染病毒的细胞无害。
Development of a highly cytotoxic, clinical-grade virus-specific T cell product for adoptive T cell therapy
At present, recipients of allogeneic hematopoietic stem-cells are still suffering from recurrent infections after transplantation. Infusion of virus-specific T cells (VST) post-transplant reportedly fights several viruses without increasing the risk of de novo graft-versus-host disease. This study targeted cytomegalovirus (CMV) for the development of an innovative approach for generating a very specific VST product following Good Manufacturing Practices (GMP) guidelines.
We used a sterile disposable compartment named the Leukoreduction System Chamber (LRS-chamber) from the apheresis platelet donation kit as the starting material, which has demonstrated high levels of T cells. Using a combination of IL-2 and IL-7 we could improve expansion of CMV-specific T cells. Moreover, by developing and establishing a new product protocol, we were able to stimulate VST proliferation and favors T cell effector memory profile. The expanded VST were enriched in a closed automated system, creating a highly pure anti-CMV product, which was pre-clinically tested for specificity in vitro and for persistence, biodistribution, and toxicity in vivo using NOD scid mice. Our results demonstrated very specific VST, able to secrete high amounts of interferon only in the presence of cells infected by the human CMV strain (AD169), and innocuous to cells partially HLA compatible without viral infection.
期刊介绍:
Cellular Immunology publishes original investigations concerned with the immunological activities of cells in experimental or clinical situations. The scope of the journal encompasses the broad area of in vitro and in vivo studies of cellular immune responses. Purely clinical descriptive studies are not considered.
Research Areas include:
• Antigen receptor sites
• Autoimmunity
• Delayed-type hypersensitivity or cellular immunity
• Immunologic deficiency states and their reconstitution
• Immunologic surveillance and tumor immunity
• Immunomodulation
• Immunotherapy
• Lymphokines and cytokines
• Nonantibody immunity
• Parasite immunology
• Resistance to intracellular microbial and viral infection
• Thymus and lymphocyte immunobiology
• Transplantation immunology
• Tumor immunity.