Anti-B-cell Maturation Antigen Chimeric Antigen Receptor T cell Function against Multiple Myeloma Is Enhanced in the Presence of Lenalidomide.

Autor:	Works M; Juno Therapeutics, A Celgene Company, Seattle, Washington. Melissa.works@junotherapeutics.com., Soni N; Juno Therapeutics, A Celgene Company, Seattle, Washington., Hauskins C; Juno Therapeutics, A Celgene Company, Seattle, Washington., Sierra C; Juno Therapeutics, A Celgene Company, Seattle, Washington., Baturevych A; Juno Therapeutics, A Celgene Company, Seattle, Washington., Jones JC; Juno Therapeutics, A Celgene Company, Seattle, Washington., Curtis W; Juno Therapeutics, A Celgene Company, Seattle, Washington., Carlson P; Juno Therapeutics, A Celgene Company, Seattle, Washington., Johnstone TG; Juno Therapeutics, A Celgene Company, Seattle, Washington., Kugler D; Juno Therapeutics, A Celgene Company, Seattle, Washington., Hause RJ; Juno Therapeutics, A Celgene Company, Seattle, Washington., Jiang Y; Juno Therapeutics, A Celgene Company, Seattle, Washington., Wimberly L; Juno Therapeutics, A Celgene Company, Seattle, Washington., Clouser CR; Juno Therapeutics, A Celgene Company, Seattle, Washington., Jessup HK; Juno Therapeutics, A Celgene Company, Seattle, Washington., Sather B; Juno Therapeutics, A Celgene Company, Seattle, Washington., Salmon RA; Juno Therapeutics, A Celgene Company, Seattle, Washington., Ports MO; Juno Therapeutics, A Celgene Company, Seattle, Washington.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2019 Dec; Vol. 18 (12), pp. 2246-2257. Date of Electronic Publication: 2019 Aug 08.
DOI:	10.1158/1535-7163.MCT-18-1146
Abstrakt:	Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells have shown promising clinical responses in patients with relapsed/refractory multiple myeloma. Lenalidomide, an immunomodulatory drug, potentiates T cell functionality, drives antimyeloma activity, and alters the suppressive microenvironment; these properties may effectively combine with anti-BCMA CAR T cells to enhance function. Using an anti-BCMA CAR T, we demonstrated that lenalidomide enhances CAR T cell function in a concentration-dependent manner. Lenalidomide increased CAR T effector cytokine production, particularly under low CAR stimulation or in the presence of inhibitory ligand programmed cell death 1 ligand 1. Notably, lenalidomide also enhanced CAR T cytokine production, cytolytic activity, and activation profile relative to untreated CAR T cells in chronic stimulation assays. This unique potentiation of both short-term CAR T activity and long-term functionality during chronic stimulation prompted investigation of the molecular profile of lenalidomide-treated CAR T cells. Signatures from RNA sequencing and assay for transposase-accessible chromatin using sequencing indicated that pathways associated with T-helper 1 response, cytokine production, T cell activation, cell-cycle control, and cytoskeletal remodeling were altered with lenalidomide. Finally, study of lenalidomide and anti-BCMA CAR T cells in a murine, disseminated, multiple myeloma model indicated that lenalidomide increased CAR T cell counts in blood and significantly prolonged animal survival. In summary, preclinical studies demonstrated that lenalidomide potentiated CAR T activity in vivo in low-antigen or suppressive environments and delayed onset of functional exhaustion. These results support further investigation of lenalidomide and anti-BCMA CAR T cells in the clinic. (©2019 American Association for Cancer Research.)
Databáze:	MEDLINE
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