title: Targeting CD20+ Aggressive B-cell Non-Hodgkin Lymphoma by Anti-CD20 CAR mRNA-Modified Expanded Natural Killer Cells In Vitro and in NSG Mice.
abstract: The prognosis is very dismal for patients with relapsed CD20(+) B-cell non-Hodgkin lymphoma (B-NHL). Facilitating the development of alternative novel therapeutic strategies is required to improve outcomes in patients with recurrent/refractory CD20(+) B-NHL. In this study, we investigated functional activities of anti-CD20 CAR-modified, expanded peripheral blood NK cells (exPBNK) following mRNA nucleofection against CD20(+) B-NHL in vitro and in vivo. CAR(+) exPBNK had significantly enhanced in vitro cytotoxicity, compared with CAR(-) exPBNK against CD20(+) Ramos (P < 0.05), Daudi, Raji, and two rituximab-resistant cell lines, Raji-2R and Raji-4RH (P < 0.001). As expected, there was no significant difference against CD20(-) RS4;11 and Jurkat cells. CD107a degranulation and intracellular IFNγ production were also enhanced in CAR(+) exPBNK in response to CD20(+) B-NHL -: specific stimulation. In Raji-Luc and Raji-2R-Luc xenografted NOD/SCID/γ-chain(-/-) (NSG) mice, the luciferase signals measured in the CAR(+) exPBNK-treated group were significantly reduced, compared with the signals measured in the untreated mice and in mice treated with the CAR(-) exPBNK. Furthermore, the CAR exPBNK-treated mice had significantly extended survival time (P < 0.001) and reduced tumor size, compared with those of the untreated and the CAR(-) exPBNK-treated mice (P < 0.05). These preclinical data suggest that ex vivo-exPBNK modified with anti-CD20 CAR may have therapeutic potential for treating patients with poor-risk CD20(+) hematologic malignancies.
authors.affiliation: Department of Pediatrics, Maria Fareri Children's Hospital, New York Medical College, Valhalla, New York.
authors.forename: Yaya
authors.initials: Y
authors.lastname: Chu
authors.affiliation: Department of Pediatrics, Maria Fareri Children's Hospital, New York Medical College, Valhalla, New York.
authors.forename: Jessica
authors.initials: J
authors.lastname: Hochberg
authors.affiliation: Department of Pediatrics, Maria Fareri Children's Hospital, New York Medical College, Valhalla, New York.
authors.forename: Ashlin
authors.initials: A
authors.lastname: Yahr
authors.affiliation: Department of Pediatrics, Maria Fareri Children's Hospital, New York Medical College, Valhalla, New York.
authors.forename: Janet
authors.initials: J
authors.lastname: Ayello
authors.affiliation: Department of Pediatrics, Maria Fareri Children's Hospital, New York Medical College, Valhalla, New York.
authors.forename: Carmella
authors.initials: C
authors.lastname: van de Ven
authors.affiliation: Department of Pediatrics, State University of New York at Buffalo, Buffalo, New York.
authors.forename: Matthew
authors.initials: M
authors.lastname: Barth
authors.affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York. Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Myron
authors.initials: M
authors.lastname: Czuczman
authors.affiliation: Department of Pediatrics, Maria Fareri Children's Hospital, New York Medical College, Valhalla, New York. Department of Medicine, New York Medical College, Valhalla, New York. Department of Pathology, New York Medical College, Valhalla, New York. Department of Microbiology and Immunology, New York Medical College, Valhalla, New York. Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York. mitchell_cairo@nymc.edu.
authors.forename: Mitchell S
authors.initials: MS
authors.lastname: Cairo
mesh_terms: D000818:Animals; D018951:Antigens, CD20 / Q000032:analysis / Q000235:genetics / Q000276:immunology*; D002051:Burkitt Lymphoma / Q000276:immunology / Q000628:therapy; D002465:Cell Movement / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000637:transplantation; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000628:therapy*; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D012333:RNA, Messenger / Q000235:genetics; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D018951:Antigens, CD20; D052118:Lysosomal-Associated Membrane Protein 1; D012333:RNA, Messenger