Synergy between tumor immunotherapy and antiangiogenic therapy.
This study tested the hypothesis that combination of antiangiogenic therapy and tumor immunotherapy of cancer is synergistic. To inhibit angiogenesis, mice were immunized with dendritic cells (DCs) transfected with mRNA that encode products that are preferentially expressed during neoangiogenesis: vascular endothelial growth factor receptor-2 (VEGFR-2) and Tie2 expressed in proliferating endothelial cells, and vascular endothelial growth factor (VEGF) expressed in the angiogenic stroma as well as the tumor cells used in this study. Immunization of mice against VEGF or VEGFR-2 stimulated cytotoxic T lymphocyte (CTL) responses and led to partial inhibition of angiogenesis. Antiangiogenic immunity was not associated with morbidity or mortality except for a transient impact on fertility seen in mice immunized against VEGFR-2, but not VEGF. Tumor growth was significantly inhibited in mice immunized against VEGF, VEGFR-2, and Tie2, either before tumor challenge or in the setting of pre-existing disease in murine B16/F10.9 melanoma and MBT-2 bladder tumor models. Coimmunization of mice against VEGFR-2 or Tie2 and total tumor RNA exhibited a synergistic antitumor effect. Synergism was also observed when mice were coimmunized with various combinations of defined tumor-expressed antigens, telomerase reverse transcriptase (TERT) or TRP-2, and VEGF or VEGFR-2. This study shows that coimmunizing mice against angiogenesis-associated and tumor-expressed antigens can deliver 2 compatible and synergistic cancer treatment modalities via a common treatment, namely immunization.
Nair
Smita
S
Center for Genetic and Cellular Therapies, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Boczkowski
David
D
Moeller
Benjamin
B
Dewhirst
Mark
M
Vieweg
Johannes
J
Gilboa
Eli
E
D000818:Animals; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000378:metabolism / Q000637:transplantation; D016228:Endothelial Growth Factors / Q000235:genetics / Q000276:immunology; D005260:Female; D016219:Immunotherapy, Adoptive / Q000009:adverse effects / Q000379:methods*; D007246:Infertility / Q000209:etiology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008222:Lymphokines / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009363:Neoplasm Proteins / Q000276:immunology; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000150:complications / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000517:prevention & control* / Q000628:therapy; D011518:Proto-Oncogene Proteins; D012334:RNA, Neoplasm / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology; D042787:Receptor, TIE-2; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000276:immunology; D042442:Vascular Endothelial Growth Factors
D000951:Antigens, Neoplasm; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; C105373:MEN1 protein, human; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D012334:RNA, Neoplasm; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2