Dr Di Meo on the Rationale for Developing LILRB4–Directed CAR T-Cell Therapy in Multiple Myeloma

Francesco Di Meo, PhD, postdoctoral research fellow, Moffitt Cancer Center, discusses the role of the immunoreceptor LILRB4 in the tumor microenvironment, as well as highlights the rationale for targeting this marker through CAR T-cell development in multiple myeloma.

Di Meo and his colleagues developed a pipeline to identify biologically and therapeutically relevant targets for immunotherapy development in multiple myeloma by using mass-spectrometry analyses from 7 multiple myeloma cell lines and RNA-seq data from over 900 patients with multiple myeloma. From a pool of 4,000 candidates, multiple myeloma, emerged as a promising target. Multiple myeloma is a tyrosine-based inhibition motif-containing receptor that functions as an immune checkpoint on myeloid cells and has implications in various immune diseases.

LILRB4 shows low expression in normal tissues but is highly expressed in many primary patient samples and myeloma cell lines, similar to BCMA, making it a significant marker for multiple myeloma, Di Meo states. LILRB4 has also been implicated in the proliferation of multiple myeloma cells and has shown an immunomodulatory role in diseases like monocytic acute myeloid leukemia (AML), where it mediates T-cell inhibition and leukemia cell infiltration, he adds.

Building on these findings, investigators aimed to investigate the functional role of LILRB4 in multiple myeloma and explore the development of CAR T-cell therapies targeting LILRB4, Di Meo continues. This approach seeks to leverage the specific expression patterns and immunomodulatory properties of LILRB4 in multiple myeloma to design targeted therapies that can enhance immune responses against myeloma cells, he explains.

In this study, multiple CAR constructs developed to target LILRB4 demonstrated specific killing of myeloma cell lines in vitro, including cell lines with resistance to conventional therapies.

Overall findings from the study reinforce LILRB4's role as a negative immune receptor in multiple myeloma. Future studies will focus on validating these findings and exploring the therapeutic potential of targeting LILRB4 with CAR T-cell therapies in myeloma.