G-Secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma

Pont MJ, Hill T, Cole GO, Abbott JJ, Kelliher J, Salter AI, Hudecek M, Comstock ML, Rajan A, Patel BKR, Voutsinas JM, Wu Q, Liu L, Cowan AJ, Wood BL, Green DJ, Riddell SR (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Blood American Society of Hematology

Book Volume: 134

Pages Range: 1585-1597

Journal Issue: 19

DOI: 10.1182/blood.2019000050

Abstract

B-cell maturation antigen (BCMA) is a validated target for chimeric antigen receptor (CAR) T-cell therapy in multiple myeloma (MM). Despite promising objective response rates, most patients relapse, and low levels of BCMA on a subset of tumor cells has been suggested as a probable escape mechanism. BCMA is actively cleaved from the tumor cell surface by the ubiquitous multisubunit g-secretase (GS) complex, which reduces ligand density on tumor cells for CAR T-cell recognition and releases a soluble BCMA (sBCMA) fragment capable of inhibiting CAR T-cell function. Sufficient sBCMA can accumulate in the bone marrow of MM patients to inhibit CAR T-cell recognition of tumor cells, and potentially limit efficacy of BCMA-directed adoptive T-cell therapy. We investigated whether blocking BCMA cleavage by small-molecule GS inhibitors (GSIs) could augment BCMA-targeted CAR T-cell therapy. We found that exposure of myeloma cell lines and patient tumor samples to GSIs markedly increased surface BCMA levels in a dose-dependent fashion, concurrently decreased sBCMA concentrations, and improved tumor recognition by CAR T cells in vitro. GSI treatment of MM tumor-bearing NOD/SCID/gc2/2 mice increased BCMA expression on tumor cells, decreased sBCMA in peripheral blood, and improved antitumor efficacy of BCMA-targeted CAR T-cell therapy. Importantly, short-term GSI administration to MM patients markedly increases the percentage of BCMA1 tumor cells, and the levels of BCMA surface expression in vivo. Based on these data, a US Food and Drug Administration (FDA)-approved clinical trial has been initiated, combining GSI with concurrent BCMA CAR T-cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT03502577.

Involved external institutions

Fred Hutchinson Cancer Research Center US United States (USA) (US) University of Washington US United States (USA) (US) Universitätsklinikum Würzburg DE Germany (DE) Eli Lilly and Company US United States (USA) (US)

How to cite

APA:

Pont, M.J., Hill, T., Cole, G.O., Abbott, J.J., Kelliher, J., Salter, A.I.,... Riddell, S.R. (2019). G-Secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma. Blood, 134(19), 1585-1597. https://doi.org/10.1182/blood.2019000050

MLA:

Pont, Margot J., et al. "G-Secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma." Blood 134.19 (2019): 1585-1597.

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