Purpose: Previous studies demonstrate that intratumoral CpG immunotherapy in combination with radiotherapy acts as an in-situ vaccine inducing anti-tumor immune responses capable of eradicating systemic disease. Unfortunately, most patients fail to respond. We hypothesized that immunotherapy can paradoxically up-regulate 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 intra-tumoral 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 (Tregs) in the tumor microenvironment. This triple combination induced systemic anti-tumor effects, decreasing metastases and improving survival in a CD8+ T-cell dependent manner. We evaluated this novel triple therapy in a canine clinical trial, since spontaneous canine malignancies closely reflect human cancer. Mirroring our mouse studies, the therapy was well tolerated, reduced intra-tumoral immunosuppression, and induced robust systemic anti-tumor effects. Conclusion: These results suggest that IDO maintains immune suppression in the tumor after therapy and IDO blockade promotes a local anti-tumor immune response with systemic consequences. The efficacy and limited toxicity of this strategy are attractive for clinical translation.
- Received December 18, 2015.
- Revision received February 25, 2016.
- Accepted February 28, 2016.
- Copyright ©2016, American Association for Cancer Research.