title: Dendritic cells engineered to secrete anti-GITR antibodies are effective adjuvants to dendritic cell-based immunotherapy.
abstract: A number of monoclonal antibodies (mAbs) have been studied for their ability to enhance immune responses. Although these antibodies are effective in pre-clinical and clinical studies, they are costly and have occasionally been associated with adverse effects such as autoimmunity and cytokine storm. Numerous studies have shown that treatment of mice with an agonistic mAb, clone DTA-1, targeting murine glucocorticoid-induced tumor necrosis factor receptor (GITR) results in enhanced immune responses in tumor-bearing animals. Herein, we evaluate the novel approach of transfecting dendritic cell (DC) with mRNA encoding the heavy and light chain of the anti-GITR mAb. We show the induction of significantly enhanced tumor immunity by vaccinating with a combination of anti-GITR-secreting DC and tumor antigen-presenting DC. This enhancement is comparable to that seen with systemically delivered mAb along with the antigen-presenting DC. Importantly, when anti-GITR was delivered using RNA-transfected DC, we observed no evidence of autoimmune hypopigmentation in any tumor-free mice. We also show enhanced induction of cytotoxic T-lymphocyte responses, which is only observed when the antigen-presenting and antibody-secreting DC are co-injected at the same site. To illustrate the broad utility of this strategy, we show that DC transfected with mRNA encoding GITR-ligand/Fc fusion protein is also an effective tumor vaccine adjuvant.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: D
authors.initials: D
authors.lastname: Boczkowski
authors.forename: J
authors.initials: J
authors.lastname: Lee
authors.forename: S
authors.initials: S
authors.lastname: Pruitt
authors.forename: S
authors.initials: S
authors.lastname: Nair
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology*; D017951:Antigen Presentation; D016466:CHO Cells; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007128:Immunoglobulin Fragments / Q000235:genetics / Q000276:immunology; D007147:Immunoglobulin Light Chains / Q000235:genetics / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D012313:RNA / Q000008:administration & dosage / Q000235:genetics; D017475:Receptors, Nerve Growth Factor / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D014162:Transfection
chemical_list: D000911:Antibodies, Monoclonal; D019496:Cancer Vaccines; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007128:Immunoglobulin Fragments; D007147:Immunoglobulin Light Chains; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C106544:Tnfrsf18 protein, mouse; D012313:RNA