Background

Because of their well-described immunosuppressive properties, allogeneic adult human mesenchymal stromal cells (MSC) derived from bone marrow have demonstrated safety and efficacy in steroid refractory acute graft versus host disease (SR aGVHD). Clinical trials have resulted in variable success and an optimal source of MSC has yet to be defined. Based on the importance of maternal-fetal interface immune tolerance, extraembryonic fetal tissues, such as the umbilical cord, may provide an superior tissue source of MSC to mediate immunomodulation in aGVHD.

Methods

A two-dose cohort trial allogeneic Wharton’s Jelly-derived mesenchymal stromal cells (WJMSC, referred to as MSCTC-0010, here) were tested in 10 patients with de novo high risk (HR) or SR aGVHD post allogeneic hematopoietic stem cell transplantation (allo-HCT). Following Good Manufacturing Practices isolation, expansion and cryostorage, WJMSC were thawed and administered via intravenous infusions on days 0 and 7 at one of two doses (low dose cohort, 2 × 10⁶/kg, n = 5; high dose cohort, 10 × 10⁶/kg, n = 5). To evaluate safety, patients were monitored for infusion related toxicity, Treatment Related Adverse Events (TRAE) til day 42, or ectopic tissue formation at day 90. Clinical responses were monitored at time points up to 180 days post infusion. Serum biomarkers ST2 and REG3α were acquired 1 day prior to first MSCTC-0010 infusion and on day 14.

Results

Safety was indicated, e.g., no infusion-related toxicity, no development of TRAE, nor ectopic tissue formation in either low or high dose cohort was observed. Clinical response was suggested at day 28: the overall response rate (ORR) was 70%, 4 of 10 patients had a complete response (CR) and 3 had a partial response (PR). By study day 90, the addition of escalated immunosuppressive therapy was necessary in 2 of 9 surviving patients. Day 100 and 180 post infusion survival was 90% and 60%, respectively. Serum biomarker REG3α decreased, particularly in the high dose cohort, and with REG3α decrease correlated with clinical response.

Conclusions

Treatment of patients with de novo HR or SR aGVHD with low or high dose MSCTC-0010 was safe: the infusion was well-tolerated, and no TRAEs or ectopic tissue formation was observed. A clinical improvement was seen in about 70% patients, with 4 of 10 showing a complete response that may have been attributable to MSCTC-0010 infusions. These observations indicate safety of two different doses of MSCTC-0010, and suggest that the 10 × 10⁶ cells/ kg dose be tested in an expanded randomized, controlled Phase 2 trial.

Graphical abstract

中文翻译：

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一项 I 期研究，评估两种剂量的沃顿胶源性间充质基质细胞治疗新发高风险或类固醇难治性急性移植物抗宿主病的效果。

 背景

由于其良好的免疫抑制特性，源自骨髓的同种异体成人间充质基质细胞（MSC）已在类固醇难治性急性移植物抗宿主病（SR aGVHD）中证明了安全性和有效性。临床试验取得了不同程度的成功，但 MSC 的最佳来源尚未确定。基于母胎界面免疫耐受的重要性，胚胎外胎儿组织（例如脐带）可能提供优质的 MSC 组织来源来介导 aGVHD 的免疫调节。

 方法

在 10 名异体造血干细胞移植后患有新发高危 (HR) 或 SR aGVHD 的患者中进行了一项两剂量队列试验同种异体沃顿胶衍生间充质基质细胞（WJMSC，此处称为 MSCTC-0010）（allo -HCT）。按照良好生产规范分离、扩增和冷冻保存，将 WJMSC 解冻并在第 0 天和第 7 天通过静脉输注以两种剂量之一进行给药（低剂量组，2 × 10 ⁶ /kg， n = 5；高剂量组，10 × 10 ⁶ /kg，n = 5)。为了评估安全性，在第 42 天之前监测患者的输注相关毒性、治疗相关不良事件 (TRAE) 或在第 90 天的异位组织形成。在输注后长达 180 天的时间点监测临床反应。血清生物标志物 ST2 和 REG3α 在首次 MSCTC-0010 输注前 1 天和第 14 天采集。

 结果

表明了安全性，例如，在低剂量或高剂量组中没有观察到与输注相关的毒性、没有发生TRAE、也没有观察到异位组织形成。第28天提示临床缓解：总体缓解率（ORR）为70%，10名患者中有4名获得完全缓解（CR），3名患者获得部分缓解（PR）。到研究第 90 天，9 名幸存患者中有 2 名需要增加免疫抑制治疗。输注后第 100 天和第 180 天的存活率分别为 90% 和 60%。血清生物标志物 REG3α 下降，尤其是在高剂量组中，并且 REG3α 下降与临床反应相关。

 结论

用低剂量或高剂量 MSCTC-0010 治疗新发 HR 或 SR aGVHD 患者是安全的：输注耐受性良好，未观察到 TRAE 或异位组织形成。约 70% 的患者出现了临床改善，其中 10 名患者中有 4 名显示出完全缓解，这可能归因于 MSCTC-0010 输注。这些观察结果表明两种不同剂量的 MSCTC-0010 的安全性，并建议在扩大的随机对照 2 期试验中测试 10 × 10 ^{6 个}细胞/kg 剂量。

 图文摘要