Inhibiting γ-secretase in myeloma tumor cells to improve killing by chimeric antigen receptor T cells
Joe James Abbott
May 9, 2017
Department or Program
J. Matt Craig
Despite the development and implementation of new therapeutic approaches to hematologic malignancies, multiple myeloma, characterized by the abnormal accumulation of antibody-secreting plasma cells, remains incurable and nearly all patients relapse and die following treatment. However, advancements in genetic engineering coupled with a greater understanding of the immune system have led to the establishment of immunotherapeutic treatments for hematologic malignancies, wherein the immune system is stimulated to attack blood neoplasms. One such treatment is the use of chimeric antigen receptor (CAR) T cells, which utilize elements of antibody recognition and T cell stimulation to redirect the specificity and cytotoxicity of T cells. Previous work has demonstrated that the use of CAR T cells specific for the B cell maturation antigen (BCMA), which is selectively expressed on plasma cells, confers a robust antimyeloma response both in vitro and in vivo. Additionally, a recent study indicated that the intramembranous protease γ-secretase is responsible for the direct cleavage of BCMA from the surface of plasma cells. The primary objective of this work was to establish a novel immunotherapeutic treatment of multiple myeloma through the use of a γ-secretase inhibitor to optimize anti-BCMA CAR T cell-mediated killing of myeloma cells. Several myeloma cell lines were treated with the γ-secretase inhibitor RO4929097, and levels of surface BCMA expression were measured using flow cytometry. CD4⁺ and CD8⁺ effector T cell lines were virally transfected and stimulated to express anti-BCMA CAR constructs containing either a CD28 or 4-1BB costimulatory endodomain. Effector CAR T cells were co-cultured with target myeloma cells that had been treated with the γ-secretase inhibitor, and levels of IFN-γ were measured as a representation of T cell activity. This study reports that the in vitro incubation of myeloma cells with the γ-secretase inhibitor RO4929097 not only substantially increases the level of BCMA expression, but also promotes enhanced antitumor activity of BCMA-specific CAR T cells.