EBMT 2025 | Tackling the challenges with generating “off-the-shelf” allogeneic T-cell & NK-cell products

The major challenges I see in generating allogeneic and off-the-shelf products are many, but in addition to creating master banks, deciding what source to use, expansion protocols, which are still labor-intensive. But I think if you ask me what is the single most important challenge, it still is the risk of rejection after adoptive transfer. 

So multiple items have been made, for example, knocking out the HLA class 1 and class 2 molecules and things like that, or even the expression of HLA class molecules by things like beta 2, knocking out beta 2 microglobulin. But still, if you look at so far, the evidence is that these products still get rejected after adoptive transfer, both CAR T-cells and CAR NK cells. And that’s been probably the number one challenge in the field, that how do you make the survival, the persistence of iPSC-derived or otherwise, because you can create allogeneic products from peripheral blood-derived products as well by expanding the non-iPSC CD34s from bone marrow, for example, or cord blood, for example, those are the commonly used sources for deriving off-the-shelf products. But again, they get rejected. And despite the fact that we can knock out class 1, class 2, and there are some mitigation plans in terms of incorporating HLA-E to help prevent NK cell-mediated rejection, HLA-G is the other molecule which has been used. And there are some other novel models for non-PD-L1 expression and things like that, trying to suppress the T cell-mediated rejection. There’s an elegant paper from Baylor using ADR, they call it ADR, and it actually kills the activated T-cells which come in contact with the product. I know Fate Therapeutics has licensed and they are evaluating the use of ADR-expressing products for off-the-shelf allogeneic products and we don’t know the data yet. The clinical data is not available yet. But those are some of the approaches people are taking for addressing this key challenge, which is the lack of prolonged in vivo survival of allogeneic products, both CAR T-cells and CAR NK cells. 

There was also a recent elegant paper from Professor Michel Sadelain’s group showing that expressing one of the proteins from HIV, I believe, shuts down the class one molecules in CAR T-cell products that help them mitigate the rejection. My own group has, and we presented at ASH last year and it’s under review, generated shRNA-based approaches to mitigate rejection of the CAR and NK cells. And again, we don’t have any clinical data, but in a mouse model, if you use this particular shRNA, which targets expression, selectively express targets expression HLA, A, B, and C without touching HLA-E that lets us shut down at the T cell-mediated rejection and without enhancing the NK cell-mediated rejection. 

These are some of the common approaches for preventing rejection of adoptively transferred products, both CAR T-cells, CAR NK cells, I’m sure people are also looking into using some of these approaches in macrophages as well, because there’s other N-gamma-delta T-cells, for example. Those are the other cell products which people are pushing for allogeneic products.

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