Abstract
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.
Highlights
Despite improvements in the treatment of newly diagnosed multiple myeloma, it remains uncured, and most patients relapse and become resistant to available treatments [1]
Cytolytic activity and cytokine production of lenalidomidetreated chimeric antigen receptor (CAR) T cells transduced with the anti-B-cell maturation antigen (BCMA) CAR were evaluated in vitro in the presence of BCMA-expressing multiple myeloma cell lines with varying sensitivity to lenalidomide (Supplementary Methods)
Addition of lenalidomide did not alter BCMA target expression (Supplementary Fig. S2). These results demonstrated that when anti-BCMA CAR T cells were stimulated with 0.3:1 and 1:1 effector-to-target ratios, addition of lenalidomide increased effector functionality of CAR T cells across several metrics of CAR T function, including cytolytic activity and cytokine production
Summary
Despite improvements in the treatment of newly diagnosed multiple myeloma, it remains uncured, and most patients relapse and become resistant to available treatments [1]. On the basis of the encouraging activity of chimeric antigen receptor (CAR) T cells targeting CD19 in non-Hodgkin lymphoma, CAR T cells targeting plasma cells expressing B-cell maturation antigen (BCMA) have been developed for multiple myeloma [2]. BCMA CAR T cells have shown promise in the clinic, an immunosuppressive myeloma tumor microenvironment, including programmed cell death 1 ligand 1 (PD-L1) expression [3], and the potential for activation-induced exhaustion. Juno Therapeutics, A Celgene Company, Seattle, Washington. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
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