ICML 2025 | A first-in-human Phase I study of iPSC-derived CAR-NK cells in B-cell lymphoma

Currently when it comes to cellular therapy for B-cell lymphoma, the only cellular therapies currently approved by the FDA tend to be a) autologous and b) T-cell-based. These are some limitations. When it comes to autologous therapies, they’re very dependent, of course, on the integrity of the host immune system. They may have been affected, though, by prior lines of therapy, and also implies collection and manufacturing that adds extra time to the moment the CAR T-cell will be readily available for infusion. And unfortunately, there is a fraction of patients that has very aggressive disease that cannot wait for all that time. And some patients are unable to get access to CAR-T because of that. 

The other downside of CAR T cells is that T-cells, due to their biology, tend to be associated with sometimes life-threatening toxicity, such as cytokine-release syndrome or immune cell-associated neurotoxicity syndrome. So there’s a lot of interest in trying to come up with new cellular therapies that are going to be allogeneic, in this case derived from pluripotent stem cells, induced pluripotent stem cells, or iPSC. And they’re not T-cell-based, but rather natural killer cell or NK-cell-based, because NK-cell biology tends to be more favorable. 

So we did run this Phase I trial of FT596, which is an NK-CAR derived from iPSCs, where the CAR targets CD19, but there’s also an engineered CD16, which is high affinity and non-cleavable, able to increase the cytotoxicity of NK cells. We saw a quite significant activity, higher than 50% response rate, with a higher than 30% CR rates, even in patients who have received CAR-T previously, and including patients with aggressive B-cell lymphoma. In indolent cell lymphoma, of course, response rates and CR rates were much higher, actually close to 100%, and now quite durable with quite long median follow-up, longer than three years. 

In terms of toxicity, as expected, there was minimal to no CRS, not a single case of immune cell-associated neurotoxicity syndrome, and despite the product being allogeneic, there were no cases of GVHD. Unfortunately, this specific product, mainly due to strategy, more than biological or clinical reasons, is not moving forward. But I think it has really placed the basis for new agents in this landscape, including other allogeneics such as cord blood-derived NK cells, including some products that we’re currently developing in my institution. So I’m very hopeful that in the not so far future, we may hopefully get an approval for an allogeneic product and hopefully for an NK cell-based type of cellular therapy.

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