title: Enhancing antitumor efficacy of chimeric antigen receptor T cells through constitutive CD40L expression.
abstract: Adoptive cell therapy with genetically modified T cells expressing a chimeric antigen receptor (CAR) is a promising therapy for patients with B-cell acute lymphoblastic leukemia. However, CAR-modified T cells (CAR T cells) have mostly failed in patients with solid tumors or low-grade B-cell malignancies including chronic lymphocytic leukemia with bulky lymph node involvement. Herein, we enhance the antitumor efficacy of CAR T cells through the constitutive expression of CD40 ligand (CD40L, CD154). T cells genetically modified to constitutively express CD40L (CD40L-modified T cells) demonstrated increased proliferation and secretion of proinflammatory TH1 cytokines. Further, CD40L-modified T cells augmented the immunogenicity of CD40(+) tumor cells by the upregulated surface expression of costimulatory molecules (CD80 and CD86), adhesion molecules (CD54, CD58, and CD70), human leukocyte antigen (HLA) molecules (Class I and HLA-DR), and the Fas-death receptor (CD95). Additionally, CD40L-modified T cells induced maturation and secretion of the proinflammatory cytokine interleukin-12 by monocyte-derived dendritic cells. Finally, tumor-targeted CD19-specific CAR/CD40L T cells exhibited increased cytotoxicity against CD40(+) tumors and extended the survival of tumor-bearing mice in a xenotransplant model of CD19(+) systemic lymphoma. This preclinical data supports the clinical application of CAR T cells additionally modified to constitutively express CD40L with anticipated enhanced antitumor efficacy.
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Curran
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Beatrijs A
authors.initials: BA
authors.lastname: Seinstra
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Nikhamin
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Yeh
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Yelena
authors.initials: Y
authors.lastname: Usachenko
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Dayenne G
authors.initials: DG
authors.lastname: van Leeuwen
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Terence
authors.initials: T
authors.lastname: Purdon
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Hollie J
authors.initials: HJ
authors.lastname: Pegram
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Renier J
authors.initials: RJ
authors.lastname: Brentjens
mesh_terms: D000818:Animals; D023201:CD40 Ligand / Q000378:metabolism*; D045744:Cell Line, Tumor; D064593:Heterografts; D006801:Humans; D016130:Immunophenotyping; D007167:Immunotherapy; D008224:Lymphoma, Follicular / Q000276:immunology / Q000628:therapy*; D051379:Mice; D011993:Recombinant Fusion Proteins / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D011993:Recombinant Fusion Proteins; D023201:CD40 Ligand