EBMT 2022 | An update on CAR-T therapy in AML: challenges & emerging strategies
Chimeric antigen receptor T-cell (CAR-T) therapy has shown remarkable efficacy in many hematological malignancies. However, this success has not been translated to acute myeloid leukemia (AML). In this video, Marion Subklewe, MD, Ludwig-Maximilians-University of Munich, Munich, Germany, comments on the challenges in developing CAR-T therapy in AML. The principal challenge limiting the use of CAR-Ts in AML is the absence of an AML-specific antigen. In addition, due to the non-inflammatory immunosuppressive tumor microenvironment (TME) in the bone marrow of patients with AML, it is necessary to combine CAR-Ts with other immunostimulatory agents to enhance the activity of T-cells. This approach has been used in a recent experiment evaluating CD33-targeted CAR-Ts expressing IL-15. This interview took place at the 48th Annual Meeting of the European Group for Blood and Marrow Transplantation (EBMT) 2022, which was held virtually.
Transcript (edited for clarity)
This is something where I think we need perseverance and it’s not evolving as we had hoped for. The translation from ALL to AML is challenged by several aspects. First of all, we are still looking for the ideal target antigen. So I think CD19 is a lineage antigen for B-cell malignancies, and is clearly a very suitable target antigen. It’s homogeneously expressed on almost all the tumor cells and leukemic stem cells, and we can also live without B-cells...
This is something where I think we need perseverance and it’s not evolving as we had hoped for. The translation from ALL to AML is challenged by several aspects. First of all, we are still looking for the ideal target antigen. So I think CD19 is a lineage antigen for B-cell malignancies, and is clearly a very suitable target antigen. It’s homogeneously expressed on almost all the tumor cells and leukemic stem cells, and we can also live without B-cells. So the on-target of leukemia toxicity is less relevant. So if we look at this in the context of AML, we are challenged that all the lineage antigens are also expressed within the myeloid compartment and therefore on-target of leukemia toxicity is causing a greater challenge when performing CAR-T therapy.
But I think the other aspect that is also evolving and showing us that we probably have to be smarter in the AML setting is that the tumor microenvironment in the bone marrow of AML patients appears to be non-inflamed immunosuppressive, so that even if we have an ideal target antigen, we would probably have to possibly integrate immune-stimulatory pro-inflammatory aspects to keep T-cell function up. And I think there was an interesting, very early report from Moffitt Cancer Center, at the last ASH, where they showed CD33-directed CAR-Ts, so one of the most commonly approached target antigen CD33, but it was accompanied by an IL-15 expression, so a T-cell propagating cytokine. Although the data is much too early to conclude anything, I think we need to think of combinatory approaches, smarter CAR-Ts to be successful in the AML setting.
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