title: Cytotoxic T lymphocytes simultaneously targeting multiple tumor-associated antigens to treat EBV negative lymphoma.
abstract: Although immunotherapy with Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) can treat EBV-associated Hodgkin and non-Hodgkin lymphoma (HL/NHL), more than 50% of such tumors are EBV negative. We now describe an approach that allows us to consistently generate, in a single line, CTLs that recognize a wide spectrum of nonviral tumor-associated antigens (TAAs) expressed by human HL/NHL, including Survivin, MAGE-A4, Synovial sarcoma X (SSX2), preferentially expressed antigen in melanoma (PRAME) and NY-ESO-1. We could generate these CTLs from nine of nine healthy donors and five of eight lymphoma patients, irrespective of human leukocyte antigen (HLA) type. We reactivated TAA-directed T cells ex vivo, by stimulation with dendritic cells (DCs) pulsed with overlapping peptide libraries spanning the chosen antigens in the presence of an optimized Th1-polarizing, prosurvival/proliferative and Treg inhibitory cytokine combination. The resultant lines of CD4(+) and CD8(+), polycytokine-producing T cells are directed against a multiplicity of epitopes expressed on the selected TAAs, with cytolytic activity against autologous tumor cells. Infusion of such multispecific monocultures may extend the benefits of CTL therapy to treatment even of EBV negative HL and NHL.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, The Methodist Hospital, Texas Children's Hospital, Houston, Texas 77030, USA.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Gerdemann
authors.forename: Usha
authors.initials: U
authors.lastname: Katari
authors.forename: Anne S
authors.initials: AS
authors.lastname: Christin
authors.forename: Conrad R
authors.initials: CR
authors.lastname: Cruz
authors.forename: Tamara
authors.initials: T
authors.lastname: Tripic
authors.forename: Alexandra
authors.initials: A
authors.lastname: Rousseau
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Gottschalk
authors.forename: Barbara
authors.initials: B
authors.lastname: Savoldo
authors.forename: Juan F
authors.initials: JF
authors.lastname: Vera
authors.forename: Helen E
authors.initials: HE
authors.lastname: Heslop
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Brenner
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Bollard
authors.forename: Cliona M
authors.initials: CM
authors.lastname: Rooney
authors.forename: Ann M
authors.initials: AM
authors.lastname: Leen
mesh_terms: D000328:Adult; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D000939:Epitopes / Q000276:immunology*; D020031:Epstein-Barr Virus Infections; D005434:Flow Cytometry; D004854:Herpesvirus 4, Human; D006801:Humans; D007124:Immunoenzyme Techniques; D007167:Immunotherapy; D008213:Lymphocyte Activation; D008223:Lymphoma / Q000276:immunology* / Q000628:therapy*; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology; D019151:Peptide Library; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D000939:Epitopes; D010446:Peptide Fragments; D019151:Peptide Library