Scaling iPSC-Derived Cell Therapies From Innovation to Patient Care
Dr. Frederic Cedrone provides expert advice for developing iPSC lines for cell therapies.
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Human induced pluripotent stem cells (iPSCs) provide a novel platform for developing cell therapies targeting diseases, from rare genetic disorders to cancer, autoimmune diseases and regenerative medicines. However, significant challenges must be addressed before iPSCs can be effectively utilized for the large-scale production of cell-based therapies.
The ability of iPSCs to self-renew and differentiate into various cell types of the human body addresses a longstanding challenge in the study of human diseases: the scarcity of human cells available for cell therapies. While clinical trials utilizing iPSCs are conducted, no iPSC-based therapies have received approval yet. This is due to several challenges including complex manufacturing processes, high production costs and the need to meet ever-changing regulatory requirements.
In an interview with Technology Networks, Dr. Frederic Cedrone, vice president of corporate innovation at Catalent, discussed the challenges faced and solutions found by companies developing iPSC-derived cell therapies and the importance of partnerships in bringing these therapies to patients.
What are some pros and cons of using iPSC lines for cell therapies?
Frederic Cedrone (FC):
The issue we observe with cell therapies is that often these are based on donor samples, which means you need a donor sample collection each time you manufacture a batch of cell therapy. From one donor collection to another, you can have variations in quality and performance between batches. On the other hand, iPSCs provide an unlimited source of material for cell therapy. With iPSCs, you can pick the cells from one donor, reprogram them, identify the best clone and then you have access to a stable iPSC line that you can use forever. Therefore, providing an endless source of the same starting material. Previously, embryonic stem cells have been used for the same purpose, however, in some cases, we see ethical concerns associated with using them, especially from the public or investors.
In terms of cons, iPSC cell lines require an engineering process. We need to apply a process to reprogram the original cells into these undifferentiated cell lines using reprogramming factors. We must ensure that these reprogramming factors are fully removed from the line after the reprogramming process. This is a key step for safety. Proving how and confirming you have removed these reprogramming factors from the final line is a key component of regulatory requirements.
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FC:
There are many iPSC cell lines available on the market, and you can also develop your own. Whatever you choose you must always start with your end objective in mind. If you plan for research only, R&D grade lines are fine. But if you want to bring a potential therapy to clinic, progress to late-stage trials and eventually commercial stage you must consider regulatory authority requirements upfront, ensuring patient safety being the highest priority. By starting with the highest quality, developing a risk assessment for all parameters and working this into the design of the therapy from the offset you will be able to bring the required information to the regulators and show that you have considered all the potential risks.
When developing or selecting an iPSC line, the best line remains the one that is differentiating well into your product. If you apply a process that does not give you the highest percentage of differentiated cells, significant purification steps are required to remove any remaining iPSCs and intermediate cells from the final product, this is a requirement and a must-have for authorities: patient safety first.
Another critical factor is using and maintaining the highest quality standards. The starting material must be good manufacturing practice (GMP) standard as of the earliest steps, or at least of the highest quality possible if you want to use it to go to clinic. At Catalent, iPSCs are developed under GMP from day one, from the donor cells collection, reprogramming and lines testing, always with the end in mind.
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FC:
Catalent is highly experienced in cell therapy manufacturing, and we are applying this experience to iPSCs. Once the specificities of iPSC processes are mastered, we can further apply the expertise and know-how that we have developed for cell therapies to bring iPSC-based cell therapies to market at scale.
Initially, most of the iPSC programs were designed for smaller patient numbers, and smaller doses, where a smaller scale of manufacturing has been viable. However, as the field expands and planning begins for broader indications with larger addressable patient populations or doses, a manufacturing strategy is needed to yield a higher number of cells per batch. The need for large numbers of cells is not compatible with the iPSC processes and systems initially developed.
To get these large numbers of cells, 3D systems are developed and used, culturing iPSCs in suspension, mimicking the bioreactor-based cultures of human embryonic kidney (HEK) cells or Chinese hamster ovary cells for antibody and therapeutic protein manufacturing. However, iPSCs don’t like to be in suspension and getting them to grow and differentiate in 3D, at high volume and at scale, to the required titer is challenging. This is something many cell therapy manufacturers are trying to tackle. We are developing and using such 3D bioprocesses to make this high-scale manufacturing of iPSC-based cell therapies possible.
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FC:
Analytical testing is an important piece of the process development puzzle. The validation of GMP processes requires the development and the validation of the analytical testing. This testing is part of quality control of the iPSC and the iPSC-derived cell therapy, to ensure the product is functional and safe.
We always develop analytical testing in parallel with the development of the manufacturing process. These two processes are working hand in hand. It allows for saving time and keeping pace.
Each time you start the development of a new therapy, you must have the end in mind but think about the development stage the product is reaching, to ensure you get a product that is of the highest quality required and suitable for clinical use from the start.
One key area we took into consideration when we first began working with iPSCs is the genome integrity of the iPSC line itself. For example, some of the donor cells may have unwanted mutations or the development process itself may cause mutations. From the beginning, we have been applying whole genome sequencing at a 50x coverage to avoid these mutations in our GMP lines. This is now a requirement from regulatory agencies. Having developed this process early on as part of the analytical testing has proven crucial as it is one of the key considerations our partners developing cell therapies will need to bring to regulatory authorities. We support our partners while preparing discussions with authorities from the beginning, using our experience and expertise to ensure that they go to the regulatory authorities with the right information and can demonstrate that the iPSC line used for their product is safe for the patient.
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FC:
If we look back 10 years ago, CRISPR for gene editing had just been discovered and gene-edited allogenic cell therapies had begun to be developed and tested for patient use. The progress that has been made has been amazing but utilizing these new technologies and bringing these new therapies to patients is incredibly hard. For biotech companies, which are often small and quite isolated, the amount of work to tackle is huge.
These companies can either try to do this themselves or find the right partnership that will provide them with the additional support, experience and expertise that they need. These partnerships can prove crucial for both the company and the investing venture capitalist (VC) backing them, as the platform and the process leading to the product should be developed and secured early on to lower the risk. For a VC, these partnerships are a way to ensure the company accesses the right technology and right expertise at the right time, and that the process is part of solid plans with well-defined milestones.
Partnerships can help developers access the right resources to make the development process much faster, helping to bring new therapies to patients faster off the back of a stronger development program.
