How hMSCs Could Work in Patients, What Are Their Biomanufacturing Needs, and When Can They Be Safely Stockpiled?
On New Year’s Day, 2020, buried in the headlines was news of a novel coronavirus. Yet who could have predicted the spiraling descent of events we witnessed up to present-day, with summer now here? When SARS-CoV2 infections spread exponentially worldwide through the winter and spring, they began reaping a grim toll of millions infected, hundreds of thousands dead, and a global economy plunged into deep freeze. With elusive hints of therapeutic efficacy for some repurposed drugs – and viable vaccine candidates at least months away from full scale validation— like all biotechnology firms, RoosterBio faced some pivotal decisions. In accord with many others in our industry, we chose not to sit on the sidelines.
Among other activities, we at RoosterBio chronicled and evaluated the unfolding crises in a series of ten blog posts and one webinar. We did this with a mind toward answering the question, “Why or how could human mesenchymal stem/stromal cells (hMSCs) make a difference?” Our first entry in the series was published on 13-March, Scalable MSC Manufacturing Matters in a Rapid Response to COVID-19. The authors noted that though hMSCs could hold substantial promise pending their success in future clinical trials, their widespread use for more than tens of doses at a time could remain hampered by the ongoing critical shortage of cell manufacturing scale-up capacity. Although we and our MTEC-affiliated colleagues recently demonstrated a 3D culture bioprocess for hMSCs at 50L+ scale, this blog’s authors then noted that a relatively modest ramp-up of additional capacity would be necessary via 20-30 bioreactor runs at 500L scale. Yet looking retrospectively, if MSCs do indeed prove safe and efficacious against COVID-19/ARDS, we may have underestimated the volume of their unmet need by an order of magnitude or more.
During March, news reports began to emerge from China, where preliminary studies of hMSCs were conducted in humans. Although initially positive results from these and other trials will need to be replicated with inclusion of larger numbers of patients, matched control groups, and fully transparent SOPs, we found reason to be encouraged. Several of our following blog titles addressed this topic: from 18-March Can MSCs Treat Patients with COVID-19?; and from 24-April, The Race to Beat COVID-19 with hMSCs Revs Up. We also wrote that despite the best efforts of cellular therapy developers, hMSC use to combat COVID-19 could require some optimization before “prime-time” (see our 14-April post, Patience for hMSCs in COVID-19: We Must Crawl Before We Run).
What if hMSCs (or a comparable biotherapeutic) could rapidly soften the blow of a case of severe COVID-19? We all remember the haunting phrase “Flatten the Curve,” but we speculated that such a therapy could not only “flatten” the curve but “shrink” it in a hypothetical modeled pandemic (see our 27-March post, Honey We Shrunk the Curve). “Shrinking the curve” could free up scarce ICU beds and hospital resources, possibly allowing greater recovery for victims of both the direct SARS-CoV-2 and any austere triage conditions. Further, we considered that hMSCs could be prospectively deployed out from the Strategic National Stockpile if a later, more severe respiratory epidemic (SARS-CoV-2 or otherwise) occurred (see our related 20-May post, MSCs as Medical Stockpiled Countermeasures: Cellular “First Responders” for COVID-19 and Future Emerging Biothreats). The basic rationale goes like this: it’s better to be prepared, treating patients out of a stockpile close to the “point of panic” than waiting through weeks of biomanufacture and product release. This high-level need was clearly articulated in the latest BARDA solicitation, now re-pivoted towards COVID-19.
In other blog posts, we recognized the latest trending science on hMSCs. That is, many of these cells’ in vivo effects are observed not through direct tissue regeneration, but instead due to their paracrine conditioning of a regenerative milieu in damaged lung, via multiple effectors that include extracellular vesicles (EVs) and/or exosomes (see our 3-April piece entitled hMSCs: A Secret(ome) Weapon Against ARDS). This promising avenue of investigation may invoke several advantages pertaining to longer term drug stability and uniform quality attributes. We thus also wrote about our efforts (representative abstract links HERE and HERE) to produce EVs at RoosterBio, explaining our optimized bioproduction methods to reach large scale production of EVs via 3D cultured hMSCs (see hMSCs (see 15-May’s Productivity Metric Considerations in MSC & MSC-EV Manufacturing in Response to COVID-19). This blog post relates RoosterBios’s standard production metrics to how a scale-up might unfold in real-life. Specifically, an approximate 2667 individual doses could be manufactured out of >1 quadrillion EV particles, via 8 production runs in 500L bioreactors. Hence, a practical future for COVID-19 EV therapies could be well within reach.
RoosterBio’s mission is based on the imperative that our product Quality Begins at Inception by continually monitoring critical attributes that may affect safety, identity, potency, purity and quality. From donor qualification, to Master Cell Bank, to Working Cell Bank, we ensure that these cells and their paired media measure up to the pressures of the COVID-19 crisis, and “Fuel the Rapid Commercialization of Scalable Regenerative Cures.” Therefore, in this blog series, we’ve also reflected on the concerns in the FDA’s, ISCT’s and ISEV’s commentary in response to a few seemingly cavalier attitudes of a small number of players in the medical tourism industry and elsewhere (see 29-April’s Accelerating COVID-19 Treatments with Patient Safety As First Priority). Regarding these, RoosterBio is solidly in support of the best practice recommendations and cautions of these organizations (see 5-June’s RoosterBio Supports ISCT and ISEV Position Statement on Outlining Promise and Caution of hMSC EVs/Exosomes in COVID-19 Trials).
Though there are diverse biotechnology approaches needed to detect, monitor, characterize, prevent, and treat COVID-19, RoosterBio is not too different from its industry peers regarding the basic struggle with COVID-19’s sudden onslaught. Just as with our colleagues worldwide, we’ve course-corrected in order to meet the daunting challenges posed by the COVID threat, rolled with its punches, and are facing it head-on. While it’s our sincere wish to soon recalibrate our focus on process innovations to accelerate the 21st Century’s human health and regenerative medicine applications, we’ll nevertheless continue to observe, learn and report via our growing compilation of new COVID-19 knowledge.