title: Virological and preclinical characterization of a dendritic cell targeting, integration-deficient lentiviral vector for cancer immunotherapy.
abstract: Dendritic cells (DCs) are essential antigen-presenting cells for the initiation of cytotoxic T-cell responses and therefore attractive targets for cancer immunotherapy. We have developed an integration-deficient lentiviral vector termed ID-VP02 that is designed to deliver antigen-encoding nucleic acids selectively to human DCs in vivo. ID-VP02 utilizes a genetically and glycobiologically engineered Sindbis virus glycoprotein to target human DCs through the C-type lectin DC-SIGN (CD209) and also binds to the homologue murine receptor SIGNR1. Specificity of ID-VP02 for antigen-presenting cells in the mouse was confirmed through biodistribution studies showing that following subcutaneous administration, transgene expression was only detectable at the injection site and the draining lymph node. A single immunization with ID-VP02 induced a high level of antigen-specific, polyfunctional effector and memory CD8 T-cell responses that fully protected against vaccinia virus challenge. Upon homologous readministration, ID-VP02 induced a level of high-quality secondary effector and memory cells characterized by stable polyfunctionality and expression of IL-7Rα. Importantly, a single injection of ID-VP02 also induced robust cytotoxic responses against an endogenous rejection antigen of CT26 colon carcinoma cells and conferred both prophylactic and therapeutic antitumor efficacy. ID-VP02 is the first lentiviral vector which combines integration deficiency with DC targeting and is currently being investigated in a phase I trial in cancer patients.
authors: *Immune Design Corp. †TRIA Bioscience Corp., Seattle, WA.
authors: Jared M
authors: JM
authors: Odegard
authors: Brenna
authors: B
authors: Kelley-Clarke
authors: Semih U
authors: SU
authors: Tareen
authors: David J
authors: DJ
authors: Campbell
authors: Patrick A
authors: PA
authors: Flynn
authors: Christopher J
authors: CJ
authors: Nicolai
authors: Megan M
authors: MM
authors: Slough
authors: Chintan D
authors: CD
authors: Vin
authors: Patrick J
authors: PJ
authors: McGowan
authors: Lisa T
authors: LT
authors: Nelson
authors: Jan
authors: J
authors: Ter Meulen
authors: Thomas W
authors: TW
authors: Dubensky
authors: Scott H
authors: SH
authors: Robbins
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines; D002277:Carcinoma / Q000276:immunology / Q000628:therapy*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D045744:Cell Line, Tumor; D017321:Clinical Trials, Phase I as Topic; D003110:Colonic Neoplasms / Q000276:immunology / Q000628:therapy*; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation / Q000821:virology; D005818:Genetic Engineering; D005822:Genetic Vectors; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive; D037181:Lectins, C-Type / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000378:metabolism; D012845:Sindbis Virus / Q000235:genetics*; D014615:Vaccinia / Q000276:immunology*; D014616:Vaccinia virus / Q000276:immunology*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D016662:Virus Integration / Q000235:genetics; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D019496:Cancer Vaccines; D015815:Cell Adhesion Molecules; D006023:Glycoproteins; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D020395:Receptors, Interleukin-7; D014764:Viral Proteins; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C415350:interleukin-7 receptor, alpha chain