Center of Expertise in Research and Innovation of the International Network for the Advancement of Viable and Applicable Innovations in Life Sciences (InAvail), InAvail at Rosental Nexxt, 4058, Basel, Switzerland.
Avail Biomedical Research Institute, 80539, Munich, Germany.
Adv Ther. 2023 Jun;40(6):2626-2692. doi: 10.1007/s12325-023-02507-z. Epub 2023 Apr 17.
Serious manifestations of respiratory virus infections such as influenza and coronavirus disease 2019 (COVID-19) are associated with a dysregulated immune response and systemic inflammation. Treating the immunological/inflammatory dysfunction with glucocorticoids, Janus kinase inhibitors, and monoclonal antibodies against the interleukin-6 receptor has significantly reduced the risk of respiratory failure and death in hospitalized patients with severe COVID-19, but the proportion of those requiring invasive mechanical ventilation (IMV) and dying because of respiratory failure remains elevated. Treatment of severe influenza-associated pneumonia and acute respiratory distress syndrome (ARDS) with available immunomodulators and anti-inflammatory compounds is still not recommended. New therapies are therefore needed to reduce the use of IMV and the risk of death in hospitalized patients with rapidly increasing oxygen demand and systemic inflammation who do not respond to the current standard of care. This paper provides a critical assessment of the published clinical trials that have tested the investigational use of intravenously administered allogeneic mesenchymal stem/stromal cells (MSCs) and MSC-derived secretome with putative immunomodulatory/antiinflammatory/regenerative properties as add-on therapy to improve the outcome of these patients. Increased survival rates are reported in 5 of 12 placebo-controlled or open-label comparative trials involving patients with severe and critical COVID-19 and in the only study concerning patients with influenza-associated ARDS. Results are encouraging but inconclusive for the following reasons: small number of patients tested in each trial; differences in concomitant treatments and respiratory support; imbalances between study arms; differences in MSC source, MSC-derived product, dosing and starting time of the investigational therapy; insufficient/inappropriate reporting of clinical data. Solutions are proposed for improving the clinical development plan, with the aim of facilitating regulatory approval of the MSC-based investigational therapy for life-threatening respiratory virus infections in the future. Major issues are the absence of a biomarker predicting responsiveness to MSCs and MSC-derived secretome and the lack of pharmacoeconomic evaluations.
呼吸道病毒感染（如流感和 2019 年冠状病毒病[COVID-19]）的严重表现与免疫反应失调和全身炎症有关。用糖皮质激素、Janus 激酶抑制剂和抗白细胞介素-6 受体的单克隆抗体治疗免疫/炎症功能障碍，显著降低了住院 COVID-19 重症患者发生呼吸衰竭和死亡的风险，但需要使用有创机械通气（IMV）和因呼吸衰竭死亡的比例仍然较高。目前不推荐使用现有的免疫调节剂和抗炎化合物治疗严重流感相关肺炎和急性呼吸窘迫综合征（ARDS）。因此，需要新的治疗方法来降低对那些快速增加氧气需求和全身炎症且对当前标准治疗无反应的住院患者使用 IMV 的需求和死亡风险。本文对已发表的临床试验进行了批判性评估，这些试验测试了静脉内给予同种异体间充质干细胞（MSCs）和 MSC 衍生的分泌产物的研究性使用，这些产物具有潜在的免疫调节/抗炎/再生特性，作为附加治疗以改善这些患者的结局。在涉及严重和危重症 COVID-19 患者的 12 项安慰剂对照或开放标签比较试验中的 5 项以及唯一一项关于流感相关 ARDS 患者的研究中，报告了生存率的提高。结果令人鼓舞，但由于以下原因尚不确定：每个试验中测试的患者数量较少；伴随治疗和呼吸支持的差异；研究组之间的不平衡；MSC 来源、MSC 衍生产品、剂量和研究性治疗开始时间的差异；临床数据报告不充分/不适当。为了改进临床开发计划，提出了一些解决方案，旨在促进未来对危及生命的呼吸道病毒感染的基于 MSC 的研究性治疗的监管批准。主要问题是缺乏预测对 MSCs 和 MSC 衍生的分泌产物反应的生物标志物以及缺乏药物经济学评估。
