Houghtelin Amy, Bollard Catherine M
Program for Cell Enhancement and Technologies for Immunotherapy, Children's National Health System, The George Washington University, Washington, DC, United States.
Front Immunol. 2017 Oct 11;8:1272. doi: 10.3389/fimmu.2017.01272. eCollection 2017.
While progress has been made in the treatment of both hematologic cancers and solid tumors, chemorefractory or relapsed disease often portends a dismal prognosis, and salvage chemotherapy or radiation expose patients to intolerable toxicities and may not be effective. Hematopoietic stem cell transplant offers the promise of cure for many patients, and while mismatched, unrelated or haploidentical donors are increasingly available, the recipients are at higher risk of severe immunosuppression and immune dysregulation due to graft versus host disease. Viral infections remain a primary cause of severe morbidity and mortality in this patient population. Again, many therapeutic options for viral disease are toxic, may be ineffective or generate resistance, or fail to convey long-term protection. Adoptive cell therapy with virus-specific T cells (VSTs) is a targeted therapy that is efficacious and has minimal toxicity in immunocompromised patients with CMV and EBV infections in particular. Products have since been generated specific for multiple viral antigens (multi-VST), which are not only effective but also confer protection in 70-90% of recipients when used as prophylaxis. Notably, these products can be generated from either virus-naive or virus-experienced autologous or allogeneic sources, including partially matched HLA-matched third-party donors. Obstacles to effective VST treatment are donor availability and product generation time. Banking of third-party VST is an attractive way to overcome these constraints and provide products on an as-needed basis. Other developments include epitope discovery to broaden the number of viral antigens targets in a single product, the optimization of VST generation from naive donor sources, and the modification of VSTs to enhance persistence and efficacy .
虽然在血液系统癌症和实体瘤的治疗方面都取得了进展，但化疗难治性或复发性疾病往往预示着预后不佳，而挽救性化疗或放疗会使患者承受难以忍受的毒性，且可能无效。造血干细胞移植为许多患者带来了治愈的希望，虽然不匹配、无关或单倍体相合供体越来越容易获得，但由于移植物抗宿主病，受者面临严重免疫抑制和免疫失调的风险更高。病毒感染仍然是该患者群体严重发病和死亡的主要原因。同样，针对病毒疾病的许多治疗选择都有毒性，可能无效或产生耐药性，或者无法提供长期保护。用病毒特异性T细胞（VST）进行过继性细胞治疗是一种靶向治疗，对特别是患有巨细胞病毒和EB病毒感染的免疫受损患者有效且毒性极小。此后已经产生了针对多种病毒抗原的产品（多VST），这些产品不仅有效，而且用作预防时能使70 - 90%的受者获得保护。值得注意的是，这些产品可以从未接触过病毒或接触过病毒的自体或异体来源产生，包括部分匹配的HLA匹配第三方供体。有效的VST治疗的障碍是供体可用性和产品生产时间。储存第三方VST是克服这些限制并按需提供产品的一种有吸引力的方法。其他进展包括表位发现，以扩大单一产品中病毒抗原靶点的数量，优化从未接触过病毒的供体来源产生VST，以及对VST进行修饰以增强持久性和疗效。
