Category: Cell Therapy

Transitioning bioprocesses from R&D to full-scale production poses intricate challenges, especially in advanced modalities like cell and gene therapy. Access to high-quality equipment and materials that can support processing from the lab to the production plant can help reduce the complexity of scale-up and the associated risks. Corning Life Sciences, with its emphasis on science, innovation, and customer collaboration and its comprehensive portfolio of equipment, consumables, and ancillary materials, has long been a mainstay in the laboratory and is ideally positioned to help cell and gene therapy manufacturers bring their curative treatments to market.

Biologic, Sourcing, and Regulatory Challenges to Scaling

Scaling presents many challenges in biologics manufacturing, regardless of the type of drug substance involved — conventional monoclonal antibody, next-gen multispecifics, or novel modalities, such as viral vectors and cell therapies.

The first challenge is rooted in the fundamental biology. Process conditions in compact shake flasks vary considerably from those in expansive stirred-tank bioreactors. Factors, such as mixing dynamics, gas concentrations, nutrient and metabolite levels, and pH values across the medium, all undergo changes when transitioning from the laboratory bench to the pilot stage and eventually to full-scale commercial production. Adapting to these variations demands intricate process comprehension and, ideally, the implementation of scaled-down production models to bridge the differences in process parameters.

The second obstacle relates to the selection and procurement of raw materials. Regulatory bodies are placing heightened emphasis on the quality of even ancillary materials, which might not be present in the final product, recommending their production under GMP conditions. R&D labs typically operate at smaller scale; many of the materials they use may be designated for research use only (RUO) and may not always meet the highest quality standards. As their process scales up, the challenge arises when a vendor does not offer a GMP-grade variant of that product with consistent properties; transitioning to an acceptable alternative can then affect both the process performance and the final product quality. This issue can be mitigated substantially by initially selecting raw materials, such as Corning^® CellSTACK^® cell culture vessels, that are available with consistent characteristics in both research and GMP scales.

A third distinct challenge in bioprocess scaling stems from the need to align with the regulatory standards of the markets where the biopharmaceutical product is intended for sale. Beyond raw material standards, there are requirements for product quality and process monitoring and control. The transition into clinical and commercial production is more than just a question of biology and sourcing — it encompasses how every facet of bioprocessing converges at a larger scale to yield drug substances and products that ensure safety and efficacy for the treatment of human disease.

The Scale-Out vs. Scale-Up Question

Another pivotal consideration for manufacturers when producing larger volumes is deciding between scaling up and scaling out. It is crucial to determine the required, phase-appropriate quantities of drug substance and product and the most effective technology to meet those needs. There is a marked distinction between preclinical, phase I clinical, phase III clinical, and full commercial production stages, and the ultimate scaling approach is typically determined by the end of phase II or before phase III.

Scaling out means amplifying output by replicating the process using identical equipment, as many times as needed to meet demand. This method utilizes consistent technology, eliminating the need for additional process optimization. However, plant footprint, human resources (number of operators), and timing are critical considerations.

Increasing the output through scaling up typically requires transitioning to larger-volume or higher-surface processes, often using more expansive equipment. This approach allows the same team of operators to produce significantly more product, but more process development work is required to ensure that the process is optimized for the larger scale. This effort can be minimized by using production systems designed to be scalable, such as Corning CellSTACK, and HYPERStack^® cell culture vessels, which provide similar process conditions for adherent cell culture and thus streamlined scale-up.

In some cases, scaling up not only means producing a greater volume but also transitioning between technologies. For example, viral vector manufacturing via transient transfection typically employs adherent cell culture at smaller scales. Yet, as production processes expand, manufacturers often shift toward utilizing suspension cell culture.

An alternative approach is to keep adherent cells in a suspension process utilizing Corning’s polystyrene or dissolvable microcarriers within a single-use bioreactor (SUB). Alternatively, the Corning CellCube^® system provides a perfusion-based method in which cells are attached to both sides of layered plates within enclosed modules of 10, 25, and 100 layers. These methods facilitate significant scaling within a compact footprint.

Indeed, many pharmaceutical manufacturers strategically leverage both scaling out and scaling up, depending on the need. For instance, antibody production is often scaled to 2,000-L SUBs. When demand surpasses this scale’s capacity, instead of transitioning to larger 5,000-L bioreactors, manufacturers typically choose to scale out using 6 x 2,000-L bioreactors. This strategy circumvents additional process development and reduces risks; if one batch out of the six fails, the other five remain unaffected. This approach not only minimizes economic setbacks but also crucially prevents potential drug shortages and risks to patients.

The Need to Align Numerous Moving Parts

Successful scale-up and transfer of processes from one team to another, each with different objectives and workflows, requires alignment of many different moving parts. R&D environments often contrast sharply with manufacturing settings. The former tend to operate with more flexibility, while the latter emphasize strict control, influencing all aspects of bioprocessing. Operators oversee and observe processes, often equipped with inline sensors and automated mechanisms for media and feeds. Within a cleanroom setting, these operators are clad in full bodysuits. Furthermore, the time required to process a large-scale batch far exceeds that of a small-scale operation.

Before transitioning technology from R&D to a manufacturing setting, it is vital to account for the numerous differences between these environments. While it is standard to have teams focused on tech transfer and scaling, that alone is not necessarily adequate. R&D teams need to understand the varied approaches and workflows, aiming to adapt the biology to ensure that processes are robust and scale seamlessly.

Engaging in discussions about whether to scale up or out at the earliest stages is crucial to ensure comprehensive consideration throughout process development.

Focus on Increasing Sustainability

Corning Life Sciences, along with the entire pharmaceutical industry, recognizes the need to increase the sustainability of drug manufacturing operations. In response, Corning is rolling out a number of sustainability initiatives, including the Corning^® EcoChoice™ program. Products under the Corning EcoChoice label are manufactured, packaged, and distributed in a manner that prioritizes environmental responsibility, adhering to the FTC guidelines, which require all sustainability statements to be specific, evidence-based, and traceable. Strategies employed to increase sustainability include use of recycled materials, source reduction, process intensification, and use of renewable energy.

Corning HYPERFlask^® and HYPERStack Vessel Case Studies[1]

In the cell and gene therapy sector, scaling up from initial R&D to larger-scale adherent cell culture is a common challenge. Corning Life Sciences recognized this challenge and established a bioproduction division, offering support through class one medical devices like the Corning HYPERFlask, CellSTACK, and HYPERStack products. Corning’s extensive materials science expertise ensures uniformity in raw materials, aiding a smooth transition during scale-up and preventing variations that can affect cell adhesion and growth. Corning’s GMP-compliant technologies range from traditional spinner flasks to advanced flaskware and dissolvable microcarriers and extends to the Ascent^® Fixed Bed Bioreactor and CellCube technology to accommodate projects at various developmental stages and scales. Additionally, Corning provides a comprehensive suite of cell culture solutions, streamlining upstream processes for cell and gene therapies. Our commitment includes collaboration with customers throughout all project stages, integrating automation, adhering to regulatory standards, and gathering insights to address a host of production challenges.

For example, one customer looking to bring production in-house to supplement production at a CDMO needed a solution that would fit in an existing space and provide specific incubation conditions. Corning HYPERStack vessels were found to be the ideal solution, optimizing the utilization of their existing manufacturing space.

In another case, research scientists at a large biopharmaceutical company found themselves overwhelmed with managing hundreds of T-flasks. Seeking alternatives, they approached Corning for a solution. While the project is ongoing, the preliminary transition sees those numerous T-flasks substituted with merely 10–15 HYPERFlask vessels.

Additionally, during a phase I trial, the Ottawa Hospital Research Institute’s Cell Manufacturing Facility needed to deliver freshly cultured allogeneic bone marrow–derived MSCs to septic shock patients within a narrow 6-hour window. The Corning HYPERFlask vessel was pivotal for this emergent per-patient dosing. As the research advanced to larger and later-phase clinical trials, the consistent and scalable nature of the Corning HYPERFlask and HYPERStack cell culture vessels ensured reproducibility, maintaining the same protocol and working environment of the isolator units.

iPSC Opportunities

Stem cells, especially induced pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSCs), are gaining traction in non-genetically modified cell therapies. Traditionally, these cells have been cultivated in a 2D adherent culture. There is growing interest in suspension culture, due to its promise of greater scalability and cost-efficiency. However, moving to suspension presents challenges, particularly for stem cells, which prefer adherent environments. Microcarriers — small beads that provide a high ratio of surface area to volume — suspended in SUBs offer an alternative approach with some of the benefits of both adherent and suspension environments, and dissolvable microcarriers (DMCs), like Corning’s Synthemax^® II DMCs, enable a more efficient harvest and downstream experience.

Innovation Driven by Science

Cell and gene therapies signify a transformative approach in medical science, shifting from merely managing symptoms to achieving complete cures for patients. Corning Life Sciences stands committed to realizing this transformative vision alongside its partners. To make that happen, the company values science and strives to innovate in collaboration with customers. As partners pave the way with novel products and methods, Corning harnesses its scientific prowess to deliver cutting-edge equipment and material solutions, propelling these groundbreaking cell and gene therapies into the mainstream market.

Originally published on PharmasAlmanac.com on December 12, 2023.

Personalized gene-modified cell therapies are expensive and complex treatments, and numerous factors contribute to their success or failure for individual patients. A means for predicting outcomes for each patient is needed to ensure that clinicians — together with their patients — are able to select optimal treatments. Such data-driven decision-making will help lower the costs of cell therapies and provide confidence to insurers, ultimately increasing access. The Evidence Engine being developed by IQVIA with support from a consortium of nonprofit organizations including Be The Match BioTherapies is designed to provide the global data sets and analytical tools needed to support this approach.

The Need to Predict Outcomes

Personalized gene-modified cell therapies, initially developed for the treatment of cancer, are currently under investigation for an expanding array of diseases, including both autoimmune and genetic disorders and other conditions. There are many patient-related variables that impact the safety and efficacy of these complex treatments. Success of these therapies is also contingent on the performance of an extremely complicated and expensive manufacturing process and supply chain.

One of the biggest issues with achieving successful gene-modified cell therapy outcomes is matching the right patients with the right treatments. Clinicians are at the heart of this process and are at the center of the gene-modified cell therapy ecosystem. They need more data to make informed decisions regarding who should receive these therapies and when they should be administered. That data should address the variables that must be taken into account to anticipate what the outcome might be for each patient.

Providing this information is becoming increasingly important as gene-modified cell therapies move out of current centers of excellence and into community hospitals. Such a move to the outpatient setting must occur to expand patient access, as most cancer patients do not live near these centers of excellence. Physicians working in community oncology centers that have no experience with cell therapy may find it very difficult to determine which cell therapies are optimal for which patients.

Payers also seek data to support the treatment of patients with very expensive gene-modified cell therapies. They want evidence that a patient who received a cell therapy treatment was truly a good candidate. Similarly, policy makers are interested in increasing access while also reducing the overall cost of healthcare, including gene-modified cell therapies. Here again, this goal can only be achieved if it is possible to determine which patients are most likely to benefit from a given therapy.

A Wealth of Data

Fortunately, there is a great deal of data that can be used — in combination with artificial intelligence (AI), machine learning (ML), natural language processing (NLP), and other advanced digital technologies — to realistically predict patient outcomes.

There are extensive medical records for patients who have received cell therapies in the past, including their histories before treatment and their performance following treatment. Therefore, electronic medical records are a primary data source. Records on apheresis, patient cell packaging and shipment, the manufacturing process, and packaging and shipment of gene-modified cell therapy products are also valuable. All of these data directly or indirectly contribute to patient outcomes.

The Evidence Engine from IQVIA

The Evidence Engine being developed by IQVIA with the support of a consortium of nonprofit groups including Be The Match BioTherapies provides a mechanism for compiling these disparate data and tying them to patient outcomes for the betterment of the medical community and patients in particular.

The goal is to help clinicians determine whether patients diagnosed with different cancers are good candidates for a particular gene-modified cell therapy and why, as well as what to expect post-administration. That will lead to patients realizing the best outcomes with the lowest toxicities. It is also intended to help broaden access to therapies through data-driven decision-making.

It should also help clinical trial investigators decide which cell therapy clinical trials should be conducted at their hospitals. Currently, it is very difficult for physicians to make this assessment, because there is a lack of a means for doing so. Often, these decisions are based on instinct or scientific intuition rather than data.

The Evidence Engine data platform is designed to hold data regarding all of the variables that might impact the safety and efficacy of gene-modified cell therapies in one location. It also includes AI and ML capabilities for continual learning as more data are collated, including global data sets in particular situations

Funding for development of the Evidence Engine comes from the California Institute of Regenerative Medicine. The effort is also supported by a consortium largely comprising nonprofit organizations, including Be The Match BioTherapies and others. The fundamental vision is to combine IQVIA’s data structure and data analysis capabilities with the clinical data provided by the other consortium members. Input from manufacturers will be critical as well.

The Evidence Engine also has the potential to help address issues, such as the underrepresentation of some ethnic groups in cell therapy clinical trials. While there are societal problems that underlie this issue, such as deep-seated distrust of the medical system in certain communities, the hope is that, with more data, more people will become comfortable with participating in trials. In addition, by reducing the prices of gene-modified cell therapies through the use of data and real-world evidence, access should be expanded — not just in the United States and within Europe but around the world.

Reducing Cost

The cost of chimeric antigen receptor (CAR)-T cell therapy in the United States is approximately $350,000–$500,000. That price is out of reach for most people in the rest of the world. In order to make these life-changing treatments available to people across the globe, those prices must be reduced.

One way to reduce the cost is to eliminate poorly manufactured therapies, including those based on patient cells that are not suitable for use in the production process, which would lower the cost of goods. Another is to exert pricing pressure through the use of excellent real-world data (RWD) that show when a treatment will work very well, so that all treatments result in successful patient outcomes.

Years in the Making

Ultimately, if data-driven decision-making can be made possible, and gene-modified cell therapies can be administered in community hospitals in an outpatient setting, costs will come down, and widespread access should be possible. Those goals will take time to realize, however. It will be many years before the quantity of global data needed to enable the successful prediction of patient outcomes are available and collated into the Evidence Engine.

One issue is the fractured nature of the healthcare system in the United States. In countries with single-payer healthcare systems, in which electronic health records are maintained in state-run databases, integration of data into the Evidence Engine will be easier. In the United States, however, there are multiple proprietary platforms used to maintain electronic medical records in different file types and formats that are very difficult to integrate. Another concern that must be addressed is how drug companies can confidently share their proprietary data without losing any competitive advantage. The data will need to be anonymized and pooled.

IQVIA is making great progress. The team of experts working on the Evidence Engine are getting better at figuring out how to integrate disparate data sources and are beginning to feel comfortable with the inferences that they are able to make drawing on these disparate health records.

Pilot programs are currently underway in which data from contained studies (e.g., a multiple myeloma study using a BCMA CAR-T run at City of Hope and the University of California, San Francisco) is deposited into the Evidence Engine. This approach is enabling the consortium to build a proof of concept on the basis of discrete studies focused on single indications. Indeed, academic-run clinical studies are more predisposed to sharing data, and a huge proportion of global clinical studies in cell therapy are academic-sponsored studies, so they are a good place to start. Ultimately, data from corporate studies will be needed as well.

Changing Paradigms

There are many shifts occurring in cell therapy, but these shifts do not remove the need for data-driven decision-making to ensure better patient outcomes. The initial centralized manufacturing approach for autologous cell therapies may be shifting to one that is more decentralized. There is also growing interest in allogeneic, off-the-shelf (versus autologous, patient-specific) therapies derived from healthy donor immune cells. Nearly every company that has an autologous therapy in their pipeline now also has an allogeneic therapy as a follow-on in recognition of the challenges of the supply chain. Both shifts eliminate the need to ship patient cells and cell therapy products rapidly by air, thereby lowering costs and eliminating some of the variables that contribute to reduced efficacy.

These shifts do not preclude the need for the Evidence Engine. Whether a cell therapy is autologous or allogeneic, it still involves essential pieces of data that will have a direct impact on the success of that therapy for each patient. For allogeneic therapies, the questions will relate to the donor cells and their characteristics, as well as the distribution of these products. A global database that collects information on all of the different variables can provide invaluable support to clinicians looking to choose the right cell therapy for a specific patient and to investigators determining which clinical studies best fit their site and patient populations.

Benefiting Many Stakeholders

The most immediate beneficiaries of data-driven decision-making will be patients and the clinicians who treat them. The Evidence Engine will help decide both whether cell therapy is a reasonable next treatment and which cell therapy is best. For a patient with a blood cancer, there are several approved gene-modified cell therapies on the market, and hundreds of clinical trials underway. Choosing the one that will give the patient the best chance requires an incredibly complicated calculus. The Evidence Engine will make it possible for that choice to be based on RWD.

Often, the decision to treat a patient with a gene-modified cell therapy is not made just by the clinician and the patient — the finance, legal, and administration departments within centers of excellence also have a say, because these therapies are so expensive. In some cases, hospitals must prepay for the therapies before receiving any reimbursement, which creates an administrative and financial burden, which hopefully can be eliminated by using a data-driven decision-making process. Similarly, payers will have more confidence that the patients receiving these expensive treatments will have positive outcomes, making it possible for them to make good coverage decisions.

Regulators will clearly also benefit.

Be The Match: An Honest Data Broker

Be The Match has historically been a coordinating center. The original Health Resources and Services Administration’s (HRSA) grant awarded to the organization was specifically to coordinate the efforts of disparate entities involved in the transplant field so that they could work in unison.

The Cord Blood Alliance is a great example. Cord blood is increasingly becoming an interesting source material for allogeneic cell therapy development. There are numerous public and private cord blood banks located across the United States, and drug developers are going from one bank to another looking for source material. The Cord Blood Alliance, spearheaded by Be The Match BioTherapies, makes that process much simpler by coordinating the activities of many of the public banks and serving as a single resource for drug developers. The Alliance also provides a new and much-needed revenue source for the cord blood banking industry.

Be The Match Biotherapies can search over 300,000 units in the public banks virtually instantaneously, dramatically streamlining the process. We are well positioned to coordinate the activities of the Cord Blood Alliance, because we maintain a software platform through which the public inventory can be viewed and searched for many different biologic and demographic characteristics.

The next phase of the journey on which Be The Match has embarked is moving beyond cord units as a starting material into health donor cells. Be The Match BioTherapies has been in this business for a while already, identifying donors, gaining consent, and harvesting cells for further manufacture. There is considerable industry interest and demand for this type of service, so we are undertaking an initiative to better support the development of allogeneic cell therapies through the provision of consistent, compliant donor starting material.

IQVIA’s Evidence Engine fits with this theme of coordinating activities and working as an honest broker of data very well. In this case, we will help funnel clinical trial, patient, and other relevant data into a single repository that is easily and equably accessible to clinicians seeking to ensure the best outcomes for their patients.

Contributing to and Benefiting from The Evidence Engine

Be The Match has a very long history in cell and gene therapy, having been a leader in cell therapy — bone marrow transplants — for 35 years. The processes, procedures, and supply chain for bone marrow transplant are very similar to that for gene-modified cell therapies. Donor cells are harvested through apheresis or sometimes a bone marrow aspirate and then packaged and shipped on commercial aircraft.

Through Be The Match’s Center for International Blood and Marrow Transplant Research (CIBMTR), the outcomes of all transplants are tracked for patients as long as they survive. To date, approximately 650,000 transplant outcome data sets have been accumulated. Notably, apheresis, supply chain, and other relevant data — all of which is fundamental to the concept of the Evidence Engine — are also included.

Be The Match BioTherapies also plans to compile data on emerging cell therapies: apheresis, supply chain, and outcomes in partnership with industry. The CIBMTR is performing outcomes data gathering for the autologous CAR-T cell therapies currently on the market.

We have the ability to assemble all of those data sets and use IQVIA’s data analytics and power to round out the story. As a result, both Be The Match and Be The Match BioTherapies will continue to play very significant roles in helping to make the Evidence Engine a reality. That we will be supplying all this data in an organized manner to the clinical decision-making community through the Evidence Engine is very exciting to our organization. It is another mechanism for serving patients as an honest broker of data.

Indeed, bone marrow transplant is a cell therapy that does not work for everyone. With our mission to serve patients as effectively as possible, particularly patients that have blood and marrow cancers, we embrace a future in which transplant is not always utilized and in some cases may be replaced. It is a difficult notion for an organization founded specifically to support successful transplants, but it is possible that, at some point in the future, transplant as a treatment will be needed only by a small subset of patients. If there is an emerging cell therapy, CAR-T or otherwise, that has a better safety and efficacy profile, Be The Match will absolutely support it.

The Evidence Engine can also be used to rationalize the transplant data set to identify the really good candidates for transplant or other types of cell therapy.

Originally published on PharmasAlmanac.com on November 1, 2022.

The cell therapy sector is expanding at a fantastic rate, particularly in oncology indications, but most of the efforts thus far have unsurprisingly focused on a subset of the full panoply of immune cell types. Building on the successes of chimeric antigen receptor (CAR) therapies using α/β T cells — and being mindful of their limitations — biopharma innovators have begun pursuing other immune cells, notably including γδ T (GDT) cells, which have inherent anti-cancer and antiviral properties and are free of some of the restrictions that have limited the creation of off-the-shelf allogeneic therapeutics. One company leading the way toward safer and less expensive CAR-T products targeting cancers is TC Biopharm. In this Q&A, Chief Executive Officer Bryan Kobel discusses the tremendous potential of GDT cells and the approach TC Biopharm is taking to their development with Pharma’s Almanac Editor in Chief David Alvaro, Ph.D.

David Alvaro (DA): To get us started, how would you characterize the present moment in time for the whole development cycle of cell therapies?

Bryan Kobel (BK): This is an extremely exciting moment in the history of cell therapy. The first iterations of cell therapy were explorations for wound care way back in the 1990s. Following that, we saw the CAR-T movement around α/β T cells a decade ago — an early patient, Emily Whitehead, recently celebrated her 10-year anniversary of being cancer free following CAR-T treatment for acute lymphoblastic leukemia. Those were the first real proofs of concept of successful cell therapies in oncology. You can think about this progress along the lines of how technology advances in general: the first cell phone I had in the 1990s was huge and looked like a brick, and it could essentially only make phone calls and send and receive texts. But only 10 years later, things accelerated to the point where we had the iPhone, which is basically a minicomputer in your hand that allows you to do video calls and so much more. Technology tends to advance slowly at first and then accelerate more and more, sort of how Ernest Hemingway described going broke: very slowly at first and then very rapidly toward the end.

We’re now in that rapid acceleration phase for cell therapies. CAR-T therapies have produced some really wonderful results, and from there the cell therapy movement has really taken on a life of its own. Today, we have a significant number of cell therapies in the clinic and a range of advances going forward. Just looking at GDT cells, besides TC Biopharm, a number of companies — In8Bio, Adicet Bio, GammaDelta Therapeutics — are currently in the clinic. Then, if you include everything in the α/β space, the CAR technologies that Autolus and Algene are working on, and all the efforts with macrophages today, there’s an unbelievable amount of focus in the cell therapy sector right now, just in an indication basis. I think some of this reflects a more general focus in healthcare to use what our systems already do and use nature to make ourselves healthier rather than the blunt force, overengineered solutions of chemotherapy or whole-body radiation, where you’re hoping that a poison will kill unhealthy cells more than healthy ones. You see a similar phenomenon occurring around biohacking and things of that nature — just an overall desire in humanity to leverage our own biology to be healthier every day.

DA: I think that the concept of using α/β cells has really penetrated, but there is less understanding of the potential of GDT cells. Can you give us a quick primer on what’s unique about these cells and the therapeutic promise they present?

BK: Part of what’s so exciting about GDT cells is that we continue to learn new things about them every single day. But the easiest was to conceptualize GDT cells is that they’re the body’s first line of defense — basically the bouncers for the immune system. They float around in your system looking for the presence of an antigen called isopentenyl pyrophosphate (IPP), which is expressed by all sick and diseased cells — all tumors and all virally infected cells that have ever been discovered and studied — but not by healthy cells. So, GDT cells act like immunological sharks, floating around your system looking for this antigen, moving along concentration gradients to find the source of the IPP. When it finds the cells that are producing IPP, it triggers apoptosis and kills that cell.

As you get older and your cells continue to regenerate and proliferate, you’re always at some risk of accumulating mutations and creating cancers. One of the primary reasons why we don’t get cancer on a much more regular basis is these GDT cells locating and killing early cancer cells. Incidentally, they are also the reason why you don’t get the flu or any number of other viral diseases that you are constantly exposed to every single day: cells that are infected are killed before they have a chance to advance into an acute disease state. When cancer does take root, it typically means that it’s able to proliferate more quickly than this immune response, or that by the time the alarm bells start ringing, the cancer is already too advanced to be overwhelmed by the GDT system, either because the patient is immune suppressed or it’s simply an extremely aggressive cancer.

The therapeutic exploration of GDT cells arises from the question: what if we isolate activated GDT cells from somebody who’s really healthy, expand them into the billions, and administer them into a patient with an overwhelmed immune system? Can we turn the tide of that war with these activated GDT cells that we know can natively track down and kill these sick and diseased cells already on a naturalized basis? So far, we’ve seen success for that approach in relapsed/ refractory acute myeloid leukemia (AML), and we’re now moving it into second line for AML.

DA: With all of that potential, is there any particular reason why GDT cells haven’t been as widely explored to date? Has the issue been a knowledge issue or technology gap, or is it just contingent?

BK: It’s never just one thing! As you can imagine, we’re learning more and more about the body every single day, which is ultimately a function of overall technology: diagnostic tech like MRI machines, CAT scan machines, and so on, which are still evolving. But the primary reason why GDT cells haven’t been at the forefront of cell therapy before is simply that α/β cells are easier to find and to grow, so more groups focused on the cell type that was easier to work with; technology typically seeks the path of least resistance.

As α/β cells moved forward and as cell therapy started gaining momentum, Adrian Hayday, who is a founder at GammaDelta Therapeutics, wrote a great article that shone a new spotlight on GDT cells. As the understanding of the role of GDT cells in the immune system and the underlying mechanism has grown, they have become more of an area of focus for cell therapy developers, along with some other emerging modalities like macrophages, natural killer cells, mitochondrial factors, and so on. This will likely continue as more cell types are discovered and understood and eventually find their way into therapeutic applications.

DA: How important is the lack of MHC (major histocompatibility complex)/HLA (human leukocyte antigen) restriction in enabling allogeneic rather than autologous therapy to the pragmatic, economic promise of these cells?

BK: As much as we want to focus on the biology, at the end of the day, you have to consider the economics. It remains quite difficult to envision a broad economic use case for autologous therapies that require a unique, personalized therapeutic that’s based on each individual. There’s certainly value in autologous approaches in certain indications, but, broadly speaking, it’s a very difficult economic model.

We believe that the market is going to embrace allogeneic therapies. With GDT cells, there is no MHC restriction, and they don’t cause graft versus host disease (GVHD), which allows us to go outside of the HLA matching process that is used for bone marrow transplants. For bone marrow, matching the HLA genotype of the donor and the patient is really important, so the best hope is a first-degree relative, and the search can be very difficult otherwise. With no MHC restriction and hence no risk of GVHD, not only do you not need to derive the therapeutic from the patient, but you also open things up to a much larger population of donors.

However, even the donor process for cell therapies will have some restrictions, because there are only so many donors. As cell therapy grows, demand for those donors will grow. At some point, we will likely need to move into things like induced pluripotent stem cells (iPSCs), where you can derive an essentially unlimited amount of cells from that platform without needing additional donors. So, while allogeneic GDT cell therapies represent the next step in this trajectory, the subsequent one will involve IPSCs. There are some great companies working on that: BlueRock Therapeutics, Notch Therapeutics, and many, many others, all doing great work in that space among many other companies.

DA: As I understand it, on top of the natural anti-cancer activity of GDT cells, you’re also working on layering on co-stimulatory CAR receptor technology. Can you tell me a little bit about the idea behind that approach?

BK: One issue that we hear about a lot with CAR-T therapies, and the reason why patients can end up in the ICU, is the idea of on-site, off-tumor toxicity. Taking as an example a therapy that uses CD19 as the CAR receptor, the CAR-T α/β cell will target CD19 on tumor cells, but since CD19 is also found on healthy cells, the α/β cells can kill healthy cells as well. This is also why CAR-T cells aren’t effective against solid tumors: you can’t administer a sufficiently large dose to get the CAR-T cells out of the vasculature and into the tissue without a high rate of off-tumor effects.

Our co-stimulatory approach uses GDT receptor targeting IPP as an on/off switch for the CAR program. So, for example, if we are targeting the B7-H3 receptor — a potential target for solid tumors — with GDT CAR cells, the CAR cells will still attach to healthy cells, but since IPP isn’t present, it doesn’t complete the circuit needed to trigger apoptosis, and the CAR cell will detach without toxicity. However, if it finds a cancer cell expressing B7-H3, it will attach and complete the circuit for the kill signal. It’s basically magic. The guys who created this, our employees, are magicians doing amazing things every single day.

DA: Once you have this platform established, what are the considerations that enter into decisions about what indications to pursue, for both the unmodified GDT therapies and the CAR cell approaches?

BK: The allogeneic, unmodified gamma delta are ultimately the backbone of everything we do, but we had to determine where they were likely to be most efficacious. For us, this came down to the idea of combination therapy. You do hear a lot of companies say that they are pursuing monotherapies, but from our perspective, there may never be such a silver bullet, a monotherapy for cancer.

We looked at where we could be really helpful in combination basis with things like checkpoint inhibitors or bispecific antibodies or approaches to stimulate the immune system research around trying to turn cold tumors hot. By infusing activated GDT cells into a weakened immune system, we think we can enhance the effects of those therapies. I think that’s the strongest path forward for the allogeneic GDT cells, at least for solid tumors. We have had lots of discussions with any number of companies to develop opportunities for therapeutic combinations.

For the co-stimulatory approach, we also look for the indications where we can provide the most value, which may be an indication for which there is no treatment or where treatments options are very poor for the patient population: low life expectancy, few options, low quality of life — indications like pancreatic, ovarian, colorectal, breast, and non-small cell lung cancer and neuroblastomas. That’s where we really think that CAR and the combination therapies can be really impactful.

Beyond that, we are also exploring pediatric indications, because the unmodified GDT cells don’t have any toxicity. We should be able to dose pediatric patients in a number of different indications and be really, really impactful with very, very low toxicity for these patients. We talk regularly with groups that are focused on pediatric oncology to try and see what we can do there.

On the CAR side, we’re looking at indications around B7-H3 variants, as well as some brain indications, where there’s quite a lot to be done. We try to combine the economic benefit to drive shareholder value, which is obviously always at the forefront of our mind, with considering what will have the most value for patients and humanity more broadly.

DA: Can you share a bit about your individual clinical programs, what they are targeting, and the clinical progress you’ve made thus far?

BK: For our OmnImmune^® program using the unmodified allogeneic GDT cells, which has orphan drug status in the United States, we have completed a phase I/II trial in relapsed/refractory AML. These are patients in palliative care with typically four to six weeks to live. We generated stellar data from that program. We have now launched a phase IIb/III trial in the UK and the EU, with three open sites in which we will hopefully being dosing in the next 60 days or so for our first cohort of 19 patients. We hope to be able to begin to announce data from that trial in the first half of 2023, and we’re really excited to see where that goes. This is a second-line product; after a patient fails in the first-line induction, they’ll receive our product as a bridge to transplant. We’ll also be transitioning that trial into the United States, and we’re hoping to have our FDA side of that trial prepared in Q4 of 2022. This will be really interesting from an investor perspective, because we should be able to see data out of the UK/EU in AML before or right after we start our U.S. trial, which means we’ll get AML as an indication.

From there, we will look at a number of different areas in which we can get our combination therapies into the clinic. We hope to have a combination therapy targeting solid tumors in the clinic in the first half of 2023, but we don’t yet know who our partner will be or which specific indication we will end up pursuing. Beyond that, we’re exploring how to advance our CAR program into the clinic in 2023, and it currently looks like that will target B7-H3, but we’re still doing some heavy work on that. We also have another preclinical cell program that we’re really excited about, which would be a combination therapy that we would do in-house, and we hope to get that into the clinic in 2023 as well. We are still trying to decide on our next steps, but our development team — including our co-founders COO Angela Scott and Executive Chairman Dr. Michael Leek — is doing a great job working on that.

DA: I understand that TC Biopharm is taking a somewhat atypical approach to both manufacturing and clinical research, keeping things in-house as much as possible. Can you tell me a little bit about that and why it makes sense to perform those activities yourselves?

BK: For cell therapies, it’s always hard to get a manufacturing perspective. If you’re going to be working with these cells every day, you need to understand them as best you can, which means you can’t just order cells from someone else and expect to understand them without really knowing how to make the cells. We decided that we needed to do that work in-house, so one of the first things we did is build the manufacturing plant.

On top of that, there is a real the supply–demand issue — there’s a real constraint in cell therapies today around access to cells from manufacturers. That’s why you see cell and gene therapy manufacturing plants going up all over the world. Our ability to move swiftly and our deep understanding of these cells is largely a function of our ability to manufacture them. A joke I often make is that, since we’re really at the forefront of knowledge on GDT cells, we are deep in the GDT jungle, swinging a machete every single day and ultimately either stepping on a pit of snakes or a pile of gold bricks.

Keeping those operations in-house has allowed us to morph ourselves into other areas with which we might otherwise have struggled. A good example is frozen-thawed product: we now have Omnimmune in a frozen-thawed basis, where we can freeze and ship the product and store it for up to nine months across the world, which means it is truly an off-the-shelf product. If there is a patient who will need an infusion of allogeneic GDT cells six months down the road, we can have frozen product stored in advance and ready to use when needed. That’s a core component of a true off-the-shelf technology: being able to call up the cell therapy storage place and order GDT cells and have them delivered that day — and it was enabled by our keeping all those things inhouse.

At the same time, rats and mice don’t have a functional GDT system, so you need to engineer the response when you do that preclinical work. There’s nothing inherently wrong with that approach, but we prefer to work in an environment that is more likely to translate. So, what would be animal work ends up in human phase Ib/II studies that provide us with safety data right away while allowing us to observe how it operates in actual patients and understand more to allow us to tweak dosages or make decisions aboutlipid depletion.

Doing things this way unlocks economic benefits by accelerating clinical trials and making them cheaper while allowing us to better understand cells and the function of the system in the patient, which makes for a better therapeutic when we actually develop it. It also spurs the development of other products or different uses of our products that may not have been possible if we were ordering a third-party cell bank. Mike (Leek) likes to joke that cells are sort of like teenagers: on some days, they wake up and they’re cranky, and on other days they wake up ready to go. You’re dealing with an organism more so than you are a chemistry. Outsourcing makes a lot of sense when it involves a chemical recipe, but cell therapy manufacturing requires a deep understanding of the actual cell itself, how it grows, when it’s at a point where you can freeze it, or when it’s at the point where you should use it. And I think that Angela’s (Scott) expertise in GMP cell manufacturing and Mike’s expertise has driven us far in that regard.

DA: Is there anything else you can share about the team at TC and the culture and mission that is driving all of this innovation?

BK: A company is only as good as its people, and we build our team on a really strong foundation. Mike and Angela have each been in cell therapy for about 40 years. Angela is the “mother god” — she’s actually known as that — and she grew the cells that became the first cloned animal. Mike was part of the team that discovered and named apoptosis.

They’ve also done a great job of building a team around them. Dr. Sebastian Wanless, our Senior Clinical Director, spent 20 years at BMS successfully running clinical trials on every single continent (except for Antarctica — it’s pretty hard to infuse a polar bear with a drug) and was the driving force behind the global clinical trials for retroviral AIDS treatments. Emilio Cosimo, our Product Development Manager, has done an incredible job over the last several years moving development forward in a number of areas and keeping focus not only on what we are doing today but what we will be doing 12, 24, 36, or 48 months down the road. I see my role as essentially a mouthpiece amplifying all the great things that all these other people are doing, and it makes my job easier that they are always able to answer my questions in plain, layman’s English so that I simply have to repeat it. Mike and Angela have done an incredible job of hiring the right people, training them, and putting them in the best position to succeed, allowing us to be really nimble and effective. We’re excited as a team to be moving forward on programs that will really help people, and that’s what drives us all.

We also have a fantastic board: Morris, who’s on the board of Viridian and Cogent; Eddie Niemczyk, who sits on the board of Bridges Investment Management and as the healthcare PM there; James Culverwells in the UK; and Dr. Mark Bonyhadi, who’s a senior advisor at Qiming and was head of R&D at Juno Therapeutics, which led some of the first cell therapy revolutions. Having them as a neural network has been really incredible.

DA: Can you tell us about the decision to take the company public and the impact that had on TC’s trajectory?

BK: The reality is: at some point you have to take the next step as a company. For us, that next step was expanding our balance sheet and getting our story out, which the IPO allowed us to do. You can only tell so much as a private company, and we felt like it was time to access the capital markets and have currency with which to be nimble, whether that means making acquisitions, rewarding our investors and employees, bolting on a new technology, or giving our shareholders an exit. Once you’re public, now you have a lot of options.

The IPO was a seminal moment for the company, and I think that the story is a great public market story. The technology is very complex, but it can be boiled down to be understood by a layperson. Cell therapy is definitely the place to be, and we would argue that GDT is the hottest space in cell therapy.

DA: As a closing thought, can you discuss how you see the cell therapy landscape in general changing over the next several years and what impact you think GDT cells and TC Biopharma more specifically will have?

BK: Obviously, we are believers in the cell therapy movement. I think that the real next iteration for cell therapy is combination therapies within the cell therapy world. The immune system is the result of literally millennia of development. The next iteration for cell therapies is leveraging that system to specifically fight off disease states. This will present a great option for very difficult-to-treat indications, as well as things like aging. It’s an exciting place to be. Taking unmodified and modified cells and putting them together into a system to recreate the immune response in its totality on an exogamous basis sounds like magic, but it is within reach.

Originally published on PharmasAlmanac.com on August 9, 2022.

Demand for human mesenchymal stem cells (hMSCs) is increasing dramatically as numerous cell therapy, tissue engineering, and related products advance through clinical trials. Greater efficiency and productivity in GMP manufacturing will be essential to produce sufficient quantities of hMSCs at an acceptable cost for patients and payers.

Critical Raw Material

Human mesenchymal stem cells (hMSCs) are a critical raw material for many regenerative medicine products including cell therapies, engineered tissues like bones and organs, and, crucially, cell-derived products, such as extracellular vesicles and growth factors. This mammalian cell type is also instrumental in ongoing research to 3D-model diseases ex vivo or to reconstitute skeletal muscle tissue for so-called “clean” or cruelty-free meat. 

A few cell therapy products have received regulatory approval around the world, and others are rapidly advancing through late-stage clinical trials. Bioprinted bones and organs and meat grown from animal muscle precursor cells derived from MSCs will require more research and technology advances to be realized, but the progress made to date suggests that multi-application success is likely to be achieved in the next decade or so.

Focusing on therapeutic applications, hMSCs have been identified for the potential treatment of many different diseases. Bone and cartilage and cardiovascular diseases and diabetes account for the largest percentage of clinical trials, but others receiving attention include Crohn’s, Alzheimer’s, hematological, lung, liver, kidney and host-graft diseases, spinal cord injury, multiple sclerosis, cancer, and many more.

A Few Growing Pains

Like other technologies, hMSC development has followed what is known as the Gartner hype cycle, in which an “innovation trigger” leads to a “peak of inflated expectations” followed by a “trough of disillusionment” and then a “slope of enlightenment” leading to a “plateau of productivity.”  The hMSC hype cycle can be seen in Figure 1.¹

Results of early studies with hMSCs led to significant interest and investment in the first decade of the 2000s. Nevertheless, owing to variable manufacturing practices, differences in isolation techniques, an underappreciation of the impact of culture methods on final product quality, a lack of understanding of hMSC mechanisms of action, and poor potency assays, there have been initial failures and limited adoption. Yet in recent years, manufacturing advances, greater knowledge gained from basic and applied research, and confirmation of therapeutic properties and MSCs’ mechanisms of action led to renewed interest and the implementation of many clinical trials. 

A Technology Akin to the Microchip

Given their widespread therapeutic potential for treating many indications and their usage in a variety of applications, hMSCs can be considered the “microchips” of tomorrow’s regenerative medicine products. Initially used as a biological tool to understand cellular mechanisms, hMSCs today have become fundamental components of regenerative medicine products and are needed in large quantities at pharmaceutical grade (Figure 2). On the basis of a review of the literature and clinical trial data, it has been estimated that the average academic non-clinical or preclinical study consumes just 43 million hMSCs, while a typical cell therapy clinical trial requires 60 billion hMSCs.² Today, there are greater than 10 trillion MSCs manufactured globally per year to support these trials.  

There is interest in accelerating the development of hMSC-based products from the U.S. Food and Drug Administration (FDA). With approvals for these therapies and engineered tissues already granted outside of the United States, a strong signal of therapeutic efficacy reported in early-stage trials, and growing momentum toward later-stage clinical trials, the potential for growth of hMSCs is tremendous. Indeed, their use in therapeutic applications is increasing exponentially in a manner similar to that observed for computing power.³

Estimating the Future Demand for hMSCs

In order to estimate the future demand for hMSCs, Olsen, et al.² considered the potential for success of different hMSC-based products and the quantity of cells required for each (Figure 3).

For cell-therapy products, given that there were 46 phase II/III and phase III clinical trials using hMSCs as of November 2017 and that the FDA estimates that 25–30% of phase III clinical drugs will receive approval,⁴ it can be conservatively assumed that 10 MSC-based cell therapy products will be on the U.S. market by 2030.  Further assuming there will be two “low-dose” products with 2 million cells/dose, five “medium-dose” products with 100 million cells/dose, two “high-dose” products with 500 million cells/dose, and one “monster-dose” product with 1.5 billion cells/dose and 100,000 patients per each if the 10 indications, 300 trillion hMSCs would be required per year to satisfy this demand. Of course, if any of these indications involved large patient populations, such as diabetes or stroke, this estimate could increase by 10-fold or more.²

Estimates for engineered tissues and organs were based on research involving the biofabrication of half an adult femur, which requires 720 million hMSCs,⁵ the number of patients requiring replacement bones per year and data regarding organ transplants. Assuming that 185,000 upper and lower limb amputations are performed per year in the United States,⁶ with each full bone requiring approximately 1.5 billion hMSCs, 278 trillion cells would be needed per year to fulfill the demand for the all the patients requiring replacement bones.

While creating a functional organ via bioprinting remains a future target, it will eventually be achieved and will address a critical need for the more than 100,000 people in the United States alone waiting to receive organ transplants.⁷ Using the liver as an example, stem cells are known to be a precursor to the non-parenchymal cells (endothelial cells, Kupffer cells, and stellate cells) that make up 40% of the liver⁸ and play a functional role in liver maintenance and regeneration.^9,10 In addition, only half of a human liver is required to support life and is suitable for transplant,¹¹ and acute liver failure patients can be supported with 5–10% liver mass or a bioartificial liver composed of 10 billion cells.^12,13 Assuming conservatively that 25% of the non-parenchymal cells in a tissue-engineered liver will be hMSCs, 1 billion hMSCs would be required per liver, and thus bioprinting 6,427 livers, which was the number of people at the end of 2016 waiting for a liver,⁶ would require 6.427 trillion hMSCs.

With liver transplants accounting for approximately 12% of all organ transplants⁷ — and using the same assumptions of 40% nonparenchymal cells in solid organs generated using 25% hMSCs — an additional 10-fold multiplication factor would be needed to satisfy all organ manufacturing and provide for off-the-shelf organs, or a total of 64 trillion cells.

Extracellular vesicles (EVs), such as exosomes or microvesicles collected via hMSCs, have been shown to be quite potent^14–16 and under some conditions can elicit similar responses to whole hMSCs.¹⁷  Along with gene-modified or edited cells and therapies that leverage synthetic biology, EVs can be referred to as “MSC 2.0” products.² Given their history of clinical use without significant adverse events in controlled and monitored studies, hMSCs are a relevant cell source valued for their potential in accelerating translation of EV therapies. Limited data are available on the quantity of hMSCs necessary to provide a therapeutic dose of hMSC-EVs, although an equivalent or greater amount of hMSCs for treatment appears reasonable. The same demand as for hMSC cell therapy products — ultimately, 300 trillion hMSCs per year — is therefore assumed over the next 20 years. This estimate is once again conservative, because it does not include the hMSCs required to generate other cell-derived materials, such as cytokines and cell lysates, both of which have shown therapeutic promise.^18–20

Cytokines and growth factors derived from hMSCs as biological ingredients in so-called “cosmeceuticals” or bioprinted human skin models for animal-free testing of cosmetics and personal care products are both being explored by companies such as L’Oreal and Johnson and Johnson.²¹ Cruelty-free, “clean meat” produced from non-human MSCs, if it were to address the predicted total meat consumption, would require approximately 1.25 ×10²² cells for bioreactor inoculation.²²

Peak hMSC Demand Predicted in 2040

The staggering growth in demand for hMSCs is similar to that experienced for monoclonal antibodies (mAbs) over the first two decades of their development. As a result, it can be expected — as was observed with mAbs — that a variety of approved products will be on the market over the next 20 years as the industry moves toward peak MSC demand and consumption. Indeed, more than 50 products are predicted to be on the market by 2040, with approximately four products added each year — a trajectory similar to that taken by mAbs.²

“Cosmeceutical” products could have success initially outside of the United States, owing to the interpretation that cell products (and not the cells themselves) are the active product. Similar clinical products containing MSC-derived, “secretome”-based materials will also eventually be common (Figure 4). With FDA approvals following successful phase III trials, applications of topical MSC-derived products could find potential for discretionary, “off-label” applications in dermatologic and/or cosmetic uses by prescription. Several cell therapies based on hMSCs should be on the market by 2025, and tissue-engineered products will receive approvals by 2030. By 2040, biofabricated organs will be in clinical trials. A summary of predictions is presented in Table 1.

Success Predicated on Manufacturing Advances

Realizing this full potential will require manufacturers to develop new technologies and processes that deliver high-quality hMSCs in massive volumes—and at radically lower costs. To become a truly abundant critical therapeutic material that enables innovation at the highest level, novel manufacturing solutions will be required to support commercial manufacture of hMSC products.  

Particular technical speed bumps have challenged the industry to determine a workable trypsin- and agitation-free release step from the microcarriers used to support the MSCs in order to minimize cell damage. Quenching of the proteolytic enzymes is often achieved with 10% fetal bovine serum, an animal-based product that introduces significant contamination risk. Furthermore, to isolate the suspended cells in an efficient and automated way, one must rapidly concentrate the cells while maintaining cell viability and functionality, a step necessitating filtration of the cells at large scale.² 

Yet, much recent progress has been made, such as the development of new, gentler dissociation reagents and animal-free materials, now manufactured according to Good Manufacturing Practice (GMP) requirements. Completely dissolvable microcarriers are also being explored, which would eliminate the need for cell/microcarrier separation and streamline downstream processing.²³

Driving Down Cost

Currently, there is a reasonable supply of high-quality hMSCs produced using robust manufacturing processes — prerequisites for clinical trials — but they come at a high cost. Scalable platform technologies are needed to economically fulfill clinically and commercially relevant lot sizes.² An intermediate step for reducing time to the clinic will be the production of hMSCs with proven manufacturability and clinical-grade quality.

Despite the manufacturing challenges that still exist today, companies like RoosterBio^® are increasing access to commercially-relevant hMSC cells through supply chain industrialization. RoosterBio has developed standardized cell bank product forms, coupled with scalable manufacturing, that includes fit-for-purpose cGMP-compatible cells and media systems supported by an FDA Master File.

Such solutions enable production of hMSC products in large-scale 3D bioreactors for streamlined clinical translation and reduced time to GMP product manufacturing. Overall, access to standardized, fully tested “off-the-shelf” cell banks as manufacturing starting materials for direct use in streamlined manufacturing processes provides product developers with reduced development and go-to-market timelines and, ultimately, reduced costs.²⁴

As manufacturing breakthroughs enable larger-scale production to increase the availability of hMSCs and drive down their cost due to efficiencies of scale, further innovation will follow (Figure 5).

References

1. Lembong, Josephine, Jon Carson and Jon Rowley. “The Stabilization of hMSCs as a Technology.” RoosterBio^® White Paper. 2020.
2. Olsen, Timothy R., Kelvin S. Ng, Lye T. Lock, Tabassum Ahsan and Jon A. Rowley. “Peak MSC—Are We There Yet?” Frontiers in Medicine. 5:178 (2018).
3. Maris B. “Medicine’s transistor moment: 8 emerging technologies that could revolutionize the life sciences.” Medium (2015) Available online at: https://www.speakingtree.in/article/medicine-s-transistor-moment 
4. The Drug Development Process. (2015) Available online at: http://www.fda.gov/forpatients/approvals/drugs/default.htm
5. Nguyen, BNB, Ko H, Moriarty RA, Etheridge JM, Fisher JP. “Dynamic bioreactor culture of high volume engineered bone tissue.” Tissue Eng. Part A. 22:263–71 (2016).
6. Ziegler-Graham, K, MacKenzie EJ, Ephraim PL, Travison TG, & Brookmeyer R. “Estimating the Prevalence of Limb Loss in the United States: 2005 to 2050.” Phys. Med. Rehabil. 89:422–9 (2017).
7. Organ Donation Statistics. U.S. Department of Health and Human Services. 2017. Available online at: https://www.organdonor.gov/statistics-stories/html
8. Godoy P, Hewitt NJ, Albrecht U, Andersen ME, Ansari N, Bhattacharya S, et al. “Recent advances in 2D and 3D in vitrosystems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME.” Arch Toxicol. 87:1315–530 (2013).
9. Chan C, Berthiaume F, Nath BD, Tilles AW, Toner M, Yarmush ML. “Hepatic tissue engineering for adjunct and temporary liver support: critical technologies.” Liver Transplant. 10:1331–42 (2004).
10. Wang B, Zhao L, Fish M, Logan CY, & Nusse R. “Self-renewing diploid Axin2(+) cells fuel homeostatic renewal of the liver.” Nature. 524:180–5 (2015).
11. Clavien PA, Petrowsky H, DeOliveira ML, & Graf R. “Strategies for safer liver surgery and partial liver transplantation.” Engl. J. Med. 356:1545–59 (2007).
12. Bianconi E, Piovesan A, Facchin F, Beraudi A, Casadei R, Frabetti F, Vitale L, Pelleri MC, Tassani S, Piva F, et al. “An estimation of the number of cells in the human body. Hum. Biol. 40:463–71 (2013).
13. Chan C, Berthiaume F, Nath BD, Tilles AW, Toner M, & Yarmush ML. Hepatic tissue engineering for adjunct and temporary liver support: critical technologies. Liver Transplant. 10:1331–42 (2004).
14. Von Bahr L, Batsis I, Moll G, Hägg M, Szakos A, Sundberg B, et al. “Analysis of tissues following mesenchymal stromal cell therapy in humans indicates limited long-term engraftment and no ectopic tissue formation.” Stem Cells. 30:1575–8 (2012).
15. Gnecchi M, Zhang Z, Ni A, & Dzau VJ. “Paracrine mechanisms in adult stem cell signaling and therapy.” Res. 103:1204–19 (2008).
16. Ng KS, Kuncewicz TM, & Karp JM. “Beyond Hit-and-Run: Stem Cells Leave a Lasting Memory.” Cell Metab. 22:541–3 (2015). doi:
17. Rani S, Ryan AE, Griffin MD, & Ritter T. “Mesenchymal stem cell-derived extracellular vesicles: toward cell-free therapeutic applications.” Mol Ther. 23:812–23 (2015).
18. Liang X, Ding Y, Zhang Y, Tse HF, & Lian Q. “Paracrine mechanisms of mesenchymal stem cell-based therapy: current status and perspectives.” Cell Transplant. 23:1–32 (2013).
19. Parekkadan B, Van Poll D, Suganuma K, Carter EA, Berthiaume F, Tilles AW, et al. “Mesenchymal stem cell-derived molecules reverse fulminant hepatic failure.” PLoS ONE. 2:e941 (2007).
20. Albersen M, Fandel TM, Lin G, Wang G, Banie L, Lin CS, et al. “Injections of adipose tissue-derived stem cells and stem cell lysate improve recovery of erectile function in a rat model of cavernous nerve injury.” Sex. Med. 7:3331–40 (2010).
21. Wood L. Global Cosmeceuticals Market Worth USD 61 Billion by 2020 – Analysis, Technologies & Forecasts Report 2016-2020 – Key Vendors: Avon, Bayer, Johnson & Johnson – Research and Markets. 2016.
22. van der Weele C & Tramper J. “Cultured meat: Every village its own factory?” Trends Biotechnol. 32:294–6 (2014).
23. Olsen TR, Lock LT, & Rowley JA. “Scaling up: how manufacturing sciences will dictate the future of cell therapy.” Med.11:S15–8 (2016).
24. Rowley, J.A. and S.A. Montgomery “The Need for Adherent Cell Manufacturing: Production Platform and Media Strategies Drive Cell Production Economics.” BioProcess International 16:34-49 (2018).

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*This article draws heavily (including the republished figures) from the white paper “Peak MSC — Are We There Yet?” by Timothy R. Olsen, Kelvin S. Ng, Lye T. Lock, Tabassum Ahsan, and Jon A. Rowley published in 2018 in Frontiers in Medicine.

Originally published on PharmasAlmanac.com on March 12, 2022

Organoids, tiny yet powerful replicas of organs derived from stem cells, are revolutionizing diagnostics, drug discovery, and precision medicine. Researchers are making progress in creating more complex organoids that closely mimic the structure and function of real organs. As these advancements continue, the potential for using organoids in regenerative medicine to repair or replace damaged tissues becomes increasingly promising. Despite the exciting progress, manufacturing challenges still stand in the way of organoid-based therapies becoming widespread. The Celligent^™ platform from Cell X Technologies offers an innovative, automated, and customizable solution for producing high-quality, GMP-compliant 3D cell cultures, including organoids, paving the way for future breakthroughs.

Understanding Organoids: A Journey in Biopharma

Organoids, despite their roots stretching back to the 1970s, have only recently captured the biopharma spotlight. In the past decade, the conversation around organoids has ebbed and flowed, and now, they’re here again — and for good reason. These tiny, lab-grown organ replicas are revolutionizing therapeutics, yet they remain under-discussed. It’s high time we bring their versatility and potential to the forefront.

Think of organoids as miniature, meticulously crafted models of human organs. They mimic the structure and function of their full-sized counterparts, offering a unique window into human biology. Unlike the simpler spheroids—3D cell aggregates lacking the intricate architecture of specific organs—organoids are complex, containing multiple cell types that self-organize into structures that intend to mimic real organs. This distinction, though often blurred, is crucial.

Derived from various sources like induced pluripotent stem cells or tissue-based stem cells,¹ organoids can be tailored to model both healthy and diseased tissues, including infectious diseases, genetic disorders, and cancers. This versatility extends to their origin: they can be created from allogeneic stem cells to represent a general model or from autologous cells to reflect a patient’s unique biology.

The breadth of organoids’ applications is astounding. They’ve been generated from brain, lung, intestinal, stomach, kidney, liver, cardiac, skeletal, bone, retinal tissues, and even various tumors.^2,3 Each organoid serves as a powerful tool, offering insights that could lead to groundbreaking treatments and personalized medicine.

Let’s explore some the compelling uses of organoids the research and development of biopharmaceuticals.

Applications for Organoids Across the Industry

Regenerative Medicine

The buzz around organoids in regenerative medicine is growing. Researchers have long pursued the dream of building human organs in a dish to create accurate models of human diseases and replace worn-out or diseased organs. In regenerative medicine, the potential of organoids to repair and replace damaged tissues is markedly valuable. Imagine replacing diseased or damaged tissues with precisely engineered, functional tissues derived from organoids. This isn’t just a future possibility; it’s a rapidly approaching reality. For instance, liver and pancreatic organoids have shown great potential for restoring function in patients with organ failure. Studies have demonstrated that liver organoids can aid in liver regeneration and repair by mimicking the organ’s natural architecture and function.⁴ Similarly, pancreatic organoids have been explored for their ability to generate insulin-producing cells, offering a potential therapeutic approach for diabetes treatment.⁵ An additional example, intestinal organoids have demonstrated much promise for treating gastrointestinal diseases.⁶ These advancements highlighting the potential of organoids to develop into complex tissues open up new avenues for autologous and allogeneic cell therapies, promising to restore normal function to affected areas and change countless lives for the better. See Case Study below.

Drug Discovery and Development

In the field of drug discovery, organoids are truly transformative. These miniature organs could provide a more accurate model of human responses than traditional animal models, transforming how we identify drug targets and test potential therapies. By offering insights into efficacy and safety, organoids streamline the drug discovery process, potentially slashing costs and reducing time-to-market. Organoids from tissues like liver, kidney, and brain are pivotal for high-throughput screening, helping us select the most promising drug candidates and identify critical biomarkers. Their ability to mimic human organs surpasses traditional 2D cultures and animal models, giving us a front-row seat to disease progression and drug toxicity. The integration of engineering and computational sciences has only enhanced this technology, making organoids more scalable for widespread drug development applications. Moreover, for drug discovery and development, the promise of organoids as preclinical alternatives is immense. They can reduce costs and improve the relevance of preclinical data. Traditional preclinical models, such as mice, often fail to capture the complexities of human biology, leading to failed clinical trials due to lack of relevance and, subsequently, wasted resources. Organoids, on the other hand, can provide a better representation of human physiology, offering a path to more successful preclinical research. The FDA’s push for non-animal and in silico testing, highlighted in the Modernization Act 2.0, underscores the significance of this shift. Organoids are poised to play a critical role in this transformation, bridging the gap between preclinical promise and clinical success. 

Process Development

When it comes to cell therapy process development, even the simpler relatives of organoids, spheroids, are game-changers. The biopharmaceutical industry increasingly relies on 3D scale-down models, which are essential for process development, optimization, and validation. Given the complexity of biological products, their manufacturing processes must be thoroughly understood, characterized, and controlled. Typically, as development progresses, the process is refined and tested through benchtop bioreactors, pilot-scale bioreactors, and ultimately commercial-scale production. Scale-down models play a crucial role throughout this journey, enabling process specialists to acquire process knowledge and translate it into optimal operating conditions in a cost-effective and timely manner. For instance, these models are applied across a wide range of process development activities, such as cell line selection and high-throughput growth medium optimization. Multivariable experimental studies conducted in scale-down models allow for extensive testing of process parameters, which would be impractical or too costly to perform at commercial scale. paving the way for smoother, faster development cycles.

Personalized Medicine

Creating organoids from a patient’s cells allows us to study that individual’s unique condition in unprecedented detail, predicting how they will respond to various treatments. This ability is particularly important in rare diseases and when patient variability plays a huge role in the therapeutic decision, such as in cancer treatments. In rare diseases, research is significantly hindered by the small number of individuals available for participation in studies. Additionally, many rare diseases lack suitable animal models, making it difficult for scientists to conduct early testing of new treatments. One such example is the use of organoids to develop therapeutics for Timothy syndrome, a rare disease where 80% of children with this syndrome will die within 2.5 years after birth. Researchers developed an antisense oligonucleotide (ASO) therapeutic and successfully demonstrated correction of function in organoids derived from individuals with Timothy syndrome. Additionally, human-derived organoids were transplanted into newborn rat brains, where they integrated well, and ASO treatment reduced abnormal function.⁷ This study not only highlights a potential treatment for Timothy syndrome but also offers a promising approach for other rare genetic disorders. In cancer treatment, the ability to recapitulate the heterogeneity of a patient-specific tumor could potentially be the difference between recurrence and remission. Since cancer cells change over time, patient-specific organoids can be analyzed for responses to combinatorial treatments at various stages of disease progression. Indeed, research has shown that the timing and duration of drug exposure can significantly affect results, and since tumor organoids can be grown indefinitely, we can experiment with different drug doses and schedules in the lab until the best match for a specific patient.  In addition, patient-derived tumor organoids can also be used to select individual patients for novel targeted therapies.⁸ Altogether, these functional data help tailor therapies to individual needs, ensuring patients receive the most effective treatments for their specific conditions.

Overcoming Production Challenges: A Personal Journey into Organoids

The path to producing organoids is fraught with challenges. It demands immense time and effort, where each step often relies on the meticulous hands of skilled operators. This manual nature, while rooted in expertise, inevitably opens the door to errors, inconsistencies, and soaring production costs. The heart of the problem lies in the delicate art of culturing stem cells — the very foundation of organoids.⁹ 

Each organoid’s creation is a unique endeavor, where its specific type and function will be shaped by many factors. Factors such as the choice of starting cells, matrix material (whether biologically derived like laminins or synthetic like hydrogels), growth factors, cytokines, proteins, and physical cues like shaking or stirring, all play pivotal roles. The complexity of these variables means that producing high-quality organoids is no small feat.

To relevantly mimic the behavior and function of real organs, organoids need the right type of interactions with the right types of cells in the right places. Achieving this requires more than just careful planning — it demands the organoid produce differentiated cells, secrete crucial signaling compounds, and respond to external stimuli accurately. Yet, even under the same conditions, we often end up with a wide variety of shapes, sizes, and cell compositions. This intricate dance of biology often takes months, if not years, of painstaking experimentation and optimization.

Another hurdle is the characterization of these organoids. With such variability, aligning on standardized criteria for what makes a “good” organoid and defining and achieving critical quality attributes (CQAs) can feel like navigating a maze in the dark. This variability underscores the importance of optimizing and standardizing the workflow to minimize inconsistencies between batches.

To address these challenges, researchers are turning to innovative techniques. For instance, micropatterning in 2D cultures can create a more reproducible starting condition, which then evolves into the desired 3D structures. Controlling matrix properties and applying physical forces like stretching can direct specific tissue morphogenesis. 

As with other processes where automation provides the key to consistency and reproducibility to achieve the desired results, organoids can benefit from automated, reliable production processes. Imagine a robotic cell-culture platform where one technician oversees the simultaneous production of multiple cell lines. Imagine, furthermore, a scenario where different cell types are consistently placed in exact coordinates, ensuring the relevant spatial interactions. Furthermore, picture organoids in development undergoing automatic inspection, allowing only those that meet stringent criteria to progress, ultimately resulting in the most homogenous population of organoids possible. This would significantly accelerate the quality control process, ensuring consistency and reliability at an unprecedented level, all while boosting production rates.

Embracing Automation for Organoid Production

At Cell X Technologies, we’re passionate about tackling the hurdles in the cell therapy field, knowing that our efforts can profoundly impact the therapeutic industry. Consistent organoid production is one of those hurdles. Our solution? The Celligent™ robotic platform, designed to take the labor-intensive, error-prone steps of generating organoids and transform them into a seamless, automated process. By simplifying and standardizing the generation of organoids, Celligent ensures consistency and precision that manual methods struggle to achieve, especially at scale and under GMP conditions.

The beauty of the Celligent platform lies in its ability to automate critical tasks. Imagine having a system that handles imaging and tracking cells, changing cell culture media, selecting colonies of induced pluripotent stem cells (iPSCs), and eliminating unwanted cells. These tasks are often highly variable and operator dependent, poorly documented, and error-prone when done manually. These become effortlessly consistent, reliable, and rigorously documented when automated using the Celligent platform.

Celligent addresses two key challenges in organoid generation:

1. Consistency: By automating the preparation of initial starting materials (iPSCs) and the differentiation process (when multiple cell types are involved), Celligent ensures a uniform and high-quality foundation for organoid development.
2. Optimization: The platform tracks and fine-tunes the organoid generation process to produce organoids with most relevant attributes for specific applications, making them more effective and reliable.

Operating within a cGMP-compliant Biospherix Xvivo system, the Celligent platform maintains aseptic conditions during operations and uses disposable components, further reducing the risk of contamination. Advanced algorithms within Celligent integrate external data with real-time information generated during cell culture, identifying CQAs and crucial process parameters. Every action is documented in a GMP-compliant database, ensuring traceability.

At Cell X Technologies, we’re more than just automating processes; we’re dedicated to thoughtfully bridging gaps in cell therapy to drive down costs and improve patient access. We’ve envisioned a new era in organoid production—one where consistency, efficiency, and innovation lead to real breakthroughs in biopharma.

Case Study: Revolutionizing Clinical-Grade iPSCs with the Celligent Platform¹⁰

In an inspiring real-world application, the Celligent precision robotic platform generated high-quality, clinical-grade patient iPSCs that successfully formed organoids rich with transplantable retinal progenitor and photoreceptor precursor cells. 

The journey began with dermal fibroblasts isolated from skin biopsies of patients suffering from inherited retinal degenerative blindness. These cells were reprogrammed and, the subsequent clones of the reprogrammed iPSCs were “picked” using automated methods and  expanded. In today’s version, the Celligent platform automates the entire culture process — growth, picking, and clonal expansion of the iPSCs. Clonal populations were compared and selected based on proliferation, morphology, and differentiation attributes. Selected clones were used to generate high-quality neural organoids rich in photoreceptor cells with quality equal to traditional manual methods. 

After 10 passages, the iPSC lines underwent rigorous karyotyping and scorecard analysis to confirm their genetic integrity and potency. The subsequent retinal differentiation process yielded organoids that, by days 120 and 160, expressed key photoreceptor markers and displayed morphology and gene expression profiles akin to those generated via manual methods.

This case study illustrates the power of the Celligent platform to transform a very manual process into a series to automated, linked protocols. By automating complex and labor-intensive processes, the production of high-quality, consistent organoids suitable for clinical applications can be achieved. This streamlines workflows and  opens up new possibilities in regenerative medicine, providing hope and tangible progress in the fight against blindness and other debilitating conditions.

Cell X Technologies: Our Mission

At Cell X, our mission is to customize our manufacturing solutions to perfectly align with our customers’ unique processes and goals. We collaborate closely to design Celligent protocols tailored to customer’s specific needs. This personalized approach ensures that the operations of the Celligent system we create is suited to the unique processes and targeted iPSC- (or other stem cell) based products, including organoids.

We understand that every process is unique. As such, we have designed the Celligent platform to be programmable by a bench scientist and to adapt to the input of subject matter experts by refining cell selection and weeding algorithms as the process moves forward. We understand that time is the greatest limiting factor, and by automating cell and organoid processing steps, scientists are freed up to move to other priorities. 

We are putting a unique focus on creating documented, transferrable processes that are appropriate for GMP production. We understand that a process successful with a research-only cell line might not translate seamlessly to a GMP line. The key is to use the power of automation to establish GMP-ready cell lines earlier in the process, alleviating the necessity to have re-define process parameters when time is most critical.

By using the Celligent platform throughout the process development phase of cell therapy or organoid  development, we provide a traceable, trackable, and mineable data structure that is amenable to developing artificial intelligence approaches.

Looking to the future, Cell X is dedicated to continuously innovating and refining our solutions, remaining committed to supporting our customers in achieving their goals, and advancing the field of regenerative medicine.

References

1. Zhao, Z., Chen, X., Dowbaj, A.M. et al. “Organoids.” Nat Rev Methods Primers. 2: 94 (2022). 
2. Zieba, Jennifer. “What Are Organoids and How Are They Made?” The Scientist. 11 Aug. 2022. 
3. Chakraborty, Debomita. “An Introduction to Organoids, Organoid Creation, Culture and Applications.” Technology Networks. 17 Jan. 2023. 
4. Lam, D.T.U.H., Y.Y. Dan, Y.S. Chan, et al. “Emerging liver organoid platforms and technologies.” Cell Regen. 10: 27 (2021). 
5. Jin , Chen, Lu Jin , Wang Shu-Na , AND Miao Chao-Yu. “Application and challenge of pancreatic organoids in therapeutic research.” Frontiers in Pharmacology. 15 (2024). 
6. Sato, T., and H. Clevers. “Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications.” Science. 340: 1190–1194 (2013).  
7. Chen X, et al. “Antisense oligonucleotide therapeutic approach for Timothy syndrome.” Nature. 628: 818–825 (2024). 
8. Weeber, Fleur, Salo N. Ooft, Krijn K. Dijkstra, and Emile E. Voest. “Tumor Organoids as a Pre-clinical Cancer Model for Drug Discovery.” Cell Chemical Biology. 9: 1092–1100 (2017). 
9. Weisinger, Karen. “Intelligent Cell Processing Enables Consistent, Reproducible, and Scalable GMP-Compliant Processes.” Pharma’s Almanac. 30 May 2024.
10. Bohrer, LR, et al. “Automating iPSC generation to enable autologous photoreceptor cell replacement therapy.” J. Transl. Med. 21: 161 (2023).

Originally published on PharmasAlmanac.com on July 2, 2024

Cell Therapies: A Promising Horizon

The landscape of the biopharmaceutical industry has undergone transformative shifts over time, from a focus on small molecule drugs to the introduction of biologics and more recently the emergence of cell therapies.

Within the space of cell therapy, two distinct categories have emerged: autologous therapies, which utilize a patient’s own cells to treat individual cases, and allogeneic therapies, which draw from donors to potentially treat multiple patients. While cell therapy is often promoted as a common therapeutic modality, it’s crucial to acknowledge the truth; this field is still in its infancy.  Consider that FDA approval of the first autologous cell therapy, Kymriah® (tisagenlecleucel), a chimeric antigen receptor T cell (CAR-T) therapy, occurred just seven years ago (2017), in stark contrast to the six-decade history of chemical cancer treatments.

Since then, the landscape has rapidly evolved, with six additional autologous CAR-T therapies approved, primarily for hematological cancers. Interestingly, the most recent of these approvals, Amtagvi™ (Lifileucel), marks the first solid tumor cell therapy; a significant milestone underscoring the vast potential that lies ahead.

On the allogeneic side, there are currently no FDA-approved therapies. Encouragingly, clinical advancements, such as Vertex’s pioneering clinical trials for a fully allogeneic therapy for the treatment of type 1 diabetes and Cyanta Therapeutics’ entry into a phase II clinical trial of CYP-001 for the treatment of GvHD, as well as its CYP-004, an allogeneic, iPSC-derived mesenchymal stem cell product for osteoarthritis, are signaling a new era for allogeneic cell therapies.

We stand on the brink of an extraordinary frontier in medicine, where autologous and allogeneic therapies join the ranks of other therapeutic modalities, and where the prospect of curing diseases by restoring cellular components within the body, rather than merely alleviating symptoms, is within our grasp.

Overcoming Challenges and Charting a Path Forward

Navigating the promising yet intricate world of cell therapies, there are numerous challenges that stem from fact that the field is still in its infancy.

Manufacturing living therapies is a layered and complex process that demands meticulous attention from cell isolation to cultivation and often stretches over months to yield a single patient dose. The quest for quality in these therapies, promising as they are in their potential to cure diseases, necessitates robust processes and cutting-edge technologies to ensure consistency and compliance.

There are many process challenges encompassing variability in the product, prolonged process development times, scalability hurdles, contamination risks, cell licensing complexities, and evolving regulatory landscapes. Much of these challenges trace back to the notoriously labor-intensive manual work in the manufacturing processes, particularly evident in allogeneic induced pluripotent stem cell (iPSC)-derived therapies. Daily tasks like imaging, cell culture maintenance, passaging, and offline assays are performed manually by multiple operators, introducing an astonishing amount of variability.

These hurdles manifest in the pain points of cell therapies, including extended process development timelines, scalability issues, ambiguous quality metrics, regulatory bottlenecks, contamination, and substantial wastage, culminating in exorbitant costs per volume of product. Consequently, the lofty price tags attached to these therapeutics hinder patient accessibility and dampen investor enthusiasm for venturing into what is perceived as a high-risk domain.

Yet, in the face of these challenges, we must begin to formulate solutions. Experts may offer divergent strategies, but some common foundational threads emerge. One such common thread lies in starting with an acceptable cell population. Whether it involves sourcing T cells for autologous CAR-T therapies or procuring acceptably documented clinical-grade iPSC lines for allogeneic therapies, the importance of this initial step cannot be overstated. However, this journey is fraught with hurdles, from the scarcity of patient-derived T cells due to patients being in later stages of severe diseases, unable to readily donate large volumes of blood, in addition to being subject to time-sensitive cycles of immunosuppressants, to the labyrinth of licensing issues surrounding iPSC lines.

Another common thread that emerges as imperative is ensuring process robustness and leveraging cutting-edge technologies for characterization data. In a landscape where each bioprocess is unique, tailored characterization is essential, especially in the realm of allogeneic therapies. There’s no one-size-fits-all solution; each step demands meticulous attention and time-efficient approaches. Addressing these intricacies isn’t just essential — it’s pivotal to unlock the full potential of cell therapeutics, ensuring their reliability and reproducibility in the pursuit of transformative solutions.

Sidebar: How Cell X Came to Be

In the heart of Cell X lies a remarkable tale of innovation, born from an unexpected encounter over lunch at a Cleveland restaurant. Dr. George Muschler, from the Cleveland Clinic, voiced his need for a robotic system to handle precise and repeatable patient bone marrow culturing. Overhearing from a nearby table, an executive from Parker Hannifin, an industrial automation company, seized the moment and proposed a collaboration to tackle this challenge.

From this serendipitous meeting sprang Cell X Technologies, dedicated to the joint development of its foundational data and automation system. Fast forward to 2019, three patents were granted, and a pivotal Small Business Innovation Research grant was secured, laying the groundwork for Cell X Technologies’ establishment as a spinout. Amid the turbulence of the COVID-19 pandemic, the technology continued to evolve.

In 2021, Cell X underwent a transition in leadership, amplifying its focus on business aspects. Notably, strategic partnerships and funding rounds propelled its growth trajectory, validating its technology and addressing critical industry challenges.

Introducing the Cell X Technologies Solution: Balancing Innovation with Reliability

The realization of Cell X’s concept combines advanced engineering, proprietary algorithms, and cutting-edge biology. Using iterative optimization, Cell X integrated robotic capabilities with automated state-of-the-art, rapid, large-field-of-view imaging capabilities. This integration facilitated precision automation, enabling the selective removal of unwanted cells and the picking and transfer of desired colonies with known clump sizes. Each step was meticulously documented with high-quality images and time-stamped records, ensuring transparency and accountability throughout the process. The Celligent™ system was born.

At the core of Celligent’s success lies its algorithm-driven cell-selection process, which emulates human decision-making with unparalleled accuracy. The primary focus was not merely on technological innovation for its own sake but on value innovation. While scientists have adeptly managed cell culture for decades, the aim was not to reinvent the wheel but to bridge gaps that elevate existing practices to new heights.

The Celligent™ system demonstrates exceptional adaptability, allowing for the addition or removal of media, execution of cell maintenance tasks, and transfer of cells using various methods and combinations, all while ensuring delicate cell handling. Its user-friendly software eliminates the need for extensive programming expertise, simplifying the protocol-building process that would typically involve multiple operators in multiple hoods. Furthermore, the system excels in data collection, ensuring compliance with Title 21 of the Code of Federal Regulations (21CFR) while automatically generating, storing, and organizing data for convenient access and analysis.

As Cell X technologies pioneers the future of automation in cell processing, we continue to add to our proprietary cloud-based database called Cx Knowledge. This innovative platform allows customers to access the Cell X Technologies data sets used to train a multitude of algorithms. By leveraging these datasets, customers can significantly expedite the learning process for their own systems, fostering greater efficiency and effectiveness in their operations.

Additionally, CX Knowledge forms the basis of our ongoing developments in AI; combing knowledge graphs and models to assess data sets and ultimately develop critical quality attributes for cell therapies.

Addressing Current Bottlenecks in Cell Therapy with Celligent™

As we dive into the world of cell therapies, it’s clear that we’re on the brink of something incredible. There’s so much potential waiting to be unlocked, and automation is key to making it happen. That’s where CelligentTM comes in. It’s not just a solution; it’s a game-changing design to tackle the toughest challenges we face in the industry.

Regulatory

It’s important to recognize that, just as biotech and pharma companies are pushing the boundaries of therapeutic innovation, regulatory bodies are evolving their requirements to safeguard the introduction of new medicines. As technology progresses, so must our regulatory framework to keep pace with these advancements. Anticipating future regulatory demands is a daunting task for any company, as the regulatory environment of tomorrow may differ significantly from today’s standards Yet, foresight is essential for success. Celligent™ is designed to address this challenge head-on by prioritizing comprehensive documentation. Every action, no matter how big or small, is recorded in real time. This automated documentation serves as a valuable asset, providing a detailed record of the entire process. With Celligent™, companies can rest assured that they have a robust repository of information, enabling them to retrieve essential information and navigate future regulatory requirements whenever needed.

Licensing

Navigating the minefield of licensing clinical-grade iPSC lines can be daunting, especially for emerging companies with limited resources. The upfront costs, recurring fees, royalties, and potential freedom-to-operate constraints create formidable barriers to entry. Compounding this challenge is the scarcity of reputable iPSC-producing cell lines to choose from. In a race against time, many startups opt for research-use-only (RUO) grade lines to kickstart their R&D initiatives, intending to upgrade to GMP-grade lines later, once the company is adequately funded. However, this often proves to be a costly gamble. iPSC lines vary significantly in their kinetics and differentiation potential, leading to compatibility issues with the proposed manufacturing processes. The result: more resources are expended on process adjustments than would have been necessary with clinical-grade iPSC lines from the outset. It’s a catch-22! A common approach adopted by companies is to qualify their RUO line, thus avoiding the necessity of ensuring compatibility with another line. While this is a viable strategy, it comes with inherent risks. If previously undetected genetic abnormalities surface during the qualification process, or if any adverse events linked directly to the iPSC line occur during clinical trials conducted by other groups utilizing the same line and strategy, there is a possibility that the cell line will become unusable. This scenario not only results in wasted resources but also poses potential setbacks in research and development efforts.

With Celligent™, users have the power to generate their very own clinical-grade iPSC line from the convenience of their workspace. Whether opting to kickstart the journey with this strategy or already possessing an RUO line, Celligent™ enables efficient screening of numerous clones that seamlessly integrate into the manufacturing process rather than altering the processes to accommodate available GMP lines. What’s more, the Celligent™ platform is fully customizable, ensuring that the automation aligns perfectly with unique process requirements. With Cell X Technologies, the path to licensing clinical-grade iPSC lines becomes not just feasible, but transformative, offering a streamlined approach that puts control back in users’ hands.

Variability

Variability stands as a primary challenge in cell therapy, often compromising consistency and predictability. Unlike other therapeutic modalities, the inherent nature of living cells introduces a level of unpredictability that can be challenging to mitigate. Much of this variability stems from the intrinsic properties of the cells themselves, coupled with our limited ability to exert control over their behavior. While this topic warrants a deeper dive, for now, let’s acknowledge its pervasive influence.

Adding to the complexity is the variability introduced by human operators. In the labor-intensive landscape of cell therapy, individual approaches and subtle adjustments can inadvertently amplify variability. Despite best intentions, practices diverge, and undocumented steps further compound the issue. The cumulative effect of these nuances is a variability multiplier. The reality is, in most instances, we may not realize or fully understand how even the smallest differences among operators influence the overall variability of the product.

The solution to this conundrum echoes throughout the industry: automation. While Celligent™ cannot erase the inherent variability of living cells, it can automate all the operator steps and provide a consistent and reliable process. From scheduled media changes to real-time adjustments based on culture parameters, our algorithms ensure precision and comprehensive documentation. This not only aids in minimizing variability but also allows our scientists to dedicate their time to tasks where automation falls short –– creative and continued innovation.

Data and Analytics

In the landscape of cell therapy, navigating the intricacies of data and analytics presents a significant challenge. The quest for precise quality metrics within processes often feels like searching for a needle in a haystack. The difficulty lies not only in monitoring the right variables but also in deciphering correlations between cell behavior and molecular metrics.  This bottleneck stems largely from the initial step, which hinges on collecting comprehensive process characterization data. This crucial foundation for knowledge relies heavily on manual practices, which, as we’ve previously highlighted, introduces variability.

Furthermore, the integration of diverse data sets and analytical pipelines aimed at extracting meaningful and predictive metrics has yet to fully come to fruition. It’s a recurring scenario where companies, after investing months and years in processing, only later realize that they’ve been utilizing incorrect metrics. This revelation often coincides with ambitious scaling plans, and the absence of meaningful quality attributes sets them back significantly, in terms of both time and finances. Sadly, this setback all too frequently leads to companies shuttering their operations. The loss of potentially groundbreaking therapeutic innovations underscores the critical need for consistent process characterization data and comprehensive analysis.

Herein lies a critical juncture: the need for a paradigm shift in analytical methodologies to keep pace with the rapid evolution of this field. Celligent™ merges cutting-edge imaging technology with sophisticated data analytics. By harnessing high-quality, rapid whole-well imaging capabilities, Celligent™ offers temporal image-based tracking of iPSC clones and colonies throughout the process. What sets it apart is its ability to seamlessly integrate offline molecular measurements with image data, creating a comprehensive knowledge base in Cx Knowledge. This holistic approach captures every aspect of the process, from reagent additions to cell movements, while reducing variability and increasing the reliability of the data. Furthermore, Celligent™ leverages proprietary algorithms to extract predictive critical quality and process parameters, empowering practitioners with actionable insights. Its automated statistical testing capabilities expedite the validation process, surpassing the reproducibility of human operators. Implementing such technology promises to drive advancements across the entire industry.

Contamination

Cell culture contamination is an ever-present source of anxiety in therapeutic development and manufacturing, especially in the cell therapy world, where therapeutics can take months to manufacture. The ramifications of contamination extend beyond financial losses, reaching into the lives of patients reliant on these treatments. The imperative to monitor and prevent contamination remains paramount, yet current solutions often entail the construction, rental, or outsourcing of cleanroom facilities — a costly endeavor both in terms of finances and logistical challenges.

The Celligent™ platform offers a fully customizable and configurable solution that can be easily adapted from BSC to phase-appropriate enclosures to cleanrooms within the company’s premises.

Speed to Market

Ensuring speedy access to groundbreaking therapies is a top priority from both patient and investor perspectives. Patients eagerly await the arrival of innovative treatments, hoping for faster relief and better outcomes. Meanwhile, investors seek timely returns on their investments, which can significantly impact the trajectory of funding and development. However, the reality of creating cell therapies involves a process with numerous steps, each essential and non-negotiable. Despite these inherent challenges, there are avenues to accelerate progress. By streamlining intermediary steps, enhancing throughput, and expediting regulatory processes, we can expedite the journey from concept to market.

The Celligent™ platform emerges as a pivotal solution, facilitating consistent data collection, rapid extraction of quality metrics, and accelerated customized assay development. This capability results in error reduction and consequent time savings between successive steps.

Celligent’s automation capabilities enable continuous operation, boosting efficiency round the clock. Finally, with Celligent™ and Cx Knowledge, automated reporting and critical quality attributes enhance regulatory submissions, minimizing risks and increasing approval probabilities.

Building a Cross-Functional Team of Experts

Creating an automated imaging system like Celligent requires a collaborative effort from a multidisciplinary team encompassing engineering, biology, software, and various specialized domains.  As a company established during the onset of the COVID-19 pandemic, Cell X embraced a virtual operating model at its inception and has now moved to establishing core capabilities across three sites.

We have established an engineering and software center in Pittsburgh, made possible by investment in Cell X from Innovation Works and its Robotics Accelerator program. Through this program, we gained access to mechanical and electrical prototyping labs, as well as engineering expertise from CMU and the Pittsburgh robotic and AI ecosystem.

Our original laboratory, located at the Cleveland Clinic’s Lerner Center for Regenerative Medicine, continues to operate as a Cell X testing and development center, as well as a use case center across application areas.

We’re excited to announce our plans for a Boston-based applications lab, slated to open its doors by mid-2024. This facility offers dedicated space for application proof-of-concept studies, as well as customer projects and customer support. With GMP capabilities and a qualified cleanroom facility, it will serve as a hub for showcasing our technology to potential customers, facilitating external equipment integration prototyping, and hosting user networking groups for collaborative information sharing. 

References

1. “Sector Snapshot: Building a Next-Gen Workforce).” Alliance for Regenerative Medicine. Aug. 2023.
2. “Ongoing Clinical Trials by Phase and Therapeutic Approach.” Alliance for Regenerative Medicine. 2023.
3. “Investment Data – 2023 Q2.” Alliance for Regenerative Medicine. Oct. 2023.
4. Tobolowsky, Mark A. and Richard A. Lewis. “What Regenerative Medicine Manufacturers Have Been Waiting For.” Outsourced Pharma. 9 Nov. 2023.

Originally published on PharmasAlmanac.com on May 30, 2024