title: Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma.
abstract: Cytotoxic T lymphocytes (CTLs) directed to nonviral tumor-associated antigens do not survive long term and have limited antitumor activity in vivo, in part because such tumor cells typically lack the appropriate costimulatory molecules. We therefore engineered Epstein-Barr virus (EBV)-specific CTLs to express a chimeric antigen receptor directed to the diasialoganglioside GD2, a nonviral tumor-associated antigen expressed by human neuroblastoma cells. We reasoned that these genetically engineered lymphocytes would receive optimal costimulation after engagement of their native receptors, enhancing survival and antitumor activity mediated through their chimeric receptors. Here we show in individuals with neuroblastoma that EBV-specific CTLs expressing a chimeric GD2-specific receptor indeed survive longer than T cells activated by the CD3-specific antibody OKT3 and expressing the same chimeric receptor but lacking virus specificity. Infusion of these genetically modified cells seemed safe and was associated with tumor regression or necrosis in half of the subjects tested. Hence, virus-specific CTLs can be modified to function as tumor-directed effector cells.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine and The Methodist Hospital and Texas Children's Hospital, Houston, Texas 77030, USA.
authors.forename: Martin A
authors.initials: MA
authors.lastname: Pule
authors.forename: Barbara
authors.initials: B
authors.lastname: Savoldo
authors.forename: G Doug
authors.initials: GD
authors.lastname: Myers
authors.forename: Claudia
authors.initials: C
authors.lastname: Rossig
authors.forename: Heidi V
authors.initials: HV
authors.lastname: Russell
authors.forename: Gianpietro
authors.initials: G
authors.lastname: Dotti
authors.forename: M Helen
authors.initials: MH
authors.lastname: Huls
authors.forename: Enli
authors.initials: E
authors.lastname: Liu
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Gee
authors.forename: Zhuyong
authors.initials: Z
authors.lastname: Mei
authors.forename: Eric
authors.initials: E
authors.lastname: Yvon
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Weiss
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Cliona M
authors.initials: CM
authors.lastname: Rooney
authors.forename: Helen E
authors.initials: HE
authors.lastname: Heslop
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Brenner
mesh_terms: D000293:Adolescent; D002460:Cell Line; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D005260:Female; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D007167:Immunotherapy; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D009447:Neuroblastoma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D010641:Phenotype; D051603:Recoverin / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism* / Q000821:virology
chemical_list: D051603:Recoverin