Combination Therapy for Cold Tumor Immunotherapy Response
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current cancer treatments, particularly immunotherapy, face challenges in making non-inflamed or 'cold' tumors responsive, as they lack T-cell infiltration and are resistant to checkpoint blockade therapies due to high IDO1 expression and β-catenin activity.
Innovation Solution
Reducing β-catenin and IDO expression through specific inhibitors, such as β-catenin nucleic acid inhibitors and IDO inhibitors, in combination with immunotherapy, converts non-inflamed tumors into inflamed ones, enhancing T-cell infiltration and responsiveness to immunotherapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immunotherapy is applied to non-inflamed tumors, then T cell activation is blocked, but the tumors remain resistant due to lack of T cell infiltration and high IDO1 expression
Solution Approach 1:
The patent applies preliminary action by using IDO1 inhibitors and beta-catenin inhibitors to pre-treat non-inflamed tumors before administering immunotherapy. This pre-treatment converts the tumor microenvironment from non-inflamed to inflamed, creating T cell infiltration and making the tumors responsive to subsequent immunotherapy. The inhibitors are administered at doses and schedules that optimize the conversion of cold tumors to hot tumors, ensuring the tumor is primed for immunotherapy effectiveness.
Solution Approach 2:
The patent implements parameter changes by modifying the tumor microenvironment parameters through IDO1 inhibition and beta-catenin inhibition. Specifically, it changes the inflammatory status parameter from non-inflamed to inflamed, alters T cell infiltration levels from low to high, and modifies the amino acid metabolism parameter by blocking tryptophan degradation. These parameter changes transform the tumor characteristics to make them responsive to immunotherapy.
2Adaptability or versatility
If IDO1 expression is high in tumors, then immunosuppressive microenvironment is created, but reducing IDO1 expression can convert non-inflamed tumors to inflamed tumors
Solution Approach 1:
The patent applies the blessing in disguise principle by converting the harmful immunosuppressive microenvironment created by high IDO1 expression into a beneficial inflamed microenvironment. By using IDO1 inhibitors, the patent blocks the harmful tryptophan degradation and kynurenine production, thereby converting the tumor from an immunosuppressive state to an inflammatory state that is responsive to immunotherapy. This transforms the previously harmful IDO1 activity into a therapeutic opportunity.
Solution Approach 2:
The patent uses IDO1 inhibitors as intermediary agents that mediate the conversion between non-inflamed and inflamed tumor states. The inhibitors act as mediators by blocking IDO1 enzyme activity, which in turn alters the tumor microenvironment properties. This intermediary approach allows the transition from an immunosuppressive state to an inflammatory state without directly manipulating the tumor cells themselves, but rather through modulating the microenvironmental conditions.
3Quantity of substance
If beta-catenin activity is high in tumors, then T cell infiltration is reduced, but reducing beta-catenin expression enhances T cell infiltration and immunotherapy response
Solution Approach 1:
The patent applies the merging principle by combining IDO1 inhibitors and beta-catenin inhibitors with immunotherapy in a unified treatment regimen. This combination approach merges multiple therapeutic mechanisms into a single coordinated treatment strategy, where IDO1 inhibition addresses tryptophan metabolism, beta-catenin inhibition addresses Wnt signaling and T cell infiltration, and immunotherapy provides the immune activation. The synergistic combination of these agents creates a more effective treatment than any single agent alone, while the patent provides guidance on dosing and scheduling to simplify clinical implementation.
Data Source
AI summary
Provided herein are methods and compositions for treating cancer, including cancer that is not responsive to immunotherapy. In one aspect, the methods of treatment comprise administering to the subject a therapeutically effective amount of a β-catenin inhibitor, a therapeutically effective amount of an IDO inhibitor, and a therapeutically effective amount of an immunotherapeutic agent. Another aspect is directed to pharmaceutical compositions comprising a β-catenin inhibitor for use in treating cancer, wherein the composition is administered in combination with an IDO inhibitor and an immunotherapeutic agent. Yet another aspect is directed to a method of potentiating the therapeutic effect of immunotherapy against a cancer using a β-catenin inhibitor, such as a β-catenin nucleic acid inhibitor molecule, in combination with an IDO inhibitor.