title: Enhancing the potency of a whole-cell breast cancer vaccine in mice with an antibody-IL-2 immunocytokine that targets exposed phosphatidylserine.
abstract: Phosphatidylserine (PS), an anionic phospholipid normally restricted to the inner leaflet of the plasma membrane, is immunosuppressive when externalized on the outside of cell membranes. Exposed PS inhibits the maturation and function of dendritic cells (DCs), and induces the production of multiple immunosuppressive mediators. In the present study, we determined whether blocking these effects of PS while simultaneously introducing interleukin-2 (IL-2) could improve the immunogenicity of a whole-cell cancer vaccine. An immunocytokine (2aG4-IL2) was made by genetically linking IL-2 with a PS targeting antibody, 2aG4, that can block the immunosuppressive effects of PS. The 2aG4-IL2/4T1 vaccine was generated by coating the PS exposed on irradiated 4T1 cells with 2aG4-IL2. Tumor growth, spontaneous metastasis, and survival of vaccinated mice challenged with live 4T1 tumor cells were assessed. Eighty percent of mice inoculated with 2aG4-IL2/4T1 vaccine survived free of tumor, as compared with 20% in the 2aG4/4T1 group, 20% in the C44-IL2/4T1 group, and none in the C44/4T1 control group (P=0.001 for 2aG4-IL2/4T1 versus all others groups). The incidence, number of spontaneous lung metastases was significantly lower in the 2aG4-IL2/4T1 vaccinated group than in the other groups. Splenocytes from 2aG4-IL2/4T1 vaccinated mice had significantly higher 4T1 specific cytotoxicity and ability to secrete interferon-gamma (IFNγ) than did splenocytes from mice in the other groups. These results demonstrate that a potent whole-cell vaccine can be created by coating irradiated tumor cells with 2aG4-IL2. Such vaccine could potentially be an effective treatment modality for patients with residual disease or at "high-risk" for recurrence.
authors.affiliation: Simmons Comprehensive Cancer Center, the Department of Pharmacology, the University of Texas Southwestern Medical Center, Dallas, TX 75390-9041, USA.
authors.forename: Xianming
authors.initials: X
authors.lastname: Huang
authors.forename: Dan
authors.initials: D
authors.lastname: Ye
authors.forename: Philip E
authors.initials: PE
authors.lastname: Thorpe
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology / Q000517:prevention & control*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D005260:Female; D007376:Interleukin-2 / Q000008:administration & dosage*; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008168:Lung / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000517:prevention & control; D010718:Phosphatidylserines / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000008:administration & dosage; D013154:Spleen / Q000276:immunology; D016019:Survival Analysis
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D016207:Cytokines; D007376:Interleukin-2; D010718:Phosphatidylserines; D011994:Recombinant Proteins