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

• Published in: Blood Vol. 134; no. 19; pp. 1585 - 1597
• Main Authors: Pont, Margot J., Hill, Tyler, Cole, Gabriel O., Abbott, Joe J., Kelliher, Jessica, Salter, Alexander I., Hudecek, Michael, Comstock, Melissa L., Rajan, Anusha, Patel, Bharvin K.R., Voutsinas, Jenna M., Wu, Qian, Liu, Lingfeng, Cowan, Andrew J., Wood, Brent L., Green, Damian J., Riddell, Stanley R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.11.2019; American Society of Hematology
• Subjects: Amyloid Precursor Protein Secretases - antagonists & inhibitors; Animals; B-Cell Maturation Antigen - metabolism; Benzazepines - pharmacology; Clinical Trials as Topic; Humans; Immunobiology and Immunotherapy; Immunotherapy, Adoptive - methods; Mice; Mice, Inbred NOD; Mice, SCID; Multiple Myeloma - therapy; Receptors, Chimeric Antigen; Xenograft Model Antitumor Assays
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2019000050

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 γ-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/γc−/− 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 BCMA+ 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. •Small-molecule GSIs increase BCMA surface expression on myeloma cells, resulting in enhanced CAR T-cell efficacy. [Display omitted]