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ESH CLL 2026 | CART4-34: precision CAR-T targeting IGHV4-34+ B-cells in CLL
Jean Lemoine, MD, University of Pennsylvania, Philadelphia, PA, discusses the development of CART4-34, a precision CAR-T therapy targeting IGHV4-34 within the B-cell receptor in chronic lymphocytic leukemia (CLL). He explains how this approach may overcome key limitations of CD19-directed CAR-T therapy, including antigen loss and prolonged B-cell aplasia, by selectively targeting malignant clones while sparing most normal B cells. This interview took place at the ESH CLL 2026 congress in Stockholm, Sweden.
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Transcript
So, indeed, with my colleagues at the RUELLA Lab, we recently published a paper in Science Translational Medicine in 2026 that described the development of new CAR T strategies that target IGHB 434. So we know quite the limitation of CAR-19, eventually in CLL, but also in other lymphoid disorders, especially so the patient that will relapse can eventually have loss of the target, so loss of CD19, a mechanism known as antigen-negative relapse, but also concerning toxicity...
So, indeed, with my colleagues at the RUELLA Lab, we recently published a paper in Science Translational Medicine in 2026 that described the development of new CAR T strategies that target IGHB 434. So we know quite the limitation of CAR-19, eventually in CLL, but also in other lymphoid disorders, especially so the patient that will relapse can eventually have loss of the target, so loss of CD19, a mechanism known as antigen-negative relapse, but also concerning toxicity. So patients treated with CAR19 will have a profound and deep depletion of their normal B cells that will result in a prolonged B cell aplasia and eventually infection, including severe infection that can lead to a certain rate of non-relapse mortality that are quite the two most important limitations of CAR-19 regimen up to date. And these limitations can be also observed in the CLL treatment. So we aim to develop an alternative CAR-T strategy toward more precise and personalized medicine.
So concerning CAR19, we know that both CLL cells, so the malignant cells, but also all the B cells would be expressing the target. And so CAR19 will be resulting in the eradication of both CLL malignant clones, but also of normal B cell that is quite a. So in our paper we describe this precision targeting strategy that will target IG3-434 so that is a motif inside the BCR that would be expressed by all the CLL cells as they are clonal. Sure, it is restricted to a certain number of patients affected by CLL. I estimate this number about 10% of CLL cases. But in these patients, well, all the CLL cells will be expressing this target, IgG434, whereas in the healthy B-cell repertoire in healthy individuals, we notice that lower than 10% of normal B-cell will be expressing the target. So we expect that our car, car 434, will be able to kill efficiently the CLL cells while only affecting and targeting less than 10% of healthy B cells, resulting in no observation of B cell aplasia and just a limitation of this B cell immunosuppression.
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