RIG-I Agonist SLRs with Checkpoint Blockers for Cold Tumors
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Solution Overview
Problem
Current treatments for cancer lack effective compositions and methods to activate immunity against the disease, particularly in 'cold' tumors that are poorly infiltrated by the immune system, and existing innate immune agonists have limitations such as restricted applicability and potential resistance issues.
Innovation Solution
The use of RIG-I agonists, specifically Stem Loop RNAs (SLRs), to activate the innate immune system within tumors, combined with immune-checkpoint inhibitors like PD-1 or CTLA-4 blockers, to enhance immune response and target a broad spectrum of tumor types.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current cancer treatments are used, then general cancer therapy is provided, but they lack effectiveness in activating immunity against cancer particularly in cold tumors
Solution Approach 1:
The patent modifies the chemical structure of known RIG-I agonists by introducing specific substituents at defined positions (e.g., R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58, R59, R60, R61, R62, R63, R64, R65, R66, R67, R68, R69, R70, R71, R72, R73, R74, R75, R76, R77, R78, R79, R80, R81, R82, R83, R84, R85, R86, R87, R88, R89, R90, R91, R92, R93, R94, R95, R96, R97, R98, R99, R100) to enhance their ability to activate RIG-I and stimulate immune responses in cold tumors
Solution Approach 2:
The patent combines RIG-I agonists with immune checkpoint inhibitors (such as anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies) to create a composite therapeutic approach that synergistically enhances immune activation and tumor infiltration, thereby improving efficacy in both hot and cold tumors
2Adaptability or versatility
If existing innate immune agonists are used, then immune activation is achieved, but they have limitations such as restricted applicability and potential resistance issues
Solution Approach 1:
The patent designs RIG-I agonists with a core structure that can recognize and bind to RIG-I across different tumor types and microenvironments, enabling universal immune activation. The agonists are engineered to maintain consistent structural features (e.g., 5'-triphosphate motif, specific base sequences) that ensure reliable RIG-I binding and downstream immune signaling regardless of tumor heterogeneity
3Adaptability or versatility
If RIG-I agonists are used to activate innate immune system, then tumor infiltration by immune cells increases, but inflammatory side effects may occur
Solution Approach 1:
The patent engineers RIG-I agonists with enhanced specificity for tumor microenvironments through modifications that promote selective accumulation in tumor tissues (e.g., via EPR effect, active targeting moieties, or tumor-pH responsive features). This localized action concentrates immune activation at the tumor site while minimizing systemic inflammatory responses
Solution Approach 2:
The patent optimizes the chemical parameters of RIG-I agonists (molecular weight, charge, hydrophobicity, stability) to enhance tumor selectivity and reduce off-target effects. Specific modifications include adjusting the length and composition of RNA sequences, modifying sugar-phosphate backbones, and incorporating tumor-targeting ligands to achieve selective tumor infiltration with minimal systemic inflammation
Data Source
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AI summary
The present invention provides combination therapies that are useful for treating and/or preventing certain cancers. In certain embodiments, the therapy comprises an immune-checkpoint inhibitor and a RIG-I agonist. In other embodiments, the therapy comprises a RIG-I agonist.