Off-the-shelf cell therapies based on induced pluripotent stem cells are attracting growing interest as developers look beyond patient-specific approaches. But producing consistent, functional cells for large patient populations remains a major manufacturing challenge.
Here, Stefan Braam, Chief Technical Officer at Cellistic, discusses the evolution of allogeneic cell therapy, the bottlenecks that still limit iPSC manufacturing, and what it will take to make these therapies scalable, reproducible, and accessible.
How has the allogeneic cell therapy field evolved over the past five years, and what is the current state of the field today?
We’ve reached a point where the transition from lab-scale breakthroughs to commercial reality is happening in real-time. Earlier this year, Japan granted provisional market entrance for a cardiac product and a dopaminergic product for Parkinson’s disease. In the US, we’re seeing several pivotal trials in indications such as type 1 diabetes, Parkinson’s disease, autoimmune and seizure-related indications. The data shows these therapies are functionally curing patients in indications where treatment was previously impossible, and this clinical validation is fuelling the current momentum.
Historically, what have been the key limitations holding allogeneic approaches back?
Embryonic stem cells faced ethical and regulatory constraints in many jurisdictions, but iPSCs are bypassing this by enabling cells to be created with embryonic-like plasticity from adult somatic cells.
Another primary limitation is biological control. Unlike autologous CAR T, where an existing T-cell is modified, iPSC therapy uses an undifferentiated pluripotent starting material. Managing that journey from a stem cell to a terminally differentiated, functional therapeutic cell is a significant technical challenge.
What progress has been made in overcoming these challenges, particularly around scalability and reproducibility?
The field is adopting approaches similar to those used in biologics development and manufacturing. In traditional biologics, a gene sequence is inserted into a producer cell line to create a master cell bank (MCB). This process is now being applied to iPSCs: performing genetic modifications, establishing stable MCBs and then using those as the foundation for drug substance and drug product manufacturing. This helps with the move away from small-batch processes toward a standardized model that looks from a manufacturing perspective much more like large-scale protein production.
What are the biggest remaining bottlenecks to scaling off-the-shelf therapies?
Biological systems don’t scale linearly, and they behave differently at higher volumes. Consequently, the bottleneck is the production process itself. In iPSC differentiation, a small change in initial conditions can lead to a vastly different outcome.
Very slight variations in shear stress, media composition, pH or temperature can alter cellular differentiation. These factors can trigger a sequence of effects that prevent a reproducible outcome. Controlling this biology at scale is an order of magnitude more complex than any previous generation of cell therapy.
Where do most programs still struggle when moving from development into clinical and commercial settings?
Most developers enter the clinic with processes that were never engineered for commercial supply. Investor pressure often pushes sponsors to demonstrate clinical efficacy as quickly as possible, leading to a clinic-first strategy that doesn’t consider scale-up or chemistry, manufacturing and controls (CMC).
For example, in the iPSC space, the most critical decision is the selection of the starting cell line, and this should occur years before GMP manufacturing. If a research team doesn't have a view toward development and scale, developers may find themselves with a cell line that is biologically sound but industrially non-viable. This requires a mindset shift that integrates manufacturing into the research phase as early as possible.
What changes are needed in manufacturing to truly enable large-scale, reliable production of cell therapies?
The gap between process development and large-scale manufacturing needs to be closed. In biologics, manufacturing is often defined by 50-liter to 2,000-liter scales. In iPSC therapy, successful manufacturing has rarely reached 50 liters or beyond.
To help close this gap, the industry can adopt unit operations that are scale-agnostic. In general, developers should select technologies in Phase I that can scale at least 10x by Phase III without altering the fundamental unit operation. If a bioreactor type has to be changed mid-stream, there is a significant risk that the process change will affect the final product.
How are new technologies or process innovations helping to address these issues in practice?
Sophisticated new bioreactor platforms have been developed, which is a positive step, and digital tools utilizing artificial intelligence (AI) are also beginning to impact process development. While the field currently lacks the high-fidelity datasets required to fully train these systems, the models are improving constantly. They are helping to better understand the critical parameters that govern iPSC differentiation.
More broadly, how do you see the balance between autologous and allogeneic therapies evolving over the next decade?
Autologous therapies currently dominate the market, particularly in the CAR T space. The primary barrier to shifting to allogeneic shift therapies has been immune rejection of the transplant. We’re seeing significant innovation in gene editing to address immunogenicity, and several companies are reporting promising data. Ultimately, the shift will be driven by clinical evidence – data that supports the effectiveness of allogeneic products at scale.
What will it take to make allogeneic cell therapies more accessible to patients globally?
The cost of goods (COGs) needs to be driven down, particularly for raw materials like cytokines. These are currently a substantial cost and variability factor for global accessibility. If a single batch costs hundreds of thousands of dollars in materials, it limits the ability to iterate and optimize the process. Disruptive manufacturing technologies for these materials are needed to break the status quo and lower the barrier to entry for developers around the world.
Finally, what does success look like for the field – and how close are we to achieving it?
Success is defined by the clinical data, and we have already seen indications where therapies are delivering functional cures or significant clinical improvements for patients. The next step is proving that these results are reproducible across larger populations using allogeneic platforms. The clinical signals are there, and now the manufacturing infrastructure must be built to ensure these therapies are here to stay.
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