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ESH CLL 2026 | Future directions for CART4-34 and BCR-targeted CAR-T in CLL
Jean Lemoine, MD, University of Pennsylvania, Philadelphia, PA, discusses the future development of CART4-34, a CAR-T therapy targeting IGHV4-34 in chronic lymphocytic leukemia (CLL). He outlines efforts to expand this approach to additional B-cell receptor targets and considers how CART4-34 could be integrated into treatment sequencing alongside or following BTK inhibitors, BCL2 inhibitors, and CD19-directed CAR-T therapy. This interview took place at the ESH CLL 2026 congress in Stockholm, Sweden.
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Transcript
So I think we have good proof of concept in our paper about the limitation of this immunosuppression and other team has also reported alternative CAR-T strategies that can also limit B cell immunosuppression as targeting either kappa or lambda light chain by CAR-T or also targeting a specific variable motif of the light chain, IGLV321 with the point mutation error 110. Concerning the improvement of the efficacy, that is less clear for us and maybe we’ll need other validation steps...
So I think we have good proof of concept in our paper about the limitation of this immunosuppression and other team has also reported alternative CAR-T strategies that can also limit B cell immunosuppression as targeting either kappa or lambda light chain by CAR-T or also targeting a specific variable motif of the light chain, IGLV321 with the point mutation error 110. Concerning the improvement of the efficacy, that is less clear for us and maybe we’ll need other validation steps. But we have also the update size that CAR19 is targeting CD19 that is just a B-cell marker but has no pathogenic role. Whereas IGHV434, as part of the BCR, will have some important pathogenic role in CLL, also as supported by the fact that BCR inhibitors, especially through BTK inhibitors, have their role in the treatment of CLL. And so we expect that targeting the BCR that is quite crucial for the survival of the CLL cells will also help us to limit the resistance to this kind of approaches compared to CAR-19, eventually by decreasing the risk of antigen loss through CAR-T human pressure.
So in our group, we would try to develop new CAR-T that target specific BCR motives. So we know that 434, that is the main target we have described in this paper, is the second most common IGHV found in CLL patients. So maybe we can extend our research to other type of IGHV or specific BCR region that will help gather a number of different CAR-T that could then increase the number of patients that would be eventually in the targeted by, treated with this CAR-T. So this new product is now published, so it’s preclinical levels of evidence, I would say, so also there is all the steps toward translational of this research for clinical research. So I think it’s a bit early to talk about how we would envision this product in the treatment course of a given patient. So we have quite in the last decades developed interest in an efficacy new treatment, as we said, BTK inhibitors or BCL2 inhibitors. So I think that these treatments are still really important to face first-line therapy. So our product will have to be tested with relapse and refractory CLL. Also then the position compared to CAR19 will have to be decided eventually after CAR19 in case of failure because of antigen negative escape or other resistance mechanism, but also maybe replacing CAR19 in a more competitive strategy.
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