Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, 100044, China.
Peking-Tsinghua Center for Life Sciences, Beijing, 100871, China.
Cell Mol Immunol. 2022 Apr;19(4):482-491. doi: 10.1038/s41423-021-00829-y. Epub 2022 Jan 11.
Adoptive transfer of cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CMV-CTLs) from original transplant donors or third-party donors was effective for the treatment of CMV infection after allogenic stem cell transplantation (allo-SCT), but the antiviral activity of CMV-CTL types has not been compared. To determine whether third-party CMV-CTLs provide comparable long-term antiviral efficacy to transplant donor CMV-CTLs, we first compared the antiviral abilities of transplant donors and third-party CMV-CTLs for treatment of CMV infection in two mouse models, compared the in vivo recovery of CMV-specific immunity, and analyzed the underlying mechanisms driving sustained antiviral immunity. The results showed that both donor and third-party CMV-CTLs effectively combated systemic CMV infection by reducing CMV pathology and tumor burden 28 days postinfusion. The in vivo recovery of CMV-specific immunity after CMV-CTL infusion was comparable in both groups. A detailed analysis of the source of recovered CMV-CTLs showed the proliferation and expansion of graft-derived endogenous CMV-CTLs in both groups. Our clinical study, which enrolled 31 patients who received third-party CMV-CTLs and 62 matched pairs of individuals who received transplant donor CMV-CTLs for refractory CMV infection, further showed that adoptive therapy with donor or third-party CMV-CTLs had comparable clinical responses without significant therapy-related toxicity. We observed strong expansion of CD8 tetramer T cells and proliferation of recipient endogenous CMV-CTLs after CMV-CTL infusion, which were associated with a reduced or cleared viral load. Our data confirmed that adoptive therapy with third-party or transplant donor CMV-CTLs triggered comparable antiviral responses to CMV infection that might be mediated by restoration of endogenous CMV-specific immunity.
采用供体或第三方来源的巨细胞病毒（CMV）特异性细胞毒性 T 淋巴细胞（CMV-CTL）过继转移治疗异基因造血干细胞移植（allo-SCT）后 CMV 感染是有效的，但 CMV-CTL 类型的抗病毒活性尚未进行比较。为了确定第三方 CMV-CTL 是否能提供与移植供体 CMV-CTL 相当的长期抗病毒疗效，我们首先在两种小鼠模型中比较了移植供体和第三方 CMV-CTL 治疗 CMV 感染的抗病毒能力，比较了 CMV 特异性免疫的体内恢复情况，并分析了驱动持续抗病毒免疫的潜在机制。结果表明，供体和第三方 CMV-CTL 都通过减少 CMV 病理学和肿瘤负担，有效地对抗全身性 CMV 感染，在输注后 28 天。两组 CMV-CTL 输注后 CMV 特异性免疫的体内恢复情况相当。对恢复的 CMV-CTL 来源的详细分析表明，两组均存在移植物来源的内源性 CMV-CTL 的增殖和扩增。我们的临床研究纳入了 31 例接受第三方 CMV-CTL 治疗的患者和 62 例接受移植供体 CMV-CTL 治疗难治性 CMV 感染的匹配个体，进一步表明，接受供体或第三方 CMV-CTL 过继治疗的患者具有相当的临床反应，没有明显的治疗相关毒性。我们观察到 CMV-CTL 输注后 CD8 四聚体 T 细胞的强烈扩增和受体内源性 CMV-CTL 的增殖，与病毒载量减少或清除相关。我们的数据证实，采用第三方或移植供体 CMV-CTL 进行过继治疗可引发对 CMV 感染的相似抗病毒反应，可能是通过恢复内源性 CMV 特异性免疫介导的。
