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EBMT 2026 | CD19/CD84 IF-BETTER dual CAR T-cells for the treatment of CD19-low B-cell malignancies
Ane Altuna Mongelos, MD, Hospital Clínic de Barcelona, Barcelona, Spain, shares insight into the development of CD19/CD84 IF-BETTER dual CAR T-cells for the treatment of CD19-low B-cell malignancies, highlighting that the design of these CARs allows for enhanced activation and cytotoxicity in settings of low CD19 expression. Dr Mongelos notes that the dual CAR outperforms single CD19-targeting CAR T-cells in CD19-low in vitro and in vivo models, with findings set to be validated in additional disease models. This interview took place at the 52nd Annual Meeting of the EBMT in Madrid, Spain.
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Transcript
In a single targeting CAR T-cell, we have an scFv directed to one antigen, in this case to CD19, with a co-stimulatory domain and a CD3 ζeta domain. In the dual CAR, we have two different scFvs, one directed to the CD19, in our case composed of a complete second generation CAR, and there is then a second structure that is a second scFv with just a costimulatory domain...
In a single targeting CAR T-cell, we have an scFv directed to one antigen, in this case to CD19, with a co-stimulatory domain and a CD3 ζeta domain. In the dual CAR, we have two different scFvs, one directed to the CD19, in our case composed of a complete second generation CAR, and there is then a second structure that is a second scFv with just a costimulatory domain. So, both CARs, the single and the dual, will get activated with the expression of the CD19 in the target cell, but when the target cell is expressing also CD84, the dual CAR will get much more activated than the single CAR just with the CD19. Single targeting CAR cells, they need a first call of antigen density to get completely activated. So that way they can exert the cytotoxicity correctly and they can expand and proliferate correctly. If this antigen is not expressing at that level, the CAR will not get activated. So in our strategy, the second antigen is providing an additional activation signaling that in those settings of CD19 low expression will improve the efficacy of the CAR and that way the CAR will achieve a complete cytotoxicity and a better expansion and proliferation of the T-cell.
On the one hand, when the CD19 expression is high, they perform equally to single CD19 targeting CAR T-cells, both in vitro and in vivo. But in models of low CD19 expression, this dual CAR is outperforming single CD19 targeting CAR T-cells, both also in vitro and in vivo. One of the plans is to validate our dual CAR in some other different settings, different B-cell malignancies, especially in B-cell aggressive lymphomas, because it’s also reported that those lymphomas relapse with CD19 downregulation or CD19 heterogeneous expression. And on the other hand, we have also to perform different safety preclinical studies to better profile the specificity of our dual CAR and possible off-targets.
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Disclosures
Research funding and salary from Gyala Therapeutics S.L
