RoslinCT Blog Series: Scientific Advisory Board Perspectives

Derek Hei, RoslinCT SAB Member

Exploring the Possibilities of iPSCs

We recently spoke with Derek Hei, Ph.D., Chief Technology Officer of Kenai Therapeutics, and member of RoslinCT’s Scientific Advisory Board about the latest advances in the therapeutic use of induced pluripotent stem cells (iPSCs). Kenai Therapeutics takes a unique approach to drug discovery and development from current therapeutic offerings for neurodegenerative conditions by leveraging induced pluripotent stem cell (iPSC) technology, a Nobel Prize-winning scientific breakthrough.

What is the current landscape of iPSC-based therapeutics and what applications are generating the most interest?

These are early days for iPSC-based therapies, and we are seeing companies that are moving into indications where there is typically some kind of clinical proof of concept. For example, in Parkinson’s disease, fetal cell transplants offered glimmers of hope, but those cells were not easy to source ethically. In this case, you have clinical proof of concept, and you know what cells you need to make. iPSCs are an excellent way to potentially generate those cells and create a therapeutic that can be more broadly provided to Parkinson’s patients. The same holds for type 1 diabetes, where there is evidence of success from cadaveric islet transplants.

Use of iPSCs for CAR-T therapies where autologous has worked is a very active area. Even though these therapeutics have shown great clinical promise in hematological malignancies, the question of how you treat more than 10,000 or 15,000 patients a year remains. That number is about where the field is right now for the combined approved CAR-T therapies. iPSC versions of CAR T therapies offer a potential solution to this capacity issue, but also require an understanding of how to create an immune-cloaked version of the T cell. Once that is developed, the ability to engineer that cell to introduce CARs and other enhancements is much greater. In addition, the ability to consistently produce the same quality of cells is enhanced because it starts with the same cell material every time.

What are some of the manufacturing challenges related to iPSCs?

The first challenge is to get the reprogramming right and make sure that the cells are genetically stable and don’t have genetic alterations that could raise safety issues. Overall, I think the field has learned how to tackle this challenge.

The second challenge is understanding the biology of the cell and the disease. This is related to figuring out what the right cell type is and the right maturity of that cell type. A lot of times when we make a cell, you have the option of producing a progenitor cell or a terminally differentiated cell type. And the question is, do you transplant something that’s less mature and perhaps has the ability to replicate and do a better job of engrafting, or do you transplant a more mature cell with a longer manufacturing process that has less replicative capacity but acts more like an adult cell and therefore may be more capable of replacing the target adult cell type? It is the challenge of getting the right balance of maturity and making sure that you have the exact right cell type.

The third key point is that once you understand the exact cell type, there is a need to understand how the manufacturing process delivers it. People often overlook the need to understand and characterize the very small quantities of cell impurities that can result from the differentiation process. They are not always a safety issue, but at the same time, we need to characterize those and make sure that the process consistently delivers the same cell profile. This requires understanding the critical process parameters as you are directing the cell through the differentiation process, and which of those parameters must be modulated to optimize the process. That is a big challenge and is very different from other cell-based biologics.

What are some of the risk-based manufacturing practices that are employed for processes involving iPSCs?

One of the biggest questions that I typically address when I am working with teams is what is needed for GMP compliance in cell derivation. It is very different than a typical GMP process where you are starting with a defined material, and you get a defined drug product out. The key for an iPSC derivation and editing process is that it is very well documented with an understanding of the risks introduced by the materials used for reprogramming and editing. In the end, regulators typically focus on understanding potential risks introduced during cell line derivation. A solid documentation package with a thorough risk assessment goes a long way in addressing the key questions.

The resulting clone with all the right attributes goes into a master cell bank and working cell bank. At that point, we go to more of a typical GMP manufacturing process. But even then, it still is wise to take a risk-based approach because these complex differentiation processes are coming from the research environment, and typically, there are many changes that are needed to make it more ideal from the standpoint of scalability and GMP compliance. But if you try to make all of the process changes at once, you can really end up with a headache. So, it is wise to have a partner that you can work with that understands the set of possible risks and which are important to address early in the development continuum, versus which of those can be pushed to a later stage of development.

What role does an organization like RoslinCT play in this process?

Working with a group that has had therapies go into the clinic and successfully pass regulatory scrutiny is invaluable. Otherwise, without clear guidance, you will be guessing and assuming what regulators really want. If you are working with a team that has already done it, they have already seen some of these things and they know what the regulators are looking for. I think that’s really what the value is when working with a team like RoslinCT. They have experience with multiple programs and know exactly what you need to do.