Creating Off-the-Shelf Stem Cell Therapies Through Induced Pluripotency

I started as a physician but later realized that the opportunity to do research combined with other interests of mine—business, regulatory processes, and managing teams. So, I decided to move from clinical work into translational research.

I felt that moving into translational research, particularly within a company, provided me with the opportunity to bring value to a population of patients through clinical trials or the launch of products, as opposed to working for a single patient in front of me.

Nevertheless, my experience of clinical work and patient contact has been invaluable for what I've done afterward.

MSCs are cells that have a regenerative function and help maintain biological balance. They were one of the first cell therapy products because they are safe to administer, easily produced, and have immunomodulatory and regenerative properties. So, they were a natural candidate for use. However, they're not sufficiently potent. Nevertheless, they have been approved in multiple indications and have shown value in the treatment of several diseases. So, bottom line, they're effective, but not strongly so.

This provides an opportunity to enhance these cells. If we train, educate, and condition them to a specific therapeutic function, we can optimize their benefit. We do this by engineering cells, such as by inserting genes that confer a specific function. Through this, we can optimize a cell that has been used to deliver some benefit to deliver an even more powerful benefit.

Until recently, therapeutic cells were obtained from donors. [Following retrieval], suitable cells needed to be expanded due to limited numbers, and this process is lengthy and can cause cells to become fatigued.

Research into iPSCs aimed to produce pluripotent cells that could be differentiated into any other cell type and would not require such expansion. This approach provides an opportunity to go from donor-based to cell line-based therapy. A cell line continues to replicate, which, when considering the expansion process, provides several manufacturing benefits.

Firstly, you can achieve a large quantity of cells. Secondly, because they are derived from the same original cell, you have consistency. Consequently, you have a more cost-effective production process. So, iPSC sourcing will become the mainstream for obtaining therapeutic cells because this approach optimizes manufacturing and improves therapeutic consistency.

The key difference is the starting point; a donor material is variable and limited in quantity, whereas material from a cell line is consistent and virtually infinite.

The combination of CXCR4 and IL-10 that we have incorporated in a lentivirus, which delivers the genes to the cells, was designed to target and control inflammation precisely.

This is best explained by thinking of a parcel delivery system—you want something to go to a certain point and do something. The first thing you need is a carrier, in this context, a cell that is able to deliver a message impacting cell function. But to deliver a message, you need to guide the cell to the correct location. This is where the CXCR4 receptor comes in; it's the “postcode,” telling the cell to move toward inflammation.

When the cell reaches its destination, it offloads the parcel. In this case, an immunological homeostasis molecule—IL-10. This increases the number of T regulatory lymphocytes, non-inflammatory macrophages, and B regulatory lymphocytes. So, IL-10 controls the inflammation, guided by CXCR4.

Essentially, if you have a disease, and you know what modifies or treats that disease, you can source iPSCs and engineer them for specific functions to produce cell therapy products. Going forward, we will see three product groups: ex vivo and in vivo CAR T cells, and allogeneic, off-the-shelf, engineered iPSCs.

In autologous therapies, you need to collect materials from the patient, carry out numerous processing steps, and then bring the cells back to the patient. This takes time and uses donor material that may already be weakened and limited. It delivers a lot of value, but it's not an ideal scenario.

However, allogeneic therapies mean that I can use my cells, your cells, or those of any person, to provide an off-the-shelf solution. Allogenic therapies could become a traditional medicinal product due to their ease of application. The only difference is that, instead of being a biologic, the therapy is a cell.

Additionally, when we develop products at Kiji, we produce them in a way that provides physicians with ease of use. They can go to the fridge, collect the medication, and administer it to the patient. This goes back to understanding the patient's treatment and the importance of interactions between physicians and patients. I need to anticipate these factors and develop my product with that in mind.

One challenge is the technical and product development side—the traditional barriers. You need to generate pre-clinical data showing that the cell has quality, quantity, and potency, which is a key word in regulation. Then, this information is gathered and submitted, and the regulator must ensure that the characteristics are correct, the preparation is sufficient, the patient is safe, and the benefit is evident.

In reaching this point comes the other challenge. We need the patients, the physicians, and, above all, the funding.  These factors must align to be able to translate a concept into a product that is eventually recognized as safe, effective, and marketable. Additionally, a medicinal product must be competitive, going beyond what currently exists.

In terms of very important timelines, we're at the door of the clinic.

We should be able to start treating patients [with graft-versus-host disease] with our KJ-01 therapy within the next few months. This will give us proof of concept, and we believe that the benefit will be long-term. Following this, we will investigate inflammatory bowel disease and psoriasis, both of which have significant unmet medical needs among large numbers of patients. Again, the pre-clinical data, yet to be published, suggest this therapy could have a long-term, potentially lifelong, benefit.