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