title: Combinatorial therapy for liver metastatic colon cancer: dendritic cell vaccine and low-dose agonistic anti-4-1BB antibody co-stimulatory signal.
abstract: BACKGROUND
  The combination of dendritic cell (DC) vaccine and 4-1BB ligation may be a suitable choice of immunotherapy for incurable cancer. However, at anti-tumor effector doses over 100 μg, 4-1BB Ab ligation is toxic to CD4(+) T cells, thus limiting its therapeutic use.
  
  
  METHODS
  A liver metastatic colon cancer model was established by hepatic injection of CT26 cells into Balb/c mice. Intraperitoneal administration of 1 × 10(6)/200 μL/mouse therapeutic-DCs (tumor lysate pulsed-DCs, P-DCs) began on d 7 after tumor cell inoculation. A P-DC injection was performed twice within a 1-wk interval. Agonistic anti 4-1BB Ab was intraperitoneally injected on d 7, 9, and 11 after tumor cell inoculation. Animals were sacrificed on d 21, and tumor growth was determined by weighing the liver with the tumor.
  
  
  RESULTS
  In the 20 μg 4-1BB ligation group, significant induction of CD3(+)CD8(+) T cells was observed without toxicity to CD3(+)CD4(+) T cells. DC vaccine treatment induced tumor antigen-specific Th1 cytokine (IL-2 and IFN-γ) secretion from the splenic lymphocytes. Ligation of 4-1BB reduced the DC vaccine-related IL-10 secretion and regulatory T cell population. Compared with anti-tumor effect of DC vaccine or 20 μg 4-1BB Ab alone, the combination therapy significantly increased the tumor rejection power to the level observed with higher doses of 4-1BB Ab alone. The combination therapy did not induce high-dose 4-1BB-related toxicity with CD4(+) T cell reduction, but did significantly induce tumor antigen-specific IFN-γ secreting effector CD8(+) cytotoxic T cells.
  
  
  CONCLUSIONS
  The data from our study reveal the value of using a DC vaccine combined with as little as 20 μg 4-1BB Ab as an improved immunotherapeutic for cancer.
authors.affiliation: Office of Biomedical Sciences, Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-dong, Gangnam-gu, Seoul, Korea.
authors.forename: Hyunah
authors.initials: H
authors.lastname: Lee
authors.forename: Hae-Jung
authors.initials: HJ
authors.lastname: Park
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Sohn
authors.forename: Jong Man
authors.initials: JM
authors.lastname: Kim
authors.forename: Sung Joo
authors.initials: SJ
authors.lastname: Kim
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy / Q000556:secondary; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology*; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D016896:Treatment Outcome; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology*
chemical_list: D000888:Antibodies, Anti-Idiotypic; D019496:Cancer Vaccines; D007376:Interleukin-2; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D007371:Interferon-gamma