title: Enhancing Dendritic Cell-based Immunotherapy with IL-2/Monoclonal Antibody Complexes for Control of Established Tumors.
abstract: U.S. Food and Drug Administration-approved high-dose IL-2 therapy and dendritic cell (DC) immunization offer time-tested treatments for malignancy, but with defined issues of short in vivo t1/2, toxicity, and modest clinical benefit. Complexes of IL-2 with specific mAbs (IL-2c) exhibit improved stability in vivo with reduced toxicity and are capable of stimulating NK cell and memory phenotype CD8 T cell proliferation. In this study, we demonstrate that IL-2c treatment in tumor-bearing mice can enhance NK cell and tumor-specific CD8 T cell numbers. Importantly, DC immunization coupled with stabilized IL-2c infusion drastically improves the tumor-specific effector CD8 T cell response. DC + IL-2c treatment enhances number, 41BB and GITR expression, granzyme B production, CTL/regulatory T cell ratio, and per-cell killing capacity of CD8 T cells without increasing inhibitory molecule expression. Notably, IL-2c treatment of anti-CD3-stimulated human CD8 T cells resulted in higher number and granzyme B production, supporting the translational potential of this immunotherapy strategy for human malignancy. DC + IL-2c treatment enhances both endogenous NK cell and tumor Ag-specific CD8 T cell immunity to provide a marked reduction in tumor burden in multiple models of pre-existing malignancy in B6 and BALB/c mice. Depletion studies reveal contributions from both tumor-specific CD8 T cells and NK cells in control of tumor burden after DC + IL-2c treatment. Together, these data suggest that combination therapy with DC and IL-2c may be a potent treatment for malignancy.
authors.affiliation: Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242; Carver College of Medicine, University of Iowa, Iowa City, IA 52242;
authors.forename: Marie T
authors.initials: MT
authors.lastname: Kim
authors.affiliation: Department of Microbiology, University of Iowa, Iowa City, IA 52242;
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Richer
authors.affiliation: Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242;
authors.forename: Brett P
authors.initials: BP
authors.lastname: Gross
authors.affiliation: Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242; Department of Urology, University of Iowa, Iowa City, IA 52242; Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242; and.
authors.forename: Lyse A
authors.initials: LA
authors.lastname: Norian
authors.affiliation: Department of Pathology, University of Iowa, Iowa City, IA 52242.
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Badovinac
authors.affiliation: Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242; Department of Microbiology, University of Iowa, Iowa City, IA 52242; Department of Pathology, University of Iowa, Iowa City, IA 52242 john-harty@uiowa.edu.
authors.forename: John T
authors.initials: JT
authors.lastname: Harty
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D005434:Flow Cytometry; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000276:immunology / Q000378:metabolism; D053804:Granzymes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007376:Interleukin-2 / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D013997:Time Factors; D047368:Tumor Burden / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007376:Interleukin-2; C106544:Tnfrsf18 protein, mouse; D053804:Granzymes