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Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

RESULTS:

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.

CONCLUSIONS:

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​. 

Translational Relevance

Cancer immunotherapy consisting of radiotherapy in combination with intratumoral CpG has proven highly effective in some patients, and additional trials are ongoing. Unfortunately, most patients fail to respond to this therapy. In this report, we demonstrate that the effectiveness of this therapy may be limited by upregulation of IDO in the tumor microenvironment in response to the therapy itself. IDO upregulation maintains immune suppression within the tumor and limits an effective antitumor immune response. Addition of IDO blockade to this therapy reverses intratumoral immune suppression and substantially improves local and systemic efficacy without any apparent increase in toxicity. Given the use of IDO inhibitors and radiotherapy + CpG in clinical trials, and that this triple therapy has now been tested in large animal models, this therapy is ready for clinical translation.​ ​ 

​Author information​

Monjazeb AM1, Kent MS2, Grossenbacher SK3, Mall C3, Zamora AE3, Mirsoian A3, Chen M4, Kol A5, Shiao SL6, Reddy A7, Perks JR7, T N Culp W2, Sparger EE2, Canter RJ8, Sckisel GD3, Murphy WJ9.

1Department of Radiation Oncology, UC Davis Comprehensive Cancer Center, Sacramento, California. ammonjazeb@ucdavis.edu.

2Department of Surgical and Radiological Sciences, UC Davis School of Veterinary Medicine, Davis, California.

3Department of Dermatology, UC Davis Health Sciences, Sacramento, California.

4Department of Pathology, UC Davis Health Sciences, Sacramento, California.

5Department of Pathology, Microbiology, and Immunology, UC Davis School of Veterinary Medicine, Davis, California.

6Departments of Radiation Oncology and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California.

7Department of Radiation Oncology, UC Davis Comprehensive Cancer Center, Sacramento, California.

8Division of Surgical Oncology, Department of Surgery, UC Davis Comprehensive Cancer Center, Sacramento, California.

9Department of Dermatology, UC Davis Health Sciences, Sacramento, California. Division of Hematology and Oncology, Department of Internal Medicine, UC Davis Comprehensive Cancer Center, Sacramento, California.