Small-Molecule Immune Cell Modulation for Naïve and Memory T Cell Expansion
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Solution Overview
Problem
Existing adoptive immunotherapies face challenges in maintaining and expanding desired immune cell subsets, particularly T, NK, and NKT cells, due to differentiation during expansion processes, which affects their proliferation, persistence, and therapeutic efficacy.
Innovation Solution
Compositions and methods using specific small molecules, such as those listed in Table 1, modulate immune cells ex vivo to enhance proliferation, persistence, and cytotoxicity by improving the ratio and quality of subpopulations like naïve T cells, stem cell memory T cells, central memory T cells, adaptive NK cells, and type I NKT cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If immune cells are activated and expanded during manufacturing, then cell quantity increases, but cell differentiation increases leading to reduced proliferation and persistence capacity
Solution Approach 1:
The patent applies preliminary action by treating immune cells with small molecules (such as mTOR inhibitors, PI3K inhibitors, or Wnt pathway modulators) before and during the expansion process. This pre-treatment prevents differentiation from occurring during expansion, thereby maintaining the cells in a less differentiated state that retains high proliferation and persistence capacity while still achieving the desired cell quantity for therapy.
2Productivity
If more differentiated immune cell subsets are obtained, then cell expansion capacity increases, but persistence and long-term survival decrease
Solution Approach 1:
The patent utilizes parameter changes by modulating signaling pathway parameters (mTOR, PI3K, Wnt) through small molecule treatments. By controlling these biochemical parameters during cell culture, the method achieves a balance where cells expand sufficiently for therapeutic dosing while maintaining the molecular parameters necessary for long-term persistence and survival in the host.
3Productivity
If conventional activation methods are used, then cell proliferation is enhanced, but cell quality and therapeutic efficacy are compromised
Solution Approach 1:
The patent introduces small molecules as intermediary agents that mediate between conventional activation stimuli and the cellular response. These intermediaries (such as mTOR inhibitors or Wnt pathway modulators) fine-tune the activation signals to promote proliferation while simultaneously preventing excessive differentiation and maintaining cell quality attributes necessary for therapeutic efficacy.
Data Source
AI summary
Compounds that either produced a higher proportion or greater absolute number of phenotypically identified nave, 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 with improved efficacy are provided.