ImportanceProgressive multifocal leukoencephalopathy (PML) is a life-threatening viral infection with no approved antiviral treatment.ObjectiveTo determine whether restoring the compromised immune system of patients with PML with directly isolated allogeneic virus–specific (DIAVIS) T cells is a promising therapeutic strategy, especially if other curative options are absent.Design, Setting, and ParticipantsA retrospective case series of patients with PML who were treated with DIAVIS T cells was conducted between March 2020 and February 2022. T cells were isolated from healthy donors within 24 hours and targeted against the BK polyomavirus. Patients with PML were treated monocentrically. Eligibility for treatment with DIAVIS T cells was assessed for patients with confirmed PML, and exclusion criteria included stable PML disease and previous treatment with natalizumab.ExposureFresh DIAVIS T cells were administered with a maximum dose of 2 × 104 CD3+ cells/kg body weight. Remaining T cells were cryopreserved in divided doses and administered in additional treatments approximately 2 and 6 weeks later.Main Outcomes and MeasuresPrimary outcome measures were clinical response and survival of patients, compared with the outcomes of a historical reference group of PML cases receiving best supportive treatment (BST) and with recently published real-world data of patients with PML who were treated with immune checkpoint inhibition.ResultsThe study cohort consisted of 28 patients (median [IQR] age, 60 [51-72] years; 20 male [71.4%]). Twenty-two patients (79%) treated with DIAVIS T cells showed response, resulting in significant clinical stabilization or improvement and a reduction in viral load. Six individuals (21%) were classified as nonresponders, deteriorated rapidly, and died, as did 2 other patients during a 12-month follow-up. Older age was the only predictor of a poor treatment response. Survival analysis revealed better 12-month survival rates (hazard ratio, 0.42; 95% CI, 0.24-0.73; P =.02) from diagnosis for patients treated with DIAVIS T cells (18 of 26 [69%]; 12-mo survival rate, 69%) compared with historical controls with BST (57 of 113 [50%]; 12-mo survival rate, including censored data, 45%).Conclusion and RelevanceThis case series of DIAVIS T-cell therapy in PML provides first class IV evidence suggesting efficacy to reduce mortality and improve functional outcome. Further prospective studies are required to confirm these results.

中文翻译：

---

直接分离的同种异体病毒特异性 T 细胞治疗进行性多灶性脑白质病


重要性进行性多灶性白质脑病 （PML） 是一种危及生命的病毒感染，尚未获得批准的抗病毒治疗。目的确定使用直接分离的同种异体病毒特异性 （DIAVIS） T 细胞恢复 PML 患者受损的免疫系统是否是一种有前途的治疗策略，尤其是在没有其他治愈选择的情况下。设计、环境和参与者在 2020 年 3 月至 2022 年 2 月期间对接受 DIAVIS T 细胞治疗的 PML 患者进行了回顾性病例系列研究。在 24 小时内从健康供体中分离出 T 细胞，并靶向 BK 多瘤病毒。PML 患者接受单中心治疗。对确诊 PML 的患者评估了 DIAVIS T 细胞治疗的资格，排除标准包括稳定的 PML 疾病和既往纳他珠单抗治疗。暴露新鲜 DIAVIS T 细胞的最大剂量为 2 × 104 CD3+ 细胞/kg 体重。剩余的 T 细胞以分次剂量冷冻保存，并在大约 2 周和 6 周后进行额外处理。主要结局和指标主要结局指标是患者的临床反应和生存率，与接受最佳支持治疗 （BST） 的 PML 病例的历史参考组的结果以及最近发表的接受免疫检查点抑制治疗的 PML 患者的真实世界数据相比。结果研究队列由 28 例患者组成 （中位 [IQR] 年龄，60 [51-72] 岁;20 例男性 [71.4%]）。22 例接受 DIAVIS T 细胞治疗的患者 （79%） 表现出反应，导致临床显著稳定或改善，病毒载量降低。 在 12 个月的随访中，6 例 （21%） 被归类为无反应者，病情迅速恶化并死亡，其他 2 例患者也是如此。年龄较大是治疗反应不佳的唯一预测因素。生存分析显示更好的 12 个月生存率 （风险比，0.42;95% CI，0.24-0.73;P =.02） 与历史 BST 对照 （113 例中的 57 例 [50%];12 个月生存率，包括删失数据，45%）相比，接受 DIAVIS T 细胞治疗的患者 （26 例中有 18 例 [69%];12 个月生存率，45%）。结论和相关性DIAVIS T 细胞疗法治疗 PML 的病例系列提供了一流的 IV 级证据，表明其可降低死亡率和改善功能结局。需要进一步的前瞻性研究来证实这些结果。