title: Lenalidomide enhances antitumor functions of chimeric antigen receptor modified T cells.
abstract: Tumor immunotherapy based on the use of chimeric antigen receptor modified T cells (CAR T cells) is a promising approach for the treatment of refractory hematological malignancies. However, a robust response mediated by CAR T cells is observed only in a minority of patients and the expansion and persistence of CAR T cellsin vivois mostly unpredictable.Lenalidomide (LEN) is an immunomodulatory drug currently approved for the treatment of multiple myeloma (MM) and mantle cell lymphoma, while it is clinically tested in the therapy of diffuse large B-cell lymphoma of activated B cell immunophenotype. LEN was shown to increase antitumor immune responses at least partially by modulating the activity of E3 ubiquitin ligase Cereblon, which leads to increased ubiquitinylation of Ikaros and Aiolos transcription factors, which in turn results in changed expression of various receptors on the surface of tumor cells. In order to enhance the effectiveness of CAR-based immunotherapy, we assessed the anti-lymphoma efficacy of LEN in combination with CAR19 T cells or CAR20 T cellsin vitroandin vivousing various murine models of aggressive B-cell non-Hodgkin lymphomas (B-NHL).Immunodeficient NSG mice were transplanted with various human B-NHL cells followed by treatment with CAR19 or CAR20 T cells with or without LEN. Next, CAR19 T cells were subjected to series of testsin vitroto evaluate their response and signaling capacity following recognition of B cell in the presence or absence of LEN.Our data shows that LEN significantly enhances antitumor functions of CAR19 and CAR20 T cellsin vivo. Additionally, it enhances production of interferon gamma by CAR19 T cells and augments cell signaling via CAR19 protein in T cellsin vitro. Our data further suggests that LEN works through direct effects on T cells but not on B-NHL cells. The biochemical events underlying this costimulatory effect of LEN are currently being investigated. In summary, our data supports the use of LEN for augmentation of CAR-based immunotherapy in the clinical grounds.
authors.affiliation: Department of Hematology, Charles University General Hospital in Prague, Czech Republic; Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Otáhal
authors.affiliation: Institute of Pathological Physiology, First Faculty of Medicine, Charles University in Prague , Czech Republic.
authors.forename: Dana
authors.initials: D
authors.lastname: Průková
authors.affiliation: Institute of Molecular Genetics, Czech Academy of Sciences , Prague, Czech Republic.
authors.forename: Vlastimil
authors.initials: V
authors.lastname: Král
authors.affiliation: Institute of Molecular Genetics, Czech Academy of Sciences , Prague, Czech Republic.
authors.forename: Milan
authors.initials: M
authors.lastname: Fabry
authors.affiliation: Institute of Pathological Physiology, First Faculty of Medicine, Charles University in Prague , Czech Republic.
authors.forename: Petra
authors.initials: P
authors.lastname: Vočková
authors.affiliation: Institute of Pathological Physiology, First Faculty of Medicine, Charles University in Prague , Czech Republic.
authors.forename: Lucie
authors.initials: L
authors.lastname: Latečková
authors.affiliation: Department of Hematology, Charles University General Hospital in Prague , Czech Republic.
authors.forename: Marek
authors.initials: M
authors.lastname: Trněný
authors.affiliation: Department of Hematology, Charles University General Hospital in Prague, Czech Republic; Institute of Pathological Physiology, First Faculty of Medicine, Charles University in Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Klener
keywords: Chimeric antigenic receptor; T cells; lenalidomide; lymphoma; tumor immunotherapy