A Multi-Version Medicinal Technology System, Part II

A New Generation of MSC Applications

With scientific results dismally challenging to replicate properly across disciplines, scientists, technologists, or investors with intact survival instincts cannot be naïve. No matter how gruff it sounds, a healthy respect for due diligence and fiduciary responsibility demands that good people ask, “Where’s the beef!?” at any time. In Part I of this article, we first heard about “MSC 2.0,” ¹⁷ which is the second generation of mesenchymal stem/stromal cell (MSC) cellular technology. Like T cells, MSCs are a raw primary cellular source that irrigates multiple branches of downstream clinical applications that intermingle with other technologies. Although one potentially promising use of “v2.0” involves cell-cultured and/or cruelty-free meat (aka “clean meat”), ⁷⁶ we aim to inform you here that MSC 2.0 now supports other—more near-term—ventures of direct benefit to human health.

MSC-EVs: Engineered Nanomedicines from (and for) the Body Electric

EVs (extracellular vesicles)—sometimes referred to as exosomes ⁷⁷ —are abundantly secreted ⁷⁸ into conditioned media by MSC ⁷⁹ bioproduction systems. It’s been compellingly ⁸⁰ demonstrated ⁸¹ that part or even most of the therapeutic effect ⁸² of MSCs could be due to EVs released into the “secretome.” ⁸³ MSC-EVs’ naturally intrinsic benefit along with their engineerability turbocharged them into the pole position for an assortment of next-generation advanced therapies. ⁸⁰^,⁸⁴^,⁸⁵^,⁸⁶^,⁸⁷^,⁸⁸^,⁸⁹^,⁹⁰^,⁹¹^,⁹²

Compared with derivatives of HEK-293 cells (the mainstay for gene therapy vector production and many vaccines), MSCs don’t have a transformed phenotype. Furthermore, EVs from MSCs may uniquely express biological activities of therapeutic value, such as via localized CD73/adenosine ⁹³^,⁹⁴ or miRNA ⁹⁵ cargoes. Accordingly, mesenchymal stromal/stem cells (MSCs) have advanced to the leading edge of cellular bioproduction sources of extracellular vesicles for human clinical trials. ⁸⁰^,⁹⁶^,⁹⁷ “Why bother why bother buying the cow when you can directly buy the milk?” expresses a widely-voiced apropos analogy. ⁹⁸

In the case of monoclonal antibodies, heavily engineered CHO cells are the “cows” and their mAb products are the “milk” for an industry valued at over $200B in global sales. ⁹⁹ Likewise, to secure MSC 2.0 as a domain for EV/exosome manufacturing, ongoing efforts are underway to generate rejuvenated and clonal MSCs from iPSCs, immortalized (yet non-transformed) MSC cell lines, improved gene transfer methods, and MSC-friendly upstream ¹⁰⁰ and downstream ¹⁰¹ processes that can ultimately be scalable into bioreactor batch runs of over 1000 liters. ¹⁰² Of course, the biggest breakthroughs are yet to be realized, determined by new synthetic biologists and product developers who aim to derivatize these macromolecular particles with novel surface ligands and intraluminal cargoes. ⁸⁸^,¹⁰³^,¹⁰⁴^,¹⁰⁵

Two to Tango: Co-cultured Cell Partners for MSCs’ Dance with the Stars

In other applications of MSC 2.0, the MSCs are essential cellular components for a separate cell therapy. That is, they may “educate” co-cultured cells of a different origin to induce them into a more uniformly beneficial phenotype for re-implantation. In one example, ¹⁰⁶ Dr. Ashish Patel of King’s College London combined standardized preparations of allogeneic, off-the-shelf MSCs with ex vivo autologous patient monocytes. This procedure converts monocytes from a pro-inflammatory, pre-phagocytic cell into a potent mix of anti-fibrotic, pro-angiogenic, and anti-inflammatory cells. Given instant availability of stockpiled, clinical grade cGMP MSC cell material, a recent Phase I trial against COVID-19 ¹⁰⁷ was rolled out at lightning speed via qualified biomaterials, regulatory approvals, and patients lined up within eight months.

Still more examples of MSC 2.0 might include co-administered MSCs along with a partner cell type, such as Foxp3+ Tregs, in future human trials. With Dr. Charles Cox’s team of the University of Texas Health Center, it was shown that the combination of Tregs and MSCs for treatment of a model traumatic brain injury (TBI) ⁷ was superior to either cell type administered alone. This and similar in vivo results for conditions such as GvHD, ¹⁰⁸ recurrent spontaneous abortion, ¹⁰⁹ retinal ischemic injury, ¹¹⁰ multiple sclerosis, ¹¹¹ and many ¹¹² other conditions suggest a possible synergy ¹¹³ between MOAs of immunosuppressive T cell subtypes and MSCs. ¹¹⁴ In parallel applications that have advanced into early human trials, initial observations show that co-infused MSCs may develop a pro-tolerogenic environment for organ transplants, ¹¹⁵ reducing the doses (and side effects) of immunosuppressive drugs and risk of acute rejection. In addition, MSCs are being explored to optimize regenerative therapy outcomes when co-administered with chondrocytes for treatment of focal cartilage defects, ¹¹⁶^,¹¹⁷ along with other indications. ¹¹⁸

Induced pluripotent stem cells (iPSCs) open the gates to an entire landscape of downstream therapeutic and drug screening cellular technologies. ¹¹⁹ Their derivative cell types can be used as targets for libraries of “druggable” combinatorial chemicals as well as genetically defined disease model systems or as a source of “rejuvenated” cellular raw materials for dosed human therapeutics in regenerative medicine or immune oncology. iPSCs via MSCs do not merely comprise a compelling starting material that is potentially fully traceable and regulatory-compliant for future cell types of clinical translation interest. ¹²⁰ MSCs can also be engineered as “feeder cells” to assist in generation and propagation ¹²¹^,¹²² of new iPSC clones. The ease of mass MSC culture and its plug-and-play industrial supply chain of xeno-free, clinical grade materials could solve some of the issues challenges of variable quality and non-human features of mouse embryonic fibroblasts (MEFs).

Differentiation for Potentiation

While MSCs are often considered to serve immunosuppressive roles, Dr. Moutih Rafei and colleagues at Defence Therapeutics recently devised a means to polarize these cells ¹²³ in the opposite direction towards potent antigen presentation. ²³ With Accum™ technology, MSCs are coaxed to work as an “off-the-shelf Universal vaccine” that can synergize with immune checkpoint blocking mAbs. Functioning as programmable dendritic-like cells but without the onerous manufacturing pitfalls, these exhibited powerful anti-tumor efficacy in animal models and are en route to a Phase I trial in melanoma patients.

The capability for MSCs to exhibit unique cell fate plasticity beyond the prototypical “tri-lineage” (fat, bone, cartilage) is also relevant to neurology. Here are just two of many other examples. A readily available and abundant source of replacement neuron-like cells for treatment of Parkinson’s Disease, ALS, or other neurodegenerative conditions might be possible from MSCs that are induced to transdifferentiate into neurons. ¹²⁴ Induced cholinergic-like neurons could also credibly model ex vivo simulations of diseases like familial Alzheimer’s, ¹²⁵ of conceivable benefit to high throughput (HTS) compound library screening.

MSCs as Programmable Trojan Horses for Drug Delivery

Another theme of MSCs as anti-cancer weapons deploys them as “Trojan horses” for oncolytic viruses. That is, the MSCs may increase the amount of oncolytic virus that’s in proximity to the tumor, widening the window of efficacy in lieu of direct tumor injections. In 2019, Calidi Biotherapeutics completed a small, Phase I trial with ACAM2000, ¹²⁶ a thymidine kinase positive vaccinia virus delivered by adipose MSCs into various solid and liquid tumors. Similarly, oncolytic adenovirus has been used by Dr. Manuel Ramírez and associates of the Hospital Universitario Niño Jesús to treat refractory or relapsed solid tumors in nine children and seven adults in a Phase I trial. ¹²⁷ This approach is also being leveraged by trials for glioblastoma at MD Anderson Cancer Center (NCT03896568) and for ovarian carcinomas at the Mayo Clinic (NCT02068794).

MSC 2.0 drug delivery techs do not necessarily solely rely on “spicy,” tumor-melting viruses to selectively target and/or control a bioactive ingredient, of course. An especially fascinating such technology is hosted by Tel Aviv’s nanoGhost, ¹²⁸ which removes the nuclei of MSCs and uses their membranes as small bags for a pipeline of targeted proteins, small molecules, or mRNA drugs. Cytonus (Carlsbad, CA) ¹²⁹ has devised alternative methods for its MSC-derived drug delivery platform, which combines AI therapeutic engineering with its enucleated (yet otherwise intact) cell systems that promise spatiotemporal control over the precision release of biologic drugs.

MSCs Help Medical Innovations Flow into Vascular Engineering and Pro-Angiogenesis Applications

One of the “super-powers” of MSCs (including secretome and immune-modulation) relates to their apparent mundane “day job” as a pericyte or pericyte-like cell. ¹³⁰ On injury to a vascular net, pericytes and their MSC kinfolk can help plug the leak and promote angiogenesis. As putative progenitor cells, they can also be coaxed to differentiate into vessel-lining endothelial cells ¹³¹ as well as contractile smooth muscle, ¹³² and they can favorably respond to hypoxic stimuli ¹³³ and form nascent microvascular morphologies. ¹³⁴ Initially, such features naturally inspired development of “MSC 1.0” therapeutic approaches that have been aimed at ischemia related indications such as heart failure ¹³⁵^,¹³⁶ and acute myocardial infarction. ¹³⁷ An MSC 2.0 modality that might plausibly bridge the bumpy “efficacy gap” observed between many Phase II and Phase III trials is genetic modification of MSCs with pro-survival and pro-regenerative factors such as SDF-1, ¹³⁸ EPO, ¹³⁹ VEGF, ¹⁴⁰ or synergistic multi-gene combinations. ¹⁴¹

Exciting developments are underway not merely for classic cell therapies, but rather MSCs that are printed or layered into artificial tissues that could be constructed to meet profound unmet medical needs. MSCs have been shown to perform more robustly than primary smooth muscle cells in some ex vivo experimental contexts to devise tissue engineered blood vessels (TEBVs). ¹⁴² One format of scaffolded TEBV is the TEVG, or tissue engineered vascular graft, which can also be seeded ex vivo with MSCs that gradually remodel the device into a functional blood vessel when re-implanted in vivo. ¹⁴³ Having already demonstrated dramatic in vivo data, such bioengineered constructs could potentially resolve a shortage facing thousands of patients who await high quality, living blood vessel grafts for repair of aortic aneurisms. ¹⁴⁴^,¹⁴⁵^,¹⁴⁶ MSCs not only help restore or manufacture blood vessels; they cooperate as important cell ingredients to vascularize tissue engineered bone, highlighting a possible material for reconstructive surgeries following serious injuries. ²²^,¹⁴⁷

Mitochondria from MSCs for Advanced Therapy Power-Ups

It almost sounds like science fiction, but 2 billion years of evolution and almost 20 years of investigation has validated the idea that MSCs donate mitochondria to ailing neighbor cells ¹⁴⁸^,¹⁴⁹ in disease lesions or zones of oxidative stress. Can this natural physiologic mechanism be mimicked to augment novel human medicines? Answer: yes, and the field is advancing perhaps farther than you might think. ¹⁵⁰ At least seven human trials report mitochondrial transplantation as the MOA, and four of these appear to source these organelles directly from MSCs. Several commercial ventures use MSCs to further this goal, including Mitrix Bio, Minovia, celllvie, PEAN Biotechnology, LUCA Science, Mitosense, and Taiwan Mitochondrion Applied Technology Co. Although extensive future work will be needed (perhaps with the help of MSC 2.0 cellular platforms), transplanted mitochondria may have already saved the lives of neonatal infants in cardiac arrest, as reported in the New York Times.

Cell and Gene Therapy “Building Blocks” for MSC “Engine Blocks”

“By 2005 or so, it will become clear that the Internet’s impact on the economy has been no greater than the fax machine’s.”

–Nobel Prize Winning Economist, Paul Krugman, 1998

By the time Professor Krugman provocatively threw shade on the “dial-up” Internet of 1998, its core protocol for data exchange via the 1960s-era “ARPANET” predecessor was already 15 years old. Krugman would have been keenly aware that this emerging tech platform had already taken decades to develop. And he was directionally correct that the Web’s inflection point for mass adoption could be challenging to predict when it was then hamstrung by a lack of interested users and proportional connection nodes. “Most people have nothing to say to each other,” he quipped. However, what he may have missed was the hard work with infrastructure development and value creation modes that was already churning behind the scenes.

The long latency to load a single page would soon be ancient history with arrival of DSL, fiber optic, and 3G connections. And the iPhone? Less than a decade away. Due to subtle process innovations underlying each year’s new hardware and software, the internet first gradually and then swiftly became democratized—ubiquitous on every continent to serve a large majority of the world’s population. Similarly, many challenges that once plagued early MSC clinical products (with their outdated, regulatory-cemented bioprocesses) a decade ago are now solved due to a robust, industrialized supply chain with parallel reductions in the cost and time per billion cells. The bioproduction path to rapid MSC doses for patients in need has never been easier, with these undergoing a digital-like democratization toward worldwide access.

Young travelers riding the family “wheels” like to notoriously ask “Are we there yet?!” ¹⁷ However, to prematurely declare “yes” for an emerging technology might be “putting the CAR-T before the horse,” as some had cautioned the immune oncology field in the early 2010s, fretting about a replay of the Dendreon saga wherein a promising (yet highly complex) cell-drug faced manufacturing and scalability headaches. For the Internet of 1998, the answer was also “no,” as the standards and infrastructure (e.g., “roads”) were not yet firmly established. Likewise, MSCs are not quite “there yet,” but for different reasons than what was faced by T cell or Silicon Valley pioneers. In contrast to the ‘98 internet, however, the material and process infrastructure for MSC therapies are largely already built. That is, the obstacles to MSCs are now mostly conceptual and regulatory in nature.

One possible accelerant for MSCs effective navigation of the road ahead (as well as CAR-Ts and all cell and gene therapies) has been called technology platform “building blocks.” This concept ¹⁵¹ was recently explored in a working session co-sponsored by the Alliance for Regenerative Medicine (ARM) and the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL). The modular nature of synthetic gene construction combined with the toolkit of diverse cultured cell types and their phenotypes lends itself to rapid, bespoke solutions to both common and extremely rare human disease conditions. On the other hand, these novel therapies and cures are necessarily complex; with each minor modification to each component or process, an entire new drug process must begin again with a new IND and years of costly development.

A “building block” represents a reusable platform technology designation that could “improve time and resource efficiency of CGT development and regulatory review” that could be quickly transplanted across diverse clinical programs. A specific example might be a validated genome editing molecular toolset of CRISPR reagents and best practices. For MSCs, this building block could conceivably involve a master cell bank (MCB) and/or its paired bioreactor expansion medium and optimized process. The novel “MSC 2.0” therapy might thus involve a combination of two blocks: the standardized CRISPR system and the accompanying MSC bioprocess platform. We would not need to reinvent the wheel with each platform over and over. Given the plight of patients with only months left to live, a new IND could ideally be launched in weeks, not years.

Recent often-cited projections do not predict a plateauing of “Peak MSC” demand until the 2040s. ¹⁷ Why? Accessibility of clinical grade MSC’s with highly optimized bioprocessing conditions is now leading to more testing and experimentation than ever before. Despite recent speedbumps with MSC 1.0 in late-Phase clinical trials, mesenchymal stem/stromal cells (MSCs) are undergoing a significant evolution known as MSC 2.0, akin to the transformative journey observed in CAR-T cell therapy. Uses in clinical and/or consumer products that will supersede MSC 1.0 are likely to include tissue engineered products, muti-cell combinations, cosmeceuticals, products secreted or extracted from MSCs, MSCs derived from iPSCs, and others.

Looking at the current innovation space, it appears that hundreds of pre-commercial entities, startups, and existing biotechs already plan to incorporate MSC 2.0 into trials over the coming years. Expected progression of the MSC operating system, coupled with the right recipes for clinical success, could further accelerate waves of new therapies. This shift of focus towards “forward engineering” cell therapies emphasizes the role of genetic design and advanced bioprocessing in unlocking the full potential of MSCs. MSC 2.0’s exploration of novel applications, including extracellular vesicles, and innovative drug delivery systems will converge these concepts and position MSC 2.0 as a guide for the future development of these cells, paving the way for precision medicine and integrated regenerative therapies.

Interested to view Part 1 of this article? Click to read it here!

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Alliance for Regenerative Medicine, FDA Scientific Exchange: Unlocking the Potential of Building Blocks to Expedite CGT Development and Review. https://alliancerm.org/arm-event/arm-fda-scientific-exchange-meeting-on-platform-technologies/.

To learn more about this rapidly expanding market, view the global strategic report, “Mesenchymal Stem Cells / Medicinal Signaling Cells (MSCs) – Advances & Applications“.

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