iwCAR-T 2025 | Accelerating CAR T-cell therapeutics with small molecules and CRISPR 2.0 gene editing

My name is Michael Hudecek. I’m a CAR-T investigator at the University of Würzburg in Germany. Today in the presentation I showed one particular example of how we use FLT3 CAR-T cells to treat acute myeloid leukemia. And how we combine this with a small molecule inhibitor that is also directed against FLT3. 

So there’s a few reasons why we believe this treatment will be synergistic. First, we show that by using the FLT3 inhibitor, we can increase the target antigen density on AML cells such that they are better recognized by the FLT3-CAR-T cells. We also believe this is an important mechanism clinically to prevent antigen downmodulation and antigen loss because the AML blasts depend on the FLT3 as a survival signal. 

Another mechanism that is important is that it has been shown that AML blasts, when they are exposed to cytokines that the CAR-T cells release during the anti-leukemia response, can be activated and can enter proliferation. And with the FLT3 inhibitor, we’re also blocking this reaction. So these are the reasons why we’re going now into a clinical trial where we combine the FLT3 CAR-T cells with the FLT3 inhibitor. 

So there’s a lot of interest in using gene editing in addition to the gene transfer that they do for the CAR in this field. There is one particular example that I presented today and this takes us to the area of so-called fratricide. There is a number of target antigens that we address in hematologic malignancies that are also expressed on T-cells. That includes for example CD5, CD7, CD38 but also the SLAMF7 and that is the target that we are after in multiple myeloma. So now what happens is when we express a SLAMF7 CAR in the T-cells during the manufacturing of the cell product, some of the T-cells are starting to attack each other and kill. This is called fratricide. 

So we’ve shown that you can still make a CAR-T cell product, but there are some limitations into the dose of the CAR-T cells that we can manufacture in a short period of time. And also there are some effects on the fitness of the T-cells because essentially during the entire manufacturing process, they’re already active and they’re kind of in an idle mode. And this is what we want to prevent and this is why we are doing a gene edit to eliminate the SLAMF7 from the T-cells such that when they start expressing the CAR, they’re not doing the fratricide phenomenon and they can just grow and expand and then they’re in a much better functional state at the time of infusion. We have strong data now to support that this will increase anti-myeloma efficacy. And this is why we’re bringing this cell product also into the clinical trial, CARAMBA, that we’re doing already as essentially under the parent trial paradigm as an improvement of this original cell product that did not have the gene edit.

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