To the Editor: Pulmonary fibrosis is a severe complication in COVID-19 patients. Based on our previous success with stem cell therapy of acute lung injury in mouse models and 2 COVID-19 patients in a pilot compassionate use study,1 we describe a Phase 1 clinical trial where we treated COVID-19 patients with pulmonary fibrosis using human embryonic stem cell–derived immunityand matrix-regulatory cells (hESC-IMRCs) during the SARS-CoV-2 outbreak in Wuhan City. Based on our recruitment criteria, we identified 27 COVID-19 patients who demonstrated pulmonary fibrosis pathology (Figure S1). All subjects had remained SARS-CoV-2–positive for more than three weeks. The median age of the patients was 66.5 years, of which 70% were men (Table 1). Patients with confirmed COVID-19 were diagnosed with pulmonary fibrosis using chest CT scans. A total of 20 patients were inpatients, while the other 7 subjects were discharged patients who still presented respiratory symptoms due to pulmonary fibrosis. Of the 20 inpatients, 10 were classified as severe/critical cases while another 10 were classified as moderate cases. Of the 20 inpatients who had pulmonary fibrosis and experienced shortness of breath at rest or exercise, 16 of 20 were supported by continuous oxygen therapy, of whom 1 depended on high-flow oxygen therapy. Another 4 of 20 inpatients also had pulmonary fibrosis and various respiratory symptoms, but only needed oxygen therapy after exercise. The 7 discharged patients presented respiratory symptoms only when they walked quickly. After obtaining informed consent and approval, all 27 patients received intravenous transfusion of hESC-IMRCs at a dose of 3 × 106 cells/kg of body weight. 25 of the 27 patients received intravenous transfusion of hESC-IMRCs twice, whereas the other 2 patients received intravenous infusion of hESC-IMRCs once and thrice, respectively. The patient who received three hESC-IMRC infusions was classified as a moderate case. His clinical symptoms had disappeared 10 days after the first hESC-IMRC infusion, but remained SARS-CoV-2–positive until 28 days after treatment, upon which he was discharged. We proceeded to follow up with all the patients 84 days after the first hESC-IMRC treatment by either re-examination within the hospital or interviews over the phone. The 7 discharged patients could exercise with moderate intensity without significant symptoms upon 56 days after the hESCIMRC treatment. Their lung fibrotic lesion areas had significantly decreased as observed from their chest CT scans (Figure S1C). We collected chest CT images from 3 of the 20 inpatients 7 days after treatment (Figure S1A-B, Patients #5, #20 and #22). The chest CT images also showed that their fibrosis lesions had improved. Chest CT scans were performed for 2 of the 20 inpatients 28 days after hESC-IMRC infusion, and their lung fibrotic lesion areas were also found to have decreased significantly (Figure S1A, Patient #10, #23). One of the 20 inpatients was dropped due to withdrawal of consent from the family. For the remaining 14 of 20 inpatients, their lung fibrotic lesion areas were also significantly diminished by 84 days after treatment (Figure S1). None of the treated patients suffered any adverse events or abnormal responses related to cell therapy. All haematological and clinical chemistry parameters remained in the normal range (Table S1). In addition, no tumour markers were detected in the serum, demonstrating that hESC-IMRCs were safe for intravenous infusion. In this series of COVID-19 patients with pulmonary fibrosis, there were demonstrable improvements in many clinical symptoms within a short period after hESC-IMRC transfusion (Table 1). Our cell therapy for lung fibrosis is safe for subjects in the medium term, for up to 84 days. Long-term safety will be observed in long-term follow-up at a later stage. Due to the special emergency presented by the COVID-19 outbreak in Wuhan, it should be noted that 7 of the 10 severe/critical cases had already undergone other clinical trials and 28 days of follow-up prior to this Phase 1 trial, but had still remained positive for pulmonary fibrosis. However, 27 of 27 patients displayed clinical improvements within 84 days after treatment with our hESC-IMRC therapy. In this Phase 1 trial, we have demonstrated that hESC-IMRCs are safe for intravenous infusion in the medium term, and our preliminary results showed efficacy for pulmonary fibrosis in COVID-19 patients. In order to further evaluate the clinical efficacy of this approach, we are now performing a multicentre randomized placebo-controlled Phase 2/3 trial.

中文翻译：

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使用 hESC-IMRCs 治疗 COVID-19 肺纤维化患者的 1 期试验

致编辑：肺纤维化是 COVID-19 患者的严重并发症。基于我们之前在小鼠模型和 2 名 COVID-19 患者中进行的急性肺损伤的干细胞治疗在一项试点同情使用研究中取得的成功，我们描述了一项 1 期临床试验，在该试验中，我们使用人类胚胎干细胞治疗患有肺纤维化的 COVID-19 患者。武汉市SARS-CoV-2爆发期间干细胞衍生的免疫和基质调节细胞（hESC-IMRCs）。根据我们的招募标准，我们确定了 27 名表现出肺纤维化病理的 COVID-19 患者（图 S1）。所有受试者的 SARS-CoV-2 阳性超过三周。患者的中位年龄为 66.5 岁，其中 70% 为男性（表 1）。使用胸部 CT 扫描诊断出确诊为 COVID-19 的患者患有肺纤维化。共有20名患者为住院患者，而其他7名受试者为出院患者，但仍因肺纤维化而出现呼吸道症状。在这 20 名住院患者中，10 名被归类为严重/危重病例，而另外 10 名被归类为中度病例。在 20 名患有肺纤维化并在休息或运动时出现呼吸急促的住院患者中，20 名中有 16 名接受了持续氧疗，其中 1 名依赖于高流量氧疗。20 名住院患者中另有 4 名也有肺纤维化和各种呼吸道症状，但只需要在运动后进行氧疗。7名出院患者仅在快速行走时出现呼吸道症状。在获得知情同意和批准后，所有 27 名患者均以 3 × 106 个细胞/千克体重的剂量静脉输注 hESC-IMRC。27 名患者中的 25 名接受了两次 hESC-IMRCs 静脉输注，而另外 2 名患者分别接受了一次和三次 hESC-IMRCs 静脉输注。接受 3 次 hESC-IMRC 输注的患者被归类为中度病例。他的临床症状在第一次 hESC-IMRC 输注后 10 天消失，但在治疗后 28 天前仍保持 SARS-CoV-2 阳性，之后他出院了。在第一次 hESC-IMRC 治疗后 84 天，我们通过在医院内重新检查或电话采访对所有患者进行了随访。7例出院患者在hESCIMRC治疗后56天可进行中等强度运动，无明显症状。从他们的胸部 CT 扫描中观察到，他们的肺纤维化病变区域显着减少（图 S1C）。我们在治疗后 7 天收集了 20 名住院患者中的 3 名的胸部 CT 图像（图 S1A-B，患者 #5、#20 和 #22）。胸部CT图像也显示他们的纤维化病变有所改善。在 hESC-IMRC 输注后 28 天，对 20 名住院患者中的 2 名进行了胸部 CT 扫描，发现他们的肺纤维化病变区域也显着减少（图 S1A，患者 #10、#23）。20 名住院患者中有 1 名因撤回家属同意而退出。对于 20 名住院患者中的其余 14 名，他们的肺纤维化病变区域在治疗后 84 天也显着减少（图 S1）。接受治疗的患者均未出现任何与细胞治疗相关的不良事件或异常反应。所有血液学和临床化学参数均保持在正常范围内（表 S1）。此外，在血清中未检测到肿瘤标志物，表明 hESC-IMRCs 可安全用于静脉输注。在这一系列患有肺纤维化的 COVID-19 患者中，在 hESC-IMRC 输血后的短时间内，许多临床症状都有明显的改善（表 1）。我们针对肺纤维化的细胞疗法在中期对受试者是安全的，最长可达 84 天。长期安全性将在后期的长期随访中观察到。由于武汉爆发的 COVID-19 疫情带来的特殊紧急情况，需要注意的是，10 例重症/危重症病例中有 7 例在本 1 期试验之前已经进行了其他临床试验和 28 天的随访，但肺纤维化仍呈阳性。然而，在我们的 hESC-IMRC 疗法治疗后 84 天内，27 名患者中有 27 名表现出临床改善。在这项 1 期试验中，我们已经证明 hESC-IMRC 在中期静脉输注是安全的，我们的初步结果显示对 COVID-19 患者的肺纤维化有效。为了进一步评估这种方法的临床疗效，我们现在正在进行一项多中心随机安慰剂对照的 2/3 期试验。