title: Armed oncolytic virus enhances immune functions of chimeric antigen receptor-modified T cells in solid tumors.
abstract: The clinical efficacy of chimeric antigen receptor (CAR)-redirected T cells remains marginal in solid tumors compared with leukemias. Failures have been attributed to insufficient T-cell migration and to the highly immunosuppressive milieu of solid tumors. To overcome these obstacles, we have combined CAR-T cells with an oncolytic virus armed with the chemokine RANTES and the cytokine IL15, reasoning that the modified oncolytic virus will both have a direct lytic effect on infected malignant cells and facilitate migration and survival of CAR-T cells. Using neuroblastoma as a tumor model, we found that the adenovirus Ad5Δ24 exerted a potent, dose-dependent, cytotoxic effect on tumor cells, whereas CAR-T cells specific for the tumor antigen GD2 (GD2.CAR-T cells) were not damaged. When used in combination, Ad5Δ24 directly accelerated the caspase pathways in tumor cells exposed to CAR-T cells, whereas the intratumoral release of both RANTES and IL15 attracted CAR-T cells and promoted their local survival, respectively, increasing the overall survival of tumor-bearing mice. These preclinical data support the use of this innovative biologic platform of immunotherapy for solid tumors. Cancer Res; 74(18); 5195-205. ©2014 AACR.
authors: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.
authors: Nobuhiro
authors: N
authors: Nishio
authors: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.
authors: Iulia
authors: I
authors: Diaconu
authors: Biostatistics Shared Resource, Baylor College of Medicine Dan L. Duncan Cancer Center, Houston, Texas.
authors: Hao
authors: H
authors: Liu
authors: ImmunoViroTherapy Lab Centre for Drug research and Division of Pharmaceutical Biosciences, Faculty of Pharmacy University of Helsinki, Helsinki, Finland.
authors: Vincenzo
authors: V
authors: Cerullo
authors: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.
authors: Ignazio
authors: I
authors: Caruana
authors: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.
authors: Valentina
authors: V
authors: Hoyos
authors: Departments of Pediatrics, Texas Children's Hospital, Houston, Texas.
authors: Lisa
authors: L
authors: Bouchier-Hayes
authors: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas. Departments of Pediatrics, Texas Children's Hospital, Houston, Texas.
authors: Barbara
authors: B
authors: Savoldo
authors: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas. Department of Immunology, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas. gdotti@bcm.edu.
authors: Gianpietro
authors: G
authors: Dotti
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D016688:Mice, Inbred NOD; D018613:Microscopy, Confocal; D009447:Neuroblastoma / Q000276:immunology* / Q000628:therapy* / Q000821:virology; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D016207:Cytokines; D011948:Receptors, Antigen, T-Cell