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EBMT 2025 | The engineering of IL-12 secreting CAR-NK cells to target high-risk AML
Rémy Duléry, MD, PhD, Dana-Farber Cancer Institute, Boston, MA, comments on the engineering of IL-12 secreting CAR-NK cells to target high-risk acute myeloid leukemia (AML). He emphasizes the benefits of IL-12, which enhances NK-cell proliferation and cytotoxic potential, and identifies mesothelin and CD70 as promising targets expressed on AML cells. This approach has shown promising results in preclinical studies and is now ready for clinical trials. This interview took place at the 51st Annual Meeting of the EBMT in Florence, Italy.
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Transcript
Despite recent advances, patients with high-risk, acute myeloid leukemia still face poor outcomes. CD123 and CD33 CAR T-cells have so far shown limited efficacy and some toxicities, which highlights the need for new constructs and alternative targets. So we hypothesized that we could have a safer and more efficient new CAR by using NK cells, by using IL-12, and by using new targets. So why NK cells? NK cells obviously have unique properties to kill tumor cells, but when they are activated by cytokines, they have more proliferation, more survival, and more potential to kill tumor cells...
Despite recent advances, patients with high-risk, acute myeloid leukemia still face poor outcomes. CD123 and CD33 CAR T-cells have so far shown limited efficacy and some toxicities, which highlights the need for new constructs and alternative targets. So we hypothesized that we could have a safer and more efficient new CAR by using NK cells, by using IL-12, and by using new targets. So why NK cells? NK cells obviously have unique properties to kill tumor cells, but when they are activated by cytokines, they have more proliferation, more survival, and more potential to kill tumor cells. Also, compared to CAR T-cells, CAR NK cells have shown a better safety profile. And they can also be delivered off the shelf. And for all those reasons, there are clinical trials that are being developed showing promising results. So now why IL-12? IL-12 has a unique potential to enhance NK cell proliferation and cytotoxic potential. IL-12 compared to other cytokines has a broader immunomodulatory effect on various immune cells. It can bridge innate and adaptive immune responses. And finally, why new targets? So we identified mesothelin and CD70 as promising targets. They are expressed on several tumors, but on AML, mesothelin is expressed in 36% of AML. And CD70 is expressed in up to 86% of AML. So the reason for choosing them is also because they are absent on the hematopoietic stem cells and enriched in leukemia stem cells. So this is crucial because compared to CD23 or CD123, targeting them will reduce the risk of myeloablation. So with that in mind, we leverage these advantages to build new constructs, mesothelin CAR-NK cells secreting IL-12. First, we have shown that this CAR-NK secreting IL-12 and targeting mesothelin has a benign secretion. When we compare it to CAR-T secreting IL-12, we saw lower levels of inflammatory cytokines. Then, we compared this construct with the same construct but secreting IL-15. So it’s CAR-NK, one secreting IL-12, the other one secreting IL-15. And what we see, which is very interesting, that with IL-12, we have more production of interferon gamma, TNF-alpha, granzyme B. And also in a rich challenge, we see that long-term better tumor control in an ovarian model. So building upon this, we use this mesothelin-CAR-NK construct secreting IL-12. And we show that in vitro, it has a high cytotoxic potential against number one, AML cell lines expressing mesothelin. So it has better, higher cytotoxicity than mesothelin-CAR-NK without IL-12 and than NK cells. Then we did an in vivo model with IL-15 NSG mice and we show that we have better tumor control with this IL-12 mesothelin CAR NK compared to a mesothelin CAR without IL-12. Then we did similar experiments but with another construct except of targeting mesothelin, we target CD70. And we show in five different AML cell lines that the CD70 CAR secreting IL-12 has a higher cytotoxicity against those cell lines, irrespective of TP53 mutation status. We also show higher interferon gamma production. And finally, which is interesting, we show the ability of this IL-12 secreting CAR to activate bystander NK cells, which secrete more interferon gamma and have more degranulation and those are more able also to help killing the tumor. So finally what we see with this study that it is feasible and safe to engineer IL-12 secretion CAR NK cells. We have promising results for using this CAR. At this stage, I think we have now the rationale to build a clinical trial with this construct and it’s a promising possible off-the-shelf approach for the patient. It has also maybe a broad therapeutic potential because CD70 and mesothelin are expressed on other cancers such as hematopoietic cancer and also solid tumors. We already have good results with this construct in ovarian cancer and renal cell carcinoma and we’re working on the lymphoma model. I just would like to thank everybody in the Rumi lab because without them this study will not be possible and I’m especially thankful to Dr Rumi, Fugo, Liu, Ji-Hung-Jong, and Mubin Taranum.
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