Journal article
Enhancing Dendritic Cell-based Immunotherapy with IL-2/Monoclonal Antibody Complexes for Control of Established Tumors
The Journal of immunology (1950), Vol.195(9), pp.4537-4544
11/01/2015
DOI: 10.4049/jimmunol.1501071
PMCID: PMC4610867
PMID: 26408669
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.
Details
- Title: Subtitle
- Enhancing Dendritic Cell-based Immunotherapy with IL-2/Monoclonal Antibody Complexes for Control of Established Tumors
- Creators
- Marie T Kim - Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242; Carver College of Medicine, University of Iowa, Iowa City, IA 52242Martin J Richer - Department of Microbiology, University of Iowa, Iowa City, IA 52242Brett P Gross - Interdisciplinary Program in Immunology, University of Iowa, Iowa City, IA 52242Lyse A Norian - 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; andVladimir P Badovinac - Department of Pathology, University of Iowa, Iowa City, IA 52242John T Harty - 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
- Resource Type
- Journal article
- Publication Details
- The Journal of immunology (1950), Vol.195(9), pp.4537-4544
- DOI
- 10.4049/jimmunol.1501071
- PMID
- 26408669
- PMCID
- PMC4610867
- NLM abbreviation
- J Immunol
- ISSN
- 0022-1767
- eISSN
- 1550-6606
- Publisher
- Oxford University Press (OUP); United States
- Grant note
- R37 AI042767 / NIAID NIH HHS T32 GM007337 / NIGMS NIH HHS R01 CA181088 / NCI NIH HHS AI42767 / NIAID NIH HHS R01 AI042767 / NIAID NIH HHS CA181088 / NCI NIH HHS P30CA086862 / NCI NIH HHS P30 CA086862 / NCI NIH HHS
- Language
- English
- Date published
- 11/01/2015
- Academic Unit
- Microbiology and Immunology; Pathology
- Record Identifier
- 9984046803202771
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