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The Cymerus Process

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    An article published yesterday in Nature Medicine might be able to address a few misconceptions:

    Production, safety and efficacy of iPSC-derived mesenchymal stromal cells in acute steroid-resistant graft versus host disease: a phase I, multicenter, open-label, dose-escalation study

    Rather that just copy and paste a few snippets, I will try and put them into a Q&A style summary. If it fails, I won't try again.

    Q1: What is Cymerus?

    A1: "The Cymerus proprietary manufacturing process, which is used to manufacture CYP-001, is represented in Fig. 1. This new production platform generates MSCs from iPSCs via an apelin receptor+ lateral plate mesoderm intermediate cell with fibroblast growth factor-2 (FGF2)-dependent colony-forming potential, known as an MCA20,21. This approach allows for the production of well-defined MSCs that express lateral plate, but not paraxial or intermediate, mesoderm markers."

    Q2: Why is there a need for a different MSC manufacturing approach? I mean, MSCs have been around for decades and are currently tested in ~1,000 clinical trials all around the world.

    A2: "Mesenchymal stromal cells promote an immunosuppressive and immunoregulatory environment by secretion of cytokines, chemokines, growth factors and extracellular vesicles7,8, as well as by activation of indoleamine 2,3-dioxygenase (IDO) production in recipient phagocytes when undergoing apoptosis9. MSCs lack human leukocyte antigen class II antigen expression, which allows allogeneic administration without donor–recipient matching. There is general consensus that MSCs derived from primary sources (including bone marrow, adipose tissue, umbilical cord blood and placenta) are safe and well tolerated10.
    However, there are substantial scalability and consistency challenges associated with primary donor-derived MSC production. There is substantial donor-dependent variability in the propensity of MSCs to be activated by interferon-gamma and tumor necrosis factor-alpha, which leads to upregulation of IDO expression and results in suppression of T-cell proliferation11,12,13. Additionally, MSC gene expression, differentiation, proliferation and colony-forming capacity vary markedly among donors.14,15. Furthermore, repeated recruitment and qualification of donors is costly and logistically challenging. While extensive ex vivo culture expansion of MSCs can be employed to produce large numbers of therapeutic doses per donation, this may lead to replicative senescence and other changes to MSC properties, even at relatively low culture expansion levels15. Indeed, clinical data suggest that minimally expanded, bone marrow–derived MSCs (BM-MSCs) are associated with better outcomes in SR-aGvHD patients compared to moderately expanded passage 3–4 BM-MSCs16."

    Q3: Sounds like there is more than just challenge during that whole process. What makes Cymerus different?

    A3: "We have developed a new iPSC- and mesenchymoangioblast (MCA)-based manufacturing platform to address these challenges, by eliminating the need to rely on new donors and minimizing the level of culture expansion once MSCs are formed."

    Q4: Would you mind going into more detail, describing the Cymerus process?

    A4: "The manufacturing process consists of three stages:
    (1) iPSC banking,
    (2) iPSC expansion and differentiation to MSCs to freeze and intermediate bank and
    (3) MSC expansion and formulation of final clinical product.
    Based on the existing banking strategy, approximately 9 × 10^4 vials, each containing 1 × 10^6 iPSCs, can be generated from a single iPSC line. At the current processing scale, a single vial of 1 × 10^6 iPSCs is capable of giving rise to 3.2 × 10^10 MSCs on average, while the entire iPSC bank has the capacity to generate 2.9 × 10^15 MSCs, or 29 million clinical doses (each containing 1 × 10^8 MSCs)."

    Q5: Wow... that's a very detailed, containing a lot of numbers. Would you mind simplifying the above for me?

    A5: "A single iPSC bank is sufficient to generate ~375,000 batches of CYP-001, equating to approximately 29 million clinical doses at the current processing scale."

    Q6: Much better, thank you. Is 29 million clinical doses the limit for the Cymerus process? I mean, it sounds like a lot but given the number of cells used vary largely based on the indications they are used for, they may not be enough to meet future demand.

    A6: "Our process also has the potential to be scaled up further to produce a considerably higher number of doses per bank as development progresses."

    Q7: Excellent, thank you. You mentioned before that you have developed this process - I thought it was a licensed and patented process from WARF?

    A7: "We developed an optimized, GMP-compliant manufacturing process utilizing xenogen-, serum- and feeder-free conditions. We eliminated the use of murine feeders, in contrast to the original protocol developed by Vodyanik et al.20, instead using chemically defined conditions for iPSC maintenance as previously described by Chen et al.22. We also optimized the mesenchymal colony-forming medium (M-CFM) compared to that used by Vodyanik et al., and implemented a modified version of the protocol described by Uenishi et al.23 to achieve mesoderm induction. The optimized process generated MSCs with superior performance in a previously described immunopotency assay24."
    Note: each optimization process is covered by additional patents, meaning although the core patent might expire in 2028, each improvement process will have a seperate expiry date, some of them until 2035.

    Q8: What about the safety of this process? I have heard that iPSCs have a risk of forming teratoma?

    A8: "To avoid the risk of teratoma formation or aberrant differentiation in vivo, the CYP-001 manufacturing process was designed to ensure the absence of residual iPSCs in the final product by incorporation of the following steps:
    (1) after the induction of mesoderm, cells were cultured in a single-cell suspension in semisolid medium, which does not support iPSC survival;
    (2) cells were passed through a mesh filtration step, which eliminates small clumps of undifferentiated iPSCs; and
    (3) iPSC-derived MSCs were expanded in adherent cell culture conditions, which do not support survival or expansion of undifferentiated iPSCs.
    To confirm these mitigation steps, we conducted an experiment in which undifferentiated iPSCs were seeded in place of MSC progenitor cells in the M-CFM culture step. After culturing for a duration equivalent to that of the differentiation process, cells were collected and cultured under conditions that support the growth and expansion of human pluripotent stem cells. No iPSC colony formation was observed (lower limit of detection, 0.001%), and microscopic observations detected only single dead cells that did not attach or divide in the flowthrough fraction plated. We conclude that residual iPSCs do not survive M-CFM culture, and that any dead iPSCs in this culture are removed before the MSC expansion stage of the process, providing reassurance that the final CYP-001 product is free from residual iPSCs."

    Q9: Thank you. You keep mentioning the word "platform". I thought CYP-001 is a product for SR-aGvHD?

    A9: "[...] we have optimized the manufacture of CYP-001 and investigated its safety, tolerability and efficacy for the treatment of adults with SR-aGvHD in a multicenter, phase I, open-label, dose-escalation clinical trial (NCT02923375). As the first completed human clinical trial of iPSC-derived cells in any disease, this study is relevant not only to SR-aGvHD but also to many other diseases for which MSCs may have therapeutic utility."

    Q10: Such as?

    A10: "Encouraging data on the potential utility of iPSC-derived MSCs manufactured using this platform have already been generated in preclinical models of critical limb ischemia33, asthma34,35, organ transplant rejection36 and acute respiratory distress syndrome37. Furthermore, we note that primary MSCs have been investigated for a wide range of other therapeutic indications, and we hypothesize that iPSC-derived MSCs could be expected to show similar in vivo effects more generally. The scalability and consistency of this iPSC-derived process could prove to be even more advantageous if the cells are shown to have beneficial effects in one or more conditions with a much higher incidence than aGvHD."

    Q11: What is your take from your SR-aGvhD trial?

    A11: "Our study demonstrates that iPSC-derived MSCs can be manufactured using a new cell differentiation and expansion platform that eliminates major issues of supply, scalability and consistency."
    "[...] within a limited number of subjects with SR-aGVHD, CYP-001 is safe and tolerable. Additionally, although further trials with larger sample sizes will be required to confirm efficacy, the aGvHD response and OS rates observed are encouraging."
    "The challenges of scalability, reproducibility and consistency of iPSC-derived products, which have been overcome herein, are pertinent to the application of iPSC technology regardless of the disease target. This study represents the first report of a completed human clinical trial using iPSC-derived cells in any disease."

    Thank you for your time!
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