RT Journal Article
SR Electronic
T1 Anti–B-cell Maturation Antigen Chimeric Antigen Receptor T cell Function against Multiple Myeloma Is Enhanced in the Presence of Lenalidomide
JF Molecular Cancer Therapeutics
JO Mol Cancer Ther
FD American Association for Cancer Research
SP 2246
OP 2257
DO 10.1158/1535-7163.MCT-18-1146
VO 18
IS 12
A1 Works, Melissa
A1 Soni, Neha
A1 Hauskins, Collin
A1 Sierra, Catherine
A1 Baturevych, Alex
A1 Jones, Jon C.
A1 Curtis, Wendy
A1 Carlson, Patrick
A1 Johnstone, Timothy G.
A1 Kugler, David
A1 Hause, Ronald J.
A1 Jiang, Yue
A1 Wimberly, Lindsey
A1 Clouser, Christopher R.
A1 Jessup, Heidi K.
A1 Sather, Blythe
A1 Salmon, Ruth A.
A1 Ports, Michael O.
YR 2019
UL http://mct.aacrjournals.org/content/18/12/2246.abstract
AB 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.