title: Flt3-L gene therapy enhances immunocytokine-mediated antitumor effects and induces long-term memory.
abstract: Therapeutic treatment with hu14.18-IL-2 immunocytokine (IC) or Flt3-L (FL) protein is initially effective at resolving established intradermal NXS2 neuroblastoma tumors in mice. However, many treated animals develop recurrent disease. We previously found that tumors recurring following natural killer (NK) mediated IC treatment show augmented MHC class I expression, while the tumors that recurred following T cell dependent Flt3-L treatment exhibited decreased MHC class I expression. We hypothesized that this divergent MHC modulation on recurrent tumors was due to therapy-specific immunoediting. We further postulated that combining IC and Flt3-L treatments might decrease the likelihood of recurrent disease by preventing MHC modulation as a mechanism for immune escape. We now report that combinatorial treatment of FL plus hu14.18-IL-2 IC provides greater antitumor benefit than treatment with either alone, suppressing development of recurrent disease. We administered FL by gene therapy using a clinically relevant approach: hydrodynamic limb vein (HLV) delivery of DNA for transgene expression by myofibers. Delivery of FL DNA by HLV injection in mice resulted in systemic expression of >10 ng/ml of FL in blood at day 3, and promoted up to a fourfold and tenfold increase in splenic NK and dendritic cells (DCs), respectively. Furthermore, the combination of FL gene therapy plus suboptimal IC treatment induced a greater expansion in the absolute number of splenic NK and DCs than achieved by individual component treatments. Mice that received combined FL gene therapy plus IC exhibited complete and durable resolution of established NXS2 tumors, and demonstrated protection from subsequent rechallenge with NXS2 tumor.
authors.affiliation: Mirus Bio Corporation, Madison, WI 53719, USA.
authors.forename: Zane C
authors.initials: ZC
authors.lastname: Neal
authors.forename: Paul M
authors.initials: PM
authors.lastname: Sondel
authors.forename: Mary Kay
authors.initials: MK
authors.lastname: Bates
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Gillies
authors.forename: Hans
authors.initials: H
authors.lastname: Herweijer
mesh_terms: D000276:Adjuvants, Immunologic / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D005260:Female; D015316:Genetic Therapy; D007156:Immunologic Memory; D007376:Interleukin-2 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000378:metabolism; D013154:Spleen / Q000276:immunology; D013997:Time Factors; D019139:Tumor Escape / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D007376:Interleukin-2; D008565:Membrane Proteins; C084881:flt3 ligand protein