iPSC-Derived Effector Cells With Fas Redirector for Tumor Persistence
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Solution Overview
Problem
Current adoptive cell therapies using patient- and donor-sourced cells face challenges in consistent manufacturing, efficacy, persistence, and tumor targeting precision, with issues such as cell exhaustion, tumor escape, off-target toxicity, and low efficacy against solid tumors.
Innovation Solution
Development of iPSC-derived non-pluripotent cells with genetic modifications, including a Fas redirector receptor and chimeric antigen receptor (CAR), to enhance apoptosis resistance, tumor penetration, and cytokine signaling, addressing heterogeneity and engineering reproducibility issues in primary lymphocytes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If primary lymphocytes (T cells or NK cells) are used for adoptive cell therapy, then the therapy can be manufactured, but the cells exhibit poor persistence with high cell death and low expansion
Solution Approach 1:
The patent uses iPSC-derived cells as a copy/alternative to primary lymphocytes. Instead of using primary T cells or NK cells that have poor persistence, the invention creates differentiated cell copies from iPSCs that can be engineered to have improved persistence and reduced cell death, while maintaining therapeutic function.
Solution Approach 2:
The patent applies parameter changes by genetically modifying the iPSC-derived cells to alter their biological parameters. Specific modifications include introducing Fas redirector receptors and other genetic edits that change cell survival, persistence, and functional parameters to achieve the desired therapeutic outcome.
2Reliability
If primary lymphocytes are engineered, then therapeutic properties can be improved, but the engineering lacks reproducibility and uniformity
Solution Approach 1:
The patent uses iPSCs as a reproducible starting point that can be differentiated into uniform cell populations. This copying approach from a standardized iPSC platform provides better reproducibility and uniformity compared to direct engineering of primary lymphocytes, as the iPSC differentiation process can be tightly controlled and standardized.
Solution Approach 2:
The patent employs precise parameter changes through genetic engineering of iPSCs before differentiation. By modifying the iPSC genome (e.g., introducing Fas redirector receptors, CARs, or other therapeutic genes) before differentiation, the invention achieves uniform expression of therapeutic properties across all derived cells, improving both reproducibility and manufacturing precision.
3Reliability
If Fas redirector receptor is introduced to provide apoptosis resistance, then cell survival is improved, but the cell population becomes heterogenous
Solution Approach 1:
The patent applies parameter changes by introducing the Fas redirector receptor through precise genetic modification of iPSCs before differentiation. This ensures uniform incorporation of the apoptosis resistance mechanism across the entire cell population, maintaining homogeneity while achieving the desired functional improvement.
Data Source
AI summary
Provided are methods and compositions for obtaining functionally enhanced derivative effector cells obtained from directed differentiation of genomically engineered iPSCs. Embodiments of derivative cells provided herein have stable and functional genome editing that delivers improved or enhanced therapeutic effects. Also provided are therapeutic compositions and the use thereof comprising the functionally enhanced derivative effector cells alone, or with antibodies or checkpoint inhibitors in combination therapies.