Targeted immunotherapy is a very promising strategy in the treatment of multiple myeloma (MM). Specifically, clinical trials using chimeric antigen receptor (CAR) T-cells to target the plasma cell-specific B-cell maturation antigen (BCMA) have produced excellent responses rates. However, to increase the durability of response and prevent relapse, a recent article in Frontiers in Oncology encouraged researchers to consider dual CAR T-cell approaches in the future.
“BCMA is normally expressed solely on a subset of mature B cells and on antibody-producing plasma cells, including their malignant counterparts, the MM cells,” wrote the authors, led by Jort J. van der Schans of the Department of Hematology at the Cancer Center Amsterdam in the Netherlands. “BCMA is therefore a safe target, because other than plasma cell aplasia, no risk of adverse events resulting from on-target, off-tumor effects are expected when BCMA is targeted by CAR T-cells. Furthermore, BCMA was shown to be important in proliferation and survival of MM cells, another important feature, substantiating the value of BCMA as a suitable target for immunotherapy.”
Although early clinical responses to BCMA CAR T-cells have been good, studies with longer-term follow-up have revealed a short durability of remission and eventual relapse after BCMA-targeted CAR T-cell therapy. Therefore, the article explored other possible molecules that are highly expressed on MM cells that could be targeted. Unfortunately, the authors explained, many potential targets are expressed not only on MM cells but also on other important, non-malignant cells. Therefore, targeting those molecules would likely produce significant off-target side effects.
The authors identified G-protein coupled receptor 5D (GPRC5D) as a potential target. The antigen is highly expressed on malignant MM cells, but is found in low levels on B cells, healthy plasma cells, and hair follicles. The authors wrote that BCMA and GPRC5D are the only promising antigens discovered thus far in the fight against MM. Although only a few studies have tried the combination, they have shown potential.
“[GPRC5D’s] function, ligand, and role in MM development are not yet known, but the enhanced expression on MM cells compared to healthy plasma cells indicates a role in malignancy. Targeting this largely MM-specific molecule with CD3/GPRC5D bispecific antibodies and CAR T cells in preclinical settings has already shown promising results, and ongoing clinical studies will expose its suitability as an MM target,” the authors concluded.