Synergistic Combination of Immunologic Inhibitors for the Treatment of Cancer

SUMMARY

• Monotherapy treatment with cancer immunotherapies limits treatment efficacy by accelerating the development of drug resistance and promoting the hyper-regulation of analogous un-drugged pathways. These shortcomings can potentially be addressed by synergistically combining multiple immunotherapy drugs into a single treatment regimen.
• The inventors demonstrated that simultaneously blocking multiple immune regulatory pathways (CTLA-4, PD-L1, IDO) in various combinations improved tumor control in vivo. Therefore, using combinations of FDA approved inhibitors of these pathways may boost efficacy over treatment with single therapies.
• The invention is a treatment approach for multiple types of cancer that combines FDA approved antibodies targeting CTLA-4, PD-L1, and IDO. Simultaneously blocking these pathways promotes tumor CD8+ T cell response and natural IL-2 activity, driving a stronger anti-tumor immune response than each of these treatments alone. 
• The drug combinations were evaluated in an in vivo mouse model of melanoma (CTLA-4+PD-L1, CTLA-4+IDO, PD-L1+IDO) and showed markedly improved tumor control over single treatment, with some mice achieving complete tumor rejection. A significant increase in IL-2 production by tumor infiltrating CD8+ T cells was observed just 3 days after treatment initiation.

FIGURE

ADVANTAGES

ADVANTAGES

• Improved efficacy over monotherapy
• Effective in mature tumors
• Invigorates T-cell polyfunctionality.

APPLICATIONS

• Cancer immunotherapy
• Predictive biomarkers
• Drug repurposing/combination therapy

PUBLICATIONS

• Spranger, S; et al. Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly within the tumor microenvironment. Immunother Cancer. 2014 Feb 18; 2:3.

July 23, 2019

Pre-clinical

Patent Issued

Licensing

Thomas Gajewski

• US: 10,034,939
• Counterparts pending in the EU and Canada