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could you share what the biggest challenge you faced during your research was? And what are your expectations for future research directions?
There are two strategies currently being followed in AML. One strategy is applying CAR-T cells, achieving a morphological leukemia-free state, preferentially MRD negative, and followed by an allogeneic stem cell transplantation.And with this approach, you eliminate all the CAR-T cells. You only have the efficacy of the CAR-T cells for a very limited approach.But at least you can target myeloid antigens. And aplasia is not an issue. I think a very interesting evolving strategy is to do edited stem cell grafts. You delete sort of the target antigen by CRISPR/Cas, either the entire target antigen or by creating a non-synonymous mutation, just the epitope that is targeted, followed by CAR-T cells. And there you have the advantage. The CAR-T cells are allowed to persist. They have longer activities. So we'll see how this turns out. And currently, we have no clinical trial data for the second approach yet.
One of the major challenges, in particularly in the context of acute myeloid leukemia, is identifying a suitable target antigen. As you are aware, most of the target antigens currently being employed are myeloid lineage antigens. There's a great concern of on-target of leukemia, toxicity on the healthy hemorrhagic system, as you're aware, and some malignancies. This is less of an issue because we can live without b cells and substitute IgG deficiency with IgG replacement therapy. So that is not the case with a myeloid compartment. Identifying suitable target antigen in AML is one of the challenges. The second challenge is that we have more resistance. It's more like a solid tumor with an immunosuppressive microenvironment. These are the two challenges we address in AML.
I think besides target antigens and toxicity, another big issue in CAR-T cells and AML is resistance, mediated through the microenvironment and through T-cell, AML interaction. I think future strategies have to implement possibly other small molecules or conditioning regimens to counteract the immunosuppressive microenvironment. I think we will not be able to cure with just a CAR-T cell therapy, but need to adopt combinatory approaches. So, I think this is one of the future challenges we have to tackle.
