EBMT 2025 | The potential of iPSC-derived CD19 CAR NK cells for treating lymphoma

For years, there’s been interest in using off-the-shelf products and iPSC-derived products are attractive for one simple reason, that iPSC, these induced pluripotent stem cell-derived either CAR T cells or CAR macrophages or CAR NK cells, you can produce a lot. You can create master banks of genomically defined iPSCs and you can produce theoretically unlimited quantities of any cell product you want and that’s a huge huge advantage in terms of cost mitigation, accessibility, and the ability to do genomically edit this with multiple edits because you can make as many edits you want in the master cell line and then in the iPSC derived stem cells and then you can then produce the product of your choice with those gene edits. 

So not only does it allow the production of large quantities and potentially at a way lower cost because you don’t need to perform those gene edits every single time, you just need to produce in the master bank and then you know produce any cell you want. Not completely you know simple because of the fact that you still need several weeks of manufacturing and that does involve cost but nonetheless it allows you really truly off-the-shelf you know production. In this particular study, which was recently published in Lancet it’s an industry-sponsored trial by Fate Therapeutics and they use CD19 CAR NK cells derived from iPSC, which also incorporated some other edits, including CD16, which is a very activating receptor in NK cells. So normally CD16, which binds to the Fc part of IgG1 molecules and is important for mediating ADCC, which is the antibody-dependent cellular cytotoxicity, get sheared actually.

In my work back in my postdoc days, we found that CD16, every time it engages a monoclonal antibody-coated tumor, it gets actually clipped. That’s the downregulation mechanism. And following that work, at University of Minnesota, they identified the exact sequence, which is clipped by this enzyme called ADAM17, and they did a shared resistant version of CD16, and that’s the version which was incorporated by Fate Therapeutics into their iPSC-derived NK cells, and that they made it enhance ADCC function. So this is the first in-human clinical trial of CD19 CAR with these edits, including membrane-borne IL-15 to enhance their antitumor function and in vivo survival and had CD16 – so really a novel product. 

It’s truly an allogeneic product because it’s off the shelf and also it’s not per patient, it uses the master bank. And what was exciting was the safety again despite the fact that these are allogeneic products, none of those patients developed any graft-versus-host disease. And if you look at the response rates, they were not as good as the use of autologous CAR T-cells, but these are allogeneic products, and use of allogeneic products with all the challenges, I think the response rates were not bad. I think it can only get better, and that’s the exciting part. This establishes the kind of baseline, if you will, efficacy signal of use of iPSC-derived NK cells and can only get better from there. And again, if you look at, in this trial, especially the patients with non-aggressive diffuse large B-cell lymphoma, like non-diffuse large B-cell lymphoma, so follicular and mantle, the survival and response rate were pretty good. 

So I think this trial tells us that it’s feasible, the use of iPSC with multiple gene edits is feasible, it’s safe, and has an efficacy signal which can only be improved from there, which is exciting.

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