iPSC Technology Overcomes Cell Therapy Manufacturing Hurdles
Cynata Therapeutics is leveraging induced pluripotent stem cells to produce cell therapies consistently and at scale.
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Mesenchymal stem/stromal cells (MSCs) have been identified as a promising resource for cell therapies due to their high immunomodulation ability, anti-inflammatory properties, tissue regeneration capabilities and their good safety track record. Wild-type MSCs administered to humans have to date not been observed to exhibit any of the strong host reactions that other types of cell therapies can trigger, for example, CAR T cells triggering a cytokine storm. However, difficulties around manufacturing therapeutically effective MSCs consistently and at scale have held back their clinical use, with only one MSC-based therapy currently approved by the US Food and Drug Administration (FDA).
One of the major barriers to bringing these cell therapies to patients is the need for new tissue donations from different donors on an ongoing basis. This can lead to substantial variability and batch limitations due to the finite expansion capacity of each donation.
To overcome this, the University of Wisconsin–Madison and Cynata Therapeutics have developed the Cymerus™ platform, which utilizes induced pluripotent stem cell (iPSC) technology to enable the scalable manufacture of MSC-based therapies. Technology Networks spoke with Dr. Mathias Kroll, chief business officer at Cynata, to learn more about the Cymerus platform and the potential of MSCs as a disease-modifying treatment for underserved diseases such as osteoarthritis.
What are some of the opportunities and challenges with MSC-based therapies?
Mathias Kroll, PhD (MK):
MSCs are naturally occurring cells in the body with anti-inflammatory and immuno-modulatory functions, and they also make excellent tissue regenerators. Endogenous MSCs can differentiate into several other cell types, which then replace dysfunctional cells and thus promote healing. Because of these properties, they've been studied extensively in regenerative medicine for quite some time.
MSC-based therapies have been developed by several biotech companies but using a different process from Cynata’s Cymerus platform, which has several distinct advantages. At Cynata, we want to make MSC-based therapies using the most scientifically rigorous standards and on a large scale.
BF:
MK:
The Cymerus process is a proprietary method of creating MSCs from iPSCs. The process is stable, robust and reproducible and gives you fantastic scalability. Because iPSCs can be multiplied almost limitlessly, you can overcome the challenge of scale that MSC-based therapies have faced over the last decade.
So, how do you obtain MSCs? These cells are naturally occurring and can be found in bone marrow and certain tissues. You can isolate them from donations of bone marrow, as an example, but that is an invasive process. In addition, this typically only provides a relatively small number of cells but for a pharmaceutically relevant dose, you could require a very large number, meaning up to 200 million cells per dose. If you want to be able to serve potentially thousands of patients, and if there are several injections needed per patient, you need enormous numbers of cells. The typical tissue-derived process, therefore, forces you to go through a process of culture expansion, which disturbs the cells. It’s well established that you can’t culture MSCs too much because they become senescent and may stop producing the beneficial factors that make them useful as a therapy. In this way, donor-derived MSCs are useful in more niche, low-volume, specialized applications.
iPSC-derived processes allow you to culture MSCs at a much larger scale. Once we obtain the MSCs through this method, we find they’re homogenous and not exhausted or senescent. This means we can make MSC-based therapies accessible for diseases that impact a larger volume of people, such as osteoarthritis.
For example, we were happy to see that one of our peers was able to get FDA approval for their bone marrow-derived MSCs in a relatively small indication, but one with a very high unmet medical need. The therapy is an allogeneic (donor) bone marrow-derived MSC therapy indicated for treating steroid-refractory acute graft-versus-host disease (GVHD) in pediatric patients two months of age and older. This approval reinforced our belief that MSCs as therapies have great potential, and it’s exciting that we've got the right technology to allow us to access a much broader spectrum of diseases.
BF:
MK:
It all started with the work by Professor David Hunter at the University of Sydney, who had completed pilot studies using tissue-derived MSCs. Encouraged by the results of these trials, they approached Cynata with the hopes that our MSCs would be able to support a positive outcome in a larger clinical trial they had planned. Our objective in this trial with Hunter and colleagues is to determine to what extent MSCs can exert beneficial effects in osteoarthritis.
We believe the anti-inflammatory and tissue regenerative properties of MSCs, coupled with their potential for endogenous cartilage regrowth and protection, make them a potential candidate for slowing and perhaps even halting disease progression in osteoarthritis.
There's currently no disease-modifying osteoarthritis drug on the market. Our therapy promises that with just a few injections, that might change. You inject two doses of the Cymerus MSCs in the space of a few weeks into the intra-articular joints and then another dose one year later. Our trial has a two-year follow-up period, and at the end, we can assess the effect on pain, function and knee cartilage structure as well as the patient’s quality of life. The last patient was injected at the end of last year, and we're now in the second half of the follow-up period and are expected to conclude the trial in November of this year.
BF:
MK:
We have already concluded two Phase 1 trials with great outcomes. One was in GVHD, which was then the basis of our currently ongoing global Phase 2 trial, and the other was in diabetic foot ulcers. Hopefully, we will soon add successful outcomes of the Phase 2 trial in GVHD and the Phase 3 osteoarthritis trial discussed. We hope this will convince skeptics of the promise of MSC-based therapies and lead to increased adoption.
I hope, as chief business officer, to be able to multiply our collaborations with industry and academia and roll out our Cymerus platform to its fullest extent in a broad range of diseases. There are so many diseases that are completely underserved and in which the MSCs have great potential. For example, the anti-fibrotic effect of MSCs has shown great promise in preclinical studies of idiopathic pulmonary fibrosis in animal models. We're looking forward to bringing our MSCs into development for many more diseases.
