Introduction

Allogeneic hematopoietic stem cell (HSC) transplantation (allo-HSCT) is a treatment option for several monogenic diseases; however, its use is limited by the need for a matched donor and risk of HSCT-related complications. Autologous HSC gene addition does not have some of these limitations and may have similar efficacy with an improved safety profile. Ex vivo gene addition therapy using lentiviral vectors (LVV) is being evaluated in patients with transfusion-dependent β-thalassemia (TDT) using betibeglogene autotemcel (beti-cel, LentiGlobin for TDT) in the HGB-204, -205, -207, and -212 studies, sickle cell disease (SCD) using LentiGlobin for SCD in HGB-205 and -206, and cerebral adrenoleukodystrophy (CALD) using Lenti-D in ALD-102. The safety outcomes following autologous gene modified HSCT in these ongoing studies are summarized.

Methods

HSCs are collected using disease-appropriate procedures, then CD34+ cells are transduced with LVV encoding disease-specific therapeutic transgenes. After myeloablation with busulfan (SCD, TDT) or busulfan/cyclophosphamide (CALD), patients are infused with LVV-transduced CD34+ HSCs. Patients are followed for two years and offered participation in long term follow-up studies (LTF-303 [NCT02633943] or LTF-304 [NCT02698579]).

Results

Across all 6 studies, 110 patients have been treated as of most recent analyses (Table 1). Patients have been followed for <1 to 60.6 months and 47 patients have >2 years follow-up. No patient experienced primary or secondary graft failure. One patient with CALD experienced disease progression and died 22 months after drug product (DP) infusion of disease complications. Two additional patients with CALD withdrew from the study after DP infusion and were referred for allo-HSCT. All other patients with CALD, TDT, and SCD remain alive.

Most (107/110) patients had ≥ one grade 3 or 4 adverse event (AE) attributed to conditioning; most common AEs were cytopenia, febrile neutropenia, and stomatitis. Myelodysplastic syndrome was reported in one patient with SCD. After investigation for LVV insertion in malignant cells, the AE was assessed as not related to LentiGlobin insertion or transgene expression. AEs reported as related to the DP are shown in Table 1. There was no GVHD and no clinically relevant clonal dominance or LVV-mediated replication competent lentivirus.

Summary

Data from 110 patients followed for up to 5 years supports that the safety profile of gene-modified autologous HSCT does not carry the risks of GVHD, graft rejection, and long-term immunosuppression attendant to allo-HSCT. While the safety profile beyond 5-years is still being established, these data suggest that HSC gene therapy may be an acceptable therapy for patients with TDT, SCD, and CALD, particularly in patients at increased risk of complications from allo-HSCT, such as those who lack a suitable donor or are more advanced in age.

中文翻译：

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自体造血干细胞移植加基因治疗输血依赖性β-地中海贫血，镰状细胞病和脑肾上腺白质营养不良的安全性。

介绍

同种异体造血干细胞（HSC）移植（allo-HSCT）是几种单基因疾病的治疗选择；但是，由于需要匹配的供体以及与HSCT相关的并发症的风险，其使用受到限制。自体HSC基因的添加没有这些限制中的一些，并且可以具有相似的功效，并具有改进的安全性。离体正在使用HGB-204，-205，-207和-中的betibeglogene autotemcel（beti-cel，LentiGlobin for TDT）对患有输血依赖性β地中海贫血（TDT）的患者进行评估，使用慢病毒载体（LVV）进行基因加成治疗。 212项研究，在HGB-205和-206中使用LentiGlobin用于SCD的镰状细胞病（SCD），在ALD-102中使用Lenti-D的脑肾上腺白质营养不良（CALD）。在这些正在进行的研究中，总结了自体基因修饰的HSCT后的安全性结果。

方法

使用适合疾病的程序收集HSC，然后用编码疾病特异性治疗性转基因的LVV转导CD34 +细胞。用白消安（SCD，TDT）或白消安/环磷酰胺（CALD）进行骨髓消融后，向患者灌输LVV转导的CD34 + HSC。对患者进行了两年的随访，并提供了长期随访研究（LTF-303 [NCT02633943]或LTF-304 [NCT02698579]）。

结果

在所有6项研究中，根据最新分析，已治疗110例患者（表1）。随访患者的时间少于1至60.6个月，有47位患者的随访时间超过2年。没有患者经历原发或继发性移植失败。一名患有CALD的患者经历了疾病进展，并在输注疾病并发症的药物（DP）后22个月内死亡。DP输注后又有2例CALD患者退出研究，转诊接受allo-HSCT。所有其他患有CALD，TDT和SCD的患者仍然活着。

大多数（107/110）患者有≥1个因适应性引起的3级或4级不良事件（AE）。最常见的AE是血细胞减少，发热性中性粒细胞减少和口腔炎。一名SCD患者报告了骨髓增生异常综合征。在研究了LVV在恶性细胞中的插入后，AE被认为与LentiGlobin插入或转基因表达无关。表1显示了与DP相关的AE。没有GVHD，也没有临床相关的克隆优势或LVV介导的复制型慢病毒。

概要

来自110位患者的随访长达5年的数据支持，基因修饰的自体HSCT的安全性不存在伴随allo-HSCT的GVHD，移植物排斥和长期免疫抑制的风险。尽管仍建立了超过5年的安全性资料，但这些数据表明，HSD基因疗法可能是TDT，SCD和CALD患者的一种可接受的疗法，尤其是对于因异基因HSCT并发症风险较高的患者，例如缺乏合适的捐献者或年龄更高的人。