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Overexpression of A Proliferation Inducing Ligand (APRIL) has been linked to multiple myeloma (MM) and is thought to drive both proliferative signals as well as immunosuppressive signals in the bone marrow (BM). Therefore, targeting APRIL with blocking antibodies is a therapeutic strategy in MM. Recently, an APRIL-specific antibody (BION-1301) developed by Aduro Biotech entered an initial phase I/II clinical trial in patients (pts) with relapsed and refractory (RR) MM.
APRIL binds to two receptors, B cell maturation antigen (BCMA) and Transmembrane activator and CAML interactor (TACI), so it has been hard to decipher through which receptor individual signals emanate. However, high BCMA expression occurs on MM cells, and so BCMA is a prime target in MM, with the development of a number of BCMA-directed CAR T-cell already in clinical trials.
In a study published in Leukemia in July 2018, Yu-Tzu Tai from The Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Boston, US, and colleagues, studied the impact of APRIL on regulatory T-cells (Tregs) in the context of immunosuppression in the MM BM milieu.
TACI is expressed at significantly higher levels on Tregs than on conventional T cells from the same patient, and APRIL stimulates survival of these cells. In turn, these cells drive immunosuppressive signals in the BM of myeloma patients. In all experiments where an effect with APRIL was observed, the use of a blocking anti-APRIL mAb reversed this effect. Thus, this study provides a strong rationale for the use of an anti-APRIL antibody as a therapy in MM, and also suggests that combination with other agents, such as anti-PD1 may be beneficial.
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