ACT Cell Persistence via NKG2D Ligand Inactivation
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Solution Overview
Problem
Current adoptive cell therapy (ACT) methods face challenges in maintaining the persistence of infused cells in vivo due to innate immune responses, particularly from NK cells recognizing induced-self antigens.
Innovation Solution
Engineered immune cells with inactivated or inhibited NKG2D ligands, achieved through genetic modification using techniques like CRISPR/CAS or by administering inhibitors such as shRNA, are developed to reduce NK cell-mediated clearance.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If lymphodepletion or myeloablation is used to prevent host versus graft response, then the persistence of ACT cells is improved, but severe side effects occur due to the drastic effect on the immune system
Solution Approach 1:
The patent applies preliminary action by inactivating NKG2D ligands on ACT cells before infusion. This pre-modification prevents subsequent NK cell recognition and clearance, eliminating the need for lymphodepletion or myeloablation while ensuring cell persistence. The protective measure is implemented in advance on the therapeutic cells themselves rather than requiring preparatory immune suppression in the patient.
Solution Approach 2:
The patent converts the harmful effect of NKG2D ligand expression (which triggers NK cell-mediated clearance) into a benefit by selectively inactivating these ligands. The modification that initially seemed to alter cell identity is actually the key protective mechanism that prevents immune rejection, transforming a potential vulnerability into a protective feature that enhances cell survival without requiring immunosuppressive conditioning.
2Ease of manufacture
If transduction and culture of patient cells is performed to make them suitable for adoptive cell transfer, then the cells become more vulnerable to innate immune system attack through induced self antigens, but this processing is necessary to create effective therapeutic cells
Solution Approach 1:
The patent applies the extraction principle by specifically removing or inactivating the problematic NKG2D ligands from the ACT cell surface. This selective extraction of the harmful component (induced self antigens recognized by NK cells) allows the cells to retain their therapeutic functionality while eliminating the specific vulnerability to innate immune attack that arises during manufacturing.
Solution Approach 2:
The patent applies local quality by making a specific modification to a particular aspect of the cell surface (NKG2D ligand expression) rather than globally altering the cell. This localized change affects only the interaction with NK cells while preserving other important cell functions and characteristics, allowing the cells to maintain their therapeutic efficacy without broad immune recognition issues.
Data Source
AI summary
The present application relates to the field of immunotherapy, more particularly to the manufacture of cells for adoptive cell therapy. Provided herein are compositions and methods for improving in vivo persistence of cells intended for adoptive transfer. This is achieved by making the cells less vulnerable to clearance caused by NK cells of the subject receiving the adoptive cell therapy.