Stefan Braam, co-founder and chief technical officer of Cellistic looks at building the future of cell therapy.
Cellistic
Derived from induced pluripotent stem cells (iPSCs), the exciting potential of NK cells heralds change for patients. Offering a renewable source of allogeneic cells, iPSC-NK therapies can be precisely engineered for enhanced therapeutic functionality. Unlike conventional NK cells, iPSC-NK cells can be produced in large quantities with consistent quality, making them an ideal foundation for allogeneic applications. This shift towards standardised off-the-shelf therapies means the global cell therapy market is poised to reach $20.07 billion by 2030. However, the long-term success and commercial viability of these therapies depend on both clinical efficacy and the flexibility of the manufacturing platform.
The case for platform flexibility
In a fast-evolving field, a lack of flexibility risks time-consuming and costly delays for every manufacturing change, such as integrating a new technology or scaling up production. These delays can create a vicious cycle of regulatory hurdles, missed market opportunities, and, most critically, a negative impact on patients. For cancer patients, this means potentially life-saving therapies arrive avoidably late, and it is a primary driver behind the push for off-the-shelf therapies with resilient supply chains.
Platform flexibility accelerates innovation without sacrificing quality, and it is crucial for several key reasons:
- Accommodating New Targets: A flexible, modular platform can be used as a foundation for multiple therapies. For example, a platform designed to produce iPSC-NK cells for B-cell lymphoma could be adapted to target a different cancer simply by modifying the CAR to recognise a new antigen. This dramatically shortens development timelines and reduces costs by eliminating the need to design a new process from scratch for each new target or indication.
- Integrating New Technologies: The pace of innovation in cell therapy is rapid. New bioreactors, cryopreservation techniques, and monitoring tools are constantly emerging. A platform with a modular design allows developers to seamlessly integrate these emerging technologies without disrupting the entire workflow, ensuring they remain competitive.
- Scaling to New Geographies: As iPSC-NK therapies move toward global commercialisation, manufacturing will need to be distributed across multiple sites. A highly standardised and flexible platform can be easily replicated in different locations, streamlining technology transfer and supporting regulatory alignment across regions. This ensures global reproducibility and cross-site consistency, which are non-negotiable requirements for regulators.
Building the foundation for flexibility
Functional flexibility requires processes that can adapt to change without compromising product quality. Gene editing, particularly through advanced CRISPR-based tools, is used to precisely introduce traits that improve tumour targeting, persistence, or resistance to inhibition early in the development of iPSC-NK therapies. This makes gene editing a core component of platform design, as the quality of the final product is directly tied to how reliably those edits are maintained during expansion and differentiation.
To support this precision, automation is essential. It is often introduced during clone selection and early screening to reduce operator-related variability and streamline workflows. Imaging systems screen morphology and track growth, while liquid handling platforms standardise transfection and quality control (QC) steps. These tools enable the precise, high-throughput processes required for complex gene editing and characterisation, ensuring a reliable starting point for a flexible platform. This approach minimises the variability inherent in manual cell processing and helps manage complex multiplex edits, supporting rapid scale-up while reducing off-target effects.
Navigating manufacturing hurdles
The manufacturing process for iPSC-NK therapies is highly complex, typically designed around multiple sequential unit operations (UOPs) that must be tightly controlled and monitored. The process begins with iPSC expansion in 2D culture and progresses through stages of 3D aggregate formation, hemogenic differentiation, and lineage-specific commitment, culminating in final expansion and maturation.
The move from conventional 2D culture systems to more scalable and controlled platforms, such as stirred-tank bioreactors, is essential for large-scale production. However, even with these advances, process consistency and robustness remain ongoing concerns. Minor deviations in cell density, shear exposure, or media composition can impact cell viability and function, making it challenging to maintain a consistent product. These sensitivities pose a significant barrier to building a truly flexible and reproducible platform.
The pillars of a robust, flexible platform
To overcome these challenges, developers are implementing strategies that directly enable flexibility and control. They are moving toward modular, closed systems that integrate single-use bioreactor platforms. These systems support suspension cultures, simplify validation, and reduce turnaround times between runs. They are better suited to modular production environments because they reduce the need for manual interventions and extensive cleaning.
Cryopreservation is also being leveraged as a key tool for flexibility. Integrating cryopreservation steps at key stages, such as after intermediate differentiation steps, introduces process flexibility for scheduling and inventory control. This enables developers to create modular workflows that more closely align manufacturing with clinical needs when scaling. Final product cryopreservation also supports flexible transport and storage, while maintaining batch integrity.
To stabilise yields and reduce batch failures, many platforms incorporate real-time monitoring tools that screen for key variables, such as pH and metabolite concentrations. These insights help flag deviations before they can impact cell function, supporting more consistent manufacturing outcomes as programs scale.
Ensuring quality and regulatory readiness
Flexibility is a key enabler for modern manufacturing, but to be successful, it requires an even more robust and rigorous quality system. In a flexible environment, the risk of process variability and human error can increase, making stringent quality control and assurance protocols more critical than ever. Developers must proactively integrate these controls to ensure that each batch is consistently safe and effective, regardless of any changes made to the platform or location. This proactive, quality-by-design approach is what ultimately earns regulatory confidence and allows for the seamless scaling of these innovative therapies.
Quality control assays are essential for confirming key product attributes, including cell viability and efficacy, phenotypic identity, and purity. These assays, often performed using techniques such as flow cytometry and digital droplet PCR (ddPCR), inform release criteria and serve as the foundation for comparability protocols, which are necessary when making any changes to the platform.
To support this rigorous quality framework, many platforms now incorporate closed-system automation and electronic quality management. These tools support traceability, minimise contamination risk, and improve confidence in lot release across distributed manufacturing sites, a non-negotiable for a flexible, globalised manufacturing model.
Driving the next wave of innovation
The diverse potential of iPSC therapies to provide a renewable source of engineered cells, overcoming donor variability and a lack of manufacturing consistency, is well documented in a 2024 review paper. By building platforms with flexibility at their core — supported by advanced gene editing, automation, modular design, and robust quality control — developers can create systems that are not only efficient and cost-effective but also adaptable to the rapidly evolving therapeutic landscape. This strategic approach will be crucial for moving these therapies from small-scale studies to hospitals and patients in need of new therapeutic options.