Dr Di Meo on the Potential Efficacy of LILRB4-Targeted CAR T-Cell Therapy in Multiple Myeloma

Francesco Di Meo, postdoctoral research fellow, Moffitt Cancer Center, discusses the potential efficacy of CAR T-cells targeting the immunoreceptor LILRB4 in multiple myeloma.

Investigators launched a study in order to elucidate the functional role of LILRB4 in multiple myeloma, as well as to develop CAR T-cells targeting LILRB4.

Analysis of RNA sequencing data from patients with multiple myeloma revealed elevated LILRB4 expression in patients with high-risk cytogenetics, such as t:(14;16), t:(14;20), and t:(8;14) translocations, compared with patients without genomic abnormalities, Di Meo begins.Additionally, functional studies involving genetic depletion of LILRB4 in U266/KMS11/OPM2 myeloma cell lines showed no significant difference in cell proliferation compared with controls, as assessed by in vitro cell growth assays and migration assays using porous membranes, Di Meo explains.

Further investigation using LILRB4 knockout and overexpressing U266 myeloma cells identified approximately 3,000 differentially expressed genes compared with controls, suggesting potential extrinsic effects, he expands. Co-culture experiments with T-cells from healthy donors and LILRB4 knockout or overexpressing U266 cells revealed decreased T-cell proliferation in the presence of LILRB4 overexpressing cells, while proliferation increased with LILRB4 knockout cells, Di Meo elucidates.This effect was associated with changes in CD25 expression on T-cells, indicating a negative immune regulatory role of LILRB4, he notes.

Multiple CAR constructs targeting LILRB4 were also developed, showing specific killing of myeloma cell lines in vitro, including those resistant to conventional therapies. Notably, no effect was observed on LILRB4 null cells, Di Meo continues.

Overall, these findings suggest that LILRB4 acts as a negative immune receptor, mediating T-cell suppression in multiple myeloma. The development of LILRB4-targeting CAR T-cell therapy holds promise as a therapeutic approach, particularly for high-risk patients, he states. This indicates the potential clinical significance of targeting LILRB4 in future multiple myeloma treatment strategies, Di Meo concludes.