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Cytotherapy Corner Report - June 2022


Cytotherapy Corner


Donald G. Phinney, PhD
Senior Editor
UF Scripps Biomedical Research
Jupiter, FL, USA


Hello everyone. In keeping with the new format of highlighting select works in each Cytotherapy issue, I would like to draw attention to the paper by Kirkham et al., in the June 2022 issue that describes a systematic review and meta-analysis of MSC-based therapies for COVID-19.  While the effectiveness of MSCs for treating COVID-19 related pulmonary complications has been intensely studied, this article provides an important update on completed studies that also, in a broader sense, reflect the overall MSC clinical experience. This meta-analysis included studies that employed MSCs derived from several tissue sources. The cells were administered by various routes either alone or in combination with other therapeutics including antivirals, anti-cytokine drugs and immunomodulatory agents. Using these broad criteria, nine studies were identified that included 189 patients, of which 136 patients were administered MSCs. Importantly, while patient characteristics were well balanced, there were some important differences. For instance, there were more patients with mild COVID-19 vs. severe disease in the intervention group compared to the control group. Overall, the authors found that MSC administration significantly decreased the risk of death in patients (Risk Ratio =0.18, p=0.02), and resulted in a significant decrease in IL6 levels (Std. Mean Diff = -0.69, p=0.004). Additionally, patients administered MSCs showed more rapid improvement in clinical symptoms and were less likely to remain hospitalized when compared to controls. Overall, the data indicate that MSCs exhibit positive therapeutic effects, as has been demonstrated in the past for other disease indications. However, the authors note that the reliability of the data is limited due to reporting bias in all included studies. Since their analysis excluded studies published in languages other than English, this also likely introduced significant bias. The authors noted that all studies included in their meta-analysis were small and lacked sufficient statistical power to determine efficacy. The studies also exhibited significant heterogeneity in design, which has been a consistent problem for the field and confounds efforts to compare results across multiple trials even for the same disease indication.  

Results of the meta-analysis indicate that MSCs may be effective in treating COVID-19 related ARDS, which is consistent with other studies showing that MSCs may be most effective in patients with acute disease. The latter may be explained by the need to license the anti-inflammatory activity of MSCs in vivo. Alternatively, donor selection and manufacturing processes, which are used to produce MSC batches to treat many unrelated diseases, may select for cells that exhibit weak anti-inflammatory activity and, therefore, show effects only in patients with acute inflammation. Regardless, this study reflects a well-known and glaring deficiency in the field, which is the level of inconsistency in design and reporting of clinical data. Currently, there is interest in establishing a clinical trial registry for MSCs, which seems necessary since capturing clinical data globally and setting registry standards would help harmonize data across trials. A registry also would help discriminate between exploratory vs. confirmatory trials and ensure that data from early phase trials that may not require registration and reporting is captured. Lastly, by providing access to patient outcome data, the registry may accelerate efforts to develop potency metrics and manufacturing processes for next generation therapies.


In keeping with the cell therapy theme, I also want to highlight a paper by Stewart et al., in the July 2022 issue that discusses the need to better capture and characterize novel toxicities, such as cytokine release syndrome (CRS), associated with novel/emerging cancer immuno-therapies. CRS has emerged as one of the most common toxicities associated with cancer immunotherapies including CAR-T cell-based therapies. Because the pathophysiology of CRS has not been fully characterized, the authors argue for a standardized approach for diagnosing CRS in clinical trials and for reporting CRS in published literature. They also discuss the importance of distinguishing CRS from other infusion related reactions (IRRs), which have historically been reported in an ambiguous manner. The latter is important since IRRs may have overlapping symptoms but different pathophysiology from CRS; therefore, IRRs will require different management strategies in patients. In this paper, the authors expertly define these therapy related toxicities, describe symptoms of CRS in detail, and outline existing criteria used for grading CRS in patients. Based on their extensive clinical experience, the authors then offer a strategy to harmonize methods used to grade and report CRS in patients. By developing improved approaches/guidelines that are adopted by the medical community, it is anticipated that these efforts will lead to more consistent diagnoses and improved outcomes for patients that experience CRS during their course of treatment. 


Happy reading and keep those submissions coming.   




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