title: Loading of oncolytic vesicular stomatitis virus onto antigen-specific T cells enhances the efficacy of adoptive T-cell therapy of tumors.
abstract: Although adoptive T-cell therapy has shown clinical success, efficacy is limited by low levels of T-cell trafficking to, and survival in, the immunosuppressive environment of an established tumor. Oncolytic virotherapy has recently emerged as a promising approach to induce both direct tumor cell killing and local proinflammatory environments within tumors. However, inefficient systemic delivery of oncolytic viruses remains a barrier to use of these agents against metastatic disease that is not directly accessible to the end of a needle. Here we show that the ability of antigen-specific T cells to circulate freely, and to localize to tumors, can be exploited to achieve the systemic delivery of replication-competent, oncolytic vesicular stomatitis virus (VSV). Thus, VSV loaded onto OT-I T cells, specific for the SIINFEKL epitope of the ovalbumin antigen, was efficiently delivered to established B16ova tumors in the lungs of fully immune-competent C57Bl/6 mice leading to significant increases in therapy compared to the use of virus, or T cells, alone. Although OT-I T-cell-mediated delivery of VSV led to viral replication within tumors and direct viral oncolysis, therapy was also dependent upon an intact host immune system. Moreover, VSV loading onto the T cells increased both T-cell activation in vitro and T-cell trafficking in vivo. The combination of adoptive T-cell transfer of antigen-specific T cells, along with oncolytic virotherapy, can, therefore, increase the therapeutic utility of both approaches through multiple mechanisms and should be of direct translational value.
authors.affiliation: Molecular Medicine Program, Mayo Clinic College of Medicine, Rochester, MN 55902, USA.
authors.forename: J
authors.initials: J
authors.lastname: Qiao
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: T
authors.initials: T
authors.lastname: Kottke
authors.forename: R M
authors.initials: RM
authors.lastname: Diaz
authors.forename: C
authors.initials: C
authors.lastname: Willmon
authors.forename: A
authors.initials: A
authors.lastname: Hudacek
authors.forename: J
authors.initials: J
authors.lastname: Thompson
authors.forename: K
authors.initials: K
authors.lastname: Parato
authors.forename: J
authors.initials: J
authors.lastname: Bell
authors.forename: J
authors.initials: J
authors.lastname: Naik
authors.forename: J
authors.initials: J
authors.lastname: Chester
authors.forename: P
authors.initials: P
authors.lastname: Selby
authors.forename: K
authors.initials: K
authors.lastname: Harrington
authors.forename: A
authors.initials: A
authors.lastname: Melcher
authors.forename: R G
authors.initials: RG
authors.lastname: Vile
mesh_terms: D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D002465:Cell Movement; D003131:Combined Modality Therapy; D015316:Genetic Therapy / Q000379:methods; D008175:Lung Neoplasms / Q000556:secondary / Q000628:therapy; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000821:virology; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000628:therapy; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000628:therapy*; D050130:Oncolytic Virotherapy / Q000379:methods*; D018116:Vesiculovirus / Q000235:genetics*; D014779:Virus Replication
chemical_list: D000951:Antigens, Neoplasm