Immune Cell Modulation via Small Molecule Inhibitors
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Solution Overview
Problem
Current adoptive immunotherapies, such as CAR-T cell therapies, face challenges with CAR-T potency, persistence, migration to tumors, immunosuppressive tumor microenvironments, and tumor heterogeneity, limiting their therapeutic efficacy and patient safety.
Innovation Solution
The use of specific modulating agents like BET inhibitors, IKK inhibitors, JAK inhibitors, PDK1 inhibitors, and Syk inhibitors to enhance the proliferation, persistence, and cytotoxicity of immune cells, including T, NK, and NKT cells, by improving their expansion, maintenance, and differentiation states, thereby increasing their therapeutic potential for adoptive cell therapies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T cell therapy is administered to treat cancer, then therapeutic benefit is provided to patients, but challenges arise with CAR-T potency, persistence, and migration to tumors
Solution Approach 1:
The patent changes the differentiation state parameter of T cells by using small molecule inhibitors (BET, IKK, JAK, PDK1, Syk inhibitors) to maintain T cells in a less differentiated state during ex vivo expansion, thereby improving their persistence and therapeutic efficacy while reducing the complexity of cell therapy protocols
2Quantity of substance
If immune cells are expanded ex vivo to increase quantity, then cell numbers are improved, but cell differentiation occurs which may reduce therapeutic quality
Solution Approach 1:
The patent applies small molecule inhibitors during the ex vivo expansion process to prevent differentiation before it occurs, thereby maintaining the desired less differentiated phenotype of T cells while achieving the necessary cell numbers for therapy
Solution Approach 2:
The patent uses chemical inhibitors to alter the differentiation parameter of expanding T cells, maintaining them in a less differentiated state that provides both persistence and therapeutic efficacy
3Power
If T cells are differentiated to enhance immediate cytotoxicity, then short-term killing ability is improved, but persistence and long-term therapeutic outcomes are reduced
Solution Approach 1:
The patent changes the differentiation state parameter of T cells to a less differentiated state, which balances immediate cytotoxicity with long-term persistence, thereby achieving both short-term power and duration of action
4Reliability
If high doses of CAR-T cells are administered to overcome tumor heterogeneity, then tumor coverage is improved, but patient safety and immunosuppression risks worsen
Solution Approach 1:
The patent changes the functional quality parameter of T cells by maintaining them in a less differentiated state, which enhances their ability to clear tumors while reducing the dose required and thereby minimizing immunosuppression risks
Data Source
AI summary
Compounds that either produce a higher proportion or greater absolute number of phenotypically identified naive, stem cell memory, central memory T cells, adaptive NK cells, and type I NKT cells are identified. Compositions and methods for modulating immune cells including T, NK, and NKT cells for adoptive cell therapies, such as those providing improvements in one or more therapeutic outcomes, are provided.