Blocking Indolamine-2,3-Dioxygenase Rebound Immune Suppression Boosts Antitumor Effects of Radio-Immunotherapy in Murine Models and Spontaneous Canine Malignancies

Previous studies demonstrate that intratumoral CpG immunotherapy in combination with radiotherapy acts as an in-situ vaccine inducing antitumor immune responses capable of eradicating systemic disease. Unfortunately, most patients fail to respond. We hypothesized that immunotherapy can paradoxically...

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Bibliographic Details
Published in:Clinical cancer research 2016-09, Vol.22 (17), p.4328-4340
Main Authors: Monjazeb, Arta M, Kent, Michael S, Grossenbacher, Steven K, Mall, Christine, Zamora, Anthony E, Mirsoian, Annie, Chen, Mingyi, Kol, Amir, Shiao, Stephen L, Reddy, Abhinav, Perks, Julian R, T N Culp, William, Sparger, Ellen E, Canter, Robert J, Sckisel, Gail D, Murphy, William J
Format: Article
Language:English
Subjects:
Animals
Disease Models, Animal
Dogs
Enzyme Activation
Female
Immunomodulation - drug effects
Immunosuppression
Indoleamine-Pyrrole 2,3,-Dioxygenase - antagonists & inhibitors
Melanoma, Experimental
Mice
Neoplasms - immunology
Neoplasms - metabolism
Neoplasms - mortality
Neoplasms - therapy
Oligodeoxyribonucleotides - administration & dosage
Radioimmunotherapy - methods
T-Lymphocyte Subsets - immunology
T-Lymphocyte Subsets - metabolism
Treatment Outcome
Tumor Microenvironment - immunology
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Summary:Previous studies demonstrate that intratumoral CpG immunotherapy in combination with radiotherapy acts as an in-situ vaccine inducing antitumor immune responses capable of eradicating systemic disease. Unfortunately, most patients fail to respond. We hypothesized that immunotherapy can paradoxically upregulate immunosuppressive pathways, a phenomenon we term "rebound immune suppression," limiting clinical responses. We further hypothesized that the immunosuppressive enzyme indolamine-2,3-dioxygenase (IDO) is a mechanism of rebound immune suppression and that IDO blockade would improve immunotherapy efficacy. We examined the efficacy and immunologic effects of a novel triple therapy consisting of local radiotherapy, intratumoral CpG, and systemic IDO blockade in murine models and a pilot canine clinical trial. In murine models, we observed marked increase in intratumoral IDO expression after treatment with radiotherapy, CpG, or other immunotherapies. The addition of IDO blockade to radiotherapy + CpG decreased IDO activity, reduced tumor growth, and reduced immunosuppressive factors, such as regulatory T cells in the tumor microenvironment. This triple combination induced systemic antitumor effects, decreasing metastases, and improving survival in a CD8(+) T-cell-dependent manner. We evaluated this novel triple therapy in a canine clinical trial, because spontaneous canine malignancies closely reflect human cancer. Mirroring our mouse studies, the therapy was well tolerated, reduced intratumoral immunosuppression, and induced robust systemic antitumor effects. These results suggest that IDO maintains immune suppression in the tumor after therapy, and IDO blockade promotes a local antitumor immune response with systemic consequences. The efficacy and limited toxicity of this strategy are attractive for clinical translation. Clin Cancer Res; 22(17); 4328-40. ©2016 AACR.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.ccr-15-3026