title: Interleukin-15 gene therapy and the mammalian target of rapamycin inhibitor everolimus inhibit the growth of metastatic breast cancer.
abstract: BACKGROUND
  Novel methods to control and treat metastatic breast cancer are needed. Interleukin (IL)-15 is a promising cytokine for cancer immunotherapy, and everolimus is an orally administered mammalian target of rapamycin (mTOR) inhibitor, which is already approved for cancer treatment. In the present study, we investigated the efficacy of IL-15 gene therapy and explored the possibility of combining IL-15 therapy with everolimus to treat metastatic breast cancer.
  
  
  METHODS
  A plasmid encoding IL-15 and everolimus were given to mice inoculated with 4 T1 mouse breast cancer cells. Tumor size and metastasis were monitored to assess the effect of different treatment regimens. Immunohistochemistry was used to detect CD4⁺, CD8⁺ and NKG2D⁺ cells and also the expression of Ki-67 in tumor tissue; these analyses helped establish the immunization status and tumor proliferation rate of different treatment groups. Terminal deoxynucleotidyl transferase dUTP nick end labeling assays were performed to assess cellular apoptosis in tumor tissues.
  
  
  RESULTS
  Both IL-15 and everolimus significantly decreased tumor size. IL-15 gene therapy increased the proportion of CD4⁺ T and natural killer (NK) cells but had no effect on CD8⁺ T cells. By contrast, everolimus decreased the number of CD8⁺ T cells but had no effect on CD4⁺ T and NK cells compared to the control group. Both IL-15 and everolimus decreased expression of Ki-67 and increased rates of apoptosis. Although effective on their own, no synergistic effect was observed with a combined treatment of everolimus and IL-15 gene therapy.
  
  
  CONCLUSIONS
  IL-15 gene therapy was potentially useful for the treatment of metastatic breast cancer. The possibility of combining immunotherapy with everolimus requires further study.
authors.affiliation: Department of General Surgery, Tianjin Medical University General Hospital, Tianjin, China.
authors.forename: Na
authors.initials: N
authors.lastname: Zhao
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Li
authors.forename: Xianghui
authors.initials: X
authors.lastname: He
authors.forename: Yujie
authors.initials: Y
authors.lastname: Qiu
authors.forename: Liwei
authors.initials: L
authors.lastname: Zhu
authors.forename: Feng
authors.initials: F
authors.lastname: Qi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus; D005260:Female; D023061:Gene Order; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D007167:Immunotherapy; D019409:Interleukin-15 / Q000235:genetics*; D051379:Mice; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D019409:Interleukin-15; D047428:Protein Kinase Inhibitors; D000068338:Everolimus; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: breast cancer; everolimus; gene therapy; interleukin-15