title: Combination nonviral murine interleukin 2 and interleukin 12 gene therapy and radiotherapy for head and neck squamous cell carcinoma.
abstract: OBJECTIVE
  To demonstrate that the combination of nonviral murine interleukin (mIL) 2 and mIL-12 gene therapy and external beam radiation therapy (XRT) have an enhanced therapeutic effect for the treatment of head and neck squamous cell carcinoma (HNSCC) in an orthotopic murine model and to elucidate the mechanism of action.
  
  
  METHODS
  A randomized, controlled study in a murine HNSCC model.
  
  
  METHODS
  Tumors were established in the floor of the mouth in C3H/HeJ immunocompetent mice with the SCC VII cell line. These tumors were directly injected with single lipid-formulated mIL-2 or single polymer-formulated mIL-12 or a combination of them and with phosphate-buffered saline or vector without mIL-2 and mIL-12 gene as controls. Then the local tumor was radiated twice with a dose of 1 Gy the next day and injected again 4 days later. Antitumor responses, cytokine expression, and natural killer cell and cytolytic T-lymphocyte activity were assayed. Meanwhile, tumor sizes were measured before and after treatment and compared among the different treatment groups and the controls.
  
  
  RESULTS
  The combination mIL-2 + mIL-12 + XRT demonstrated a significant increase in antitumor effects compared with single therapy or controls. Increased expression levels of primary and secondary cytokines were found in the group treated with mIL-2 + mIL-12, and this effect was preserved when mIL-2 and mIL-12 treatments were combined with XRT. Combination therapy significantly increased antitumor effects, T-lymphocyte infiltration of CD4(+)and CD8(+), and the numerous necroses compared with monotherapy.
  
  
  CONCLUSIONS
  Combination mIL-2 and mIL-12 gene therapy and XRT generates potent antitumor immune responses against HNSCC and significantly increases necrosis (apoptosis) in an orthotopic murine model of HNSCC. The nonviral mIL-2 and mIL-12 gene delivery system was well tolerated. Further optimization of treatment strategy for patients with HNSCC is warranted as well as consideration for human clinical trials.
authors.affiliation: Department of Otolaryngology, West China Hospital, Chengdu. xianjunming@yahoo.com.cn
authors.forename: Junming
authors.initials: J
authors.lastname: Xian
authors.forename: Huan
authors.initials: H
authors.lastname: Yang
authors.forename: Yinghe
authors.initials: Y
authors.lastname: Lin
authors.forename: Shixi
authors.initials: S
authors.lastname: Liu
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation; D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006258:Head and Neck Neoplasms / Q000276:immunology / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D007150:Immunohistochemistry; D018664:Interleukin-12 / Q000235:genetics*; D007376:Interleukin-2 / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008809:Mice, Inbred C3H; D009336:Necrosis; D011878:Radiotherapy / Q000379:methods; D013154:Spleen / Q000166:cytology; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000943:Antigens, Differentiation; D007376:Interleukin-2; D008565:Membrane Proteins; C062010:leu-13 antigen; D018664:Interleukin-12