Performance of MSCs in Preclinical Models of ALI and Translation to Clinical Trials
The growing interest in the therapeutic potential of these cells for the treatment of ARDS rests solidly on their robust and reproducible performance in preclinical models of organ injury including lung bleomycin [30], intratracheal [31-33] or intraperitoneal [34, 35] endotoxin, cecal ligation and puncture [36], pseudo- monal abdominal sepsis [37], and E. coli pneumonia [38]. In most, if not all models, stem cell administration reduces the odds of death [39, 40]. This is true for overall mortality, as well as mortality at predefined time intervals [39]. MSC administration reduces death even when the initiation of MSC therapy is delayed to 6 h post induction of ALI (or sepsis). In terms of secondary outcomes, MSCs may exert their beneficial effect by reducing inflammation while enhancing bacterial clearance [41], augmenting lung repair [42], and restoring alveolarcapillary barrier function [43, 44]. The dramatic results in preclinical models of ALI has propelled rapid translation to the clinic, with a recent phase I trial completed [45, 46], a phase 2 trial in progress (NCT02097641), and another phase 1/2 randomized, double-blind, placebo-controlled trial (NCT01902082) on the way. The latter targets not only safety but also efficacy outcomes, using allogeneic adipose-derived MSCs. In both studies, cells will be administered intravenously, inclusion criteria are similar, and MSC therapeutic doses vary from 1 to 10 x 106 cells/kg. In parallel, the Canadian Critical Care Trials Group has also initiated the first human trial using stem cell as immunotherapy for the treatment of sepsis (Cellular Immunotherapy for Septic Shock, CISS Trial, NCT02421484).
As we transition from preclinical to clinical studies, many questions remain about how we will translate knowledge acquired on the bench or in animal models to the clinic. We will highlight some of these questions throughout the review, but the issue of potency deserves brief attention. The International Society for Cellular Therapy (ISCT) released in 2015 their perspective on immune functional assays for MSC potency [47]. The proposal springs from a broad consensus in the community that, despite different tissue sourcing and culture expansion protocols, human MSCs likely share fundamental mechanisms of action. Identification of functional markers of potency and harmonization of standard operating procedures to measure biological properties of stem cells intended for therapy is a primary goal of future studies. The preferred analytic methods proposed by the ISCT focus on (a) gene, (b) protein (secretome), and (c) cell marker expression that reflect current knowledge in the field. While safety and tolerability of human MSCs remain the main primary study end points, future studies will aim to address secondary efficacy end points by assessing respiratory, systemic, and biological markers of function. Here, we will briefly discuss the state of knowledge of the immunoregulatory properties of these cells and their potential for future therapeutics in ARDS.
