Anti-B-cell Maturation Antigen Chimeric Antigen Receptor T cell Function against Multiple Myeloma Is Enhanced in the Presence of Lenalidomide
| Autor: | Alex Baturevych, Yue Jiang, Michael Ports, Patrick Carlson, Heidi K. Jessup, David G. Kugler, Neha Soni, Ronald J. Hause, Catherine Sierra, Christopher R. Clouser, Collin Hauskins, Jon C. Jones, Timothy G. Johnstone, Lindsey Wimberly, Melissa Works, Ruth Salmon, Wendy Curtis, Blythe D. Sather |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.medical_treatment T cell Angiogenesis Inhibitors 03 medical and health sciences Mice 0302 clinical medicine Antigen Cell Line Tumor medicine Animals Humans Lenalidomide Multiple myeloma Receptors Chimeric Antigen Chemistry B-Cell Maturation Antigen medicine.disease Chimeric antigen receptor Disease Models Animal 030104 developmental biology Cytokine medicine.anatomical_structure Oncology Cell culture 030220 oncology & carcinogenesis Cancer research Multiple Myeloma human activities medicine.drug |
| Zdroj: | Molecular cancer therapeutics. 18(12) |
| ISSN: | 1538-8514 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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