title: Localized interleukin-12 delivery for immunotherapy of solid tumours.
abstract: Interleukin (IL)-12 is the key cytokine in the initiation of a Th1 response and has shown promise as an anti-cancer agent; however, clinical trials involving IL-12 have been unsuccessful due to toxic side-effects. To address this issue, lentiviral vectors were used to transduce tumour cell lines that were injected as an autologous tumour cell vaccine. The focus of the current study was to test the efficacy of this approach in a solid tumour model. SCCVII cells that were transduced to produce IL-12 at different concentrations were then isolated. Subcutaneous injection of parental SCCVII cells results in tumour development, while a mixture of IL-12-producing and non-producing cells results in tumour clearance. Interestingly, when comparing mice injected a mixture of SCCVII and either high IL-12-producing tumour cells or low IL-12-producing tumour cells, we observed that mixtures containing small amounts of high producing cells lead to tumour clearance, whereas mixtures containing large amounts of low producing cells fail to elicit protection, despite the production of equal amounts of total IL-12 in both mixtures. Furthermore, immunizing mice with IL-12-producing cells leads to the establishment of both local and systemic immunity against challenge with SCCVII. Using depletion antibodies, it was shown that both CD4(+) and CD8(+) cells are crucial for therapy. Lastly, we have established cell clones of other solid tumour cell lines (RM-1, LLC1 and moto1.1) that produce IL-12. Our results show that the delivery of IL-12 by cancer cells is an effective route for immune activation.
authors.affiliation: Department of Immunology, University of Toronto, Toronto, ON, Canada; Ontario Cancer Institute, University Health Network, Toronto, ON, Canada.
authors.forename: Louis Z
authors.initials: LZ
authors.lastname: Wei
authors.forename: Yixin
authors.initials: Y
authors.lastname: Xu
authors.forename: E Megan
authors.initials: EM
authors.lastname: Nelles
authors.forename: Caren
authors.initials: C
authors.lastname: Furlonger
authors.forename: James C M
authors.initials: JC
authors.lastname: Wang
authors.forename: Marco A
authors.initials: MA
authors.lastname: Di Grappa
authors.forename: Rama
authors.initials: R
authors.lastname: Khokha
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Medin
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Paige
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D005260:Female; D006258:Head and Neck Neoplasms / Q000276:immunology / Q000628:therapy*; D007156:Immunologic Memory; D007167:Immunotherapy; D018664:Interleukin-12 / Q000502:physiology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation
chemical_list: D019496:Cancer Vaccines; D018664:Interleukin-12
keywords: Interleukin-12; gene therapy; immunotherapy; lentivirus; solid tumour