iPSC-Derived γδT Cell Compositions for Persistent Tumor Killing
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Solution Overview
Problem
Allogeneic immune recognition and rejection remain obstacles in cellular transplantation and cell therapy development, primarily due to HLA mismatch, which can be suppressed by genetic ablation of HLA in iPSC-derived γδT cells.
Innovation Solution
Genomic disruptions in the SOCS1, CISH, BIM, FAS, B2M, and CIITA genes, along with the introduction of an IFNγ signal converter and a CAR that specifically binds CD19, enhance the cytotoxicity and persistence of γδT cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If HLA genetic ablation is performed in iPSC-derived γδT cells to suppress allogeneic immune recognition, then immune rejection is reduced, but cell persistence and cytotoxicity are compromised
Solution Approach 1:
The patent modifies multiple gene parameters simultaneously - knocking out SOCS1 and CISH to enhance cytokine signaling, knocking out BIM to prevent apoptosis, and knocking out FAS to block death receptor-mediated cell death. These parameter changes in gene expression and cellular function collectively improve both immune evasion and cell persistence without requiring HLA ablation
Solution Approach 2:
The patent creates a composite genetic modification strategy combining multiple gene knockouts (SOCS1, CISH, BIM, FAS) with CAR integration. This composite approach achieves synergistic effects where the combination of modifications provides superior cell persistence and cytotoxicity compared to individual modifications or HLA ablation alone
2Productivity
If multiple gene knockouts are performed to enhance cytotoxicity and persistence, then therapeutic efficacy is improved, but cell survival and stability are reduced
Solution Approach 1:
The patent applies preliminary anti-action by knocking out BIM (a pro-apoptotic gene) and FAS (a death receptor gene) before the therapeutic cells are activated. This preemptive genetic modification prevents apoptosis and death receptor-mediated cell death pathways from being activated during therapy, thereby protecting cell survival while maintaining high cytotoxicity
Solution Approach 2:
The patent converts potentially harmful genetic modifications into beneficial outcomes by carefully selecting which genes to knockout. For example, knocking out SOCS1 and CISH (which normally suppress cytokine signaling) actually enhances IL-2 signaling and cell proliferation. Similarly, knocking out BIM converts a pro-apoptotic function into a survival advantage, and knocking out FAS converts a death receptor function into protection from immune-mediated cell death
Data Source
AI summary
The present disclosure provides genetically modified iPSC-derived γδT cells and their precursors. A double genomic disruption in the suppressor of cytokine signaling 1 (SOCS1) gene and the cytokine-inducible sh2-containing protein (CISH) gene are provided, as is a triple genomic disruption in genes for SOCS1, CISH, and Bcl-2 interacting mediator of cell death (BIM), as is a quadruple genomic disruption in genes for SOCS1, CISH, BIM, and cell surface death receptor (FAS), as is a quintuple genomic disruption in genes for SOCS1, CISH, BIM, β-2-Microglobulin (B2M), and class II transactivator (CITTA), as is a sextuple genomic disruption in genes for SOCS1, CISH, BIM, B2M, CITTA, and FAS. Also provided is genetically modified iPSC-derived γδT cells and their precursors with improved proliferation and tumor killing activity. Also provided are genetically modified iPSC-derived γδT cells and their precursors further comprising CD19 CAR. The present disclosure further provides methods making and using such cells, as well as gene editing systems.