Synergistic Combination of Immunologic Inhibitors for the Treatment of Cancer

SUMMARY

• Current immunotherapy approaches often focus on targeting a single immune checkpoint or suppressive pathway, which can be insufficient given the redundancy and adaptability of tumor-mediated immune evasion. Tumors can compensate for the blockade of one pathway by upregulating alternative suppressive mechanisms, leading to limited efficacy and the persistence of disease.
• Additionally, single-agent therapies may not adequately address the metabolic suppression exerted by enzymes such as indoleamine-2,3-dioxygenase (IDO), nor the suppressive influence of regulatory T cells and other immunoregulatory receptors like LAG-3 and Tim3. This multifaceted immune suppression within the tumor microenvironment presents a significant barrier to durable and effective anti-tumor immunity, highlighting the limitations of current monotherapies and the pressing need for more synergistic, multi-targeted immunotherapeutic strategies.
• The faculty inventor developed a comprehensive cancer immunotherapy strategy that targets multiple immune suppressive pathways within the tumor microenvironment to enhance anti-tumor responses. It combines an indoleamine-2,3-dioxygenase (IDO) inhibitor with immune checkpoint inhibitors such as anti-PD-L1/PD-1 and anti-CTLA-4 antibodies, and can be further optimized with modulators like IL-7, anti-CD25, and antibodies against LAG-3, Tim3, and 41BB. The approach is designed to counteract diverse mechanisms of immune evasion, including T cell anergy, regulatory T cell suppression, and metabolic suppression via tryptophan catabolism
• 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

The three combinations of immune inhibitors tested (shaded circle) each showed an improvement in tumor size reduction as compared to monotherapy treatment (triangle and diamond) when evaluated in mouse models of melanoma.

ADVANTAGES

ADVANTAGES

• Enhanced anti-tumor immune response through synergistic targeting of multiple immune suppressive pathways
• Improved tumor control by combining IDO inhibitors with PD-L1/PD-1 and CTLA-t checkpoint blockade
• Increased antigen-specific T cell activity and function within the tumor microenvironment
• Potential applicability across diverse cancer types due to common immune evasion mechanisms
• Flexibility to incorporate additional immune modulators for optimized therapeutic effects

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

• Demonstrated efficacy in preclinical melanoma models supporting clinical development