Allogeneic Cell Therapy Graft Rejection via Checkpoint Ligands
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Solution Overview
Problem
Adoptive cell therapy, particularly allogeneic cell therapy, faces significant challenges due to undesired immune responses such as graft-versus-host disease and host-versus-graft disease, which are difficult to manage with existing methods like lymphodepletion and myeloablation, leading to severe side effects and limited clinical success.
Innovation Solution
Modified therapeutic cells expressing immune checkpoint ligands like PD-L1, CD155, CD112, FGL1, galectin-9, CD47, B7H3, or B7H4, along with MHC molecules, are used to reduce graft rejection and induce immune tolerance, thereby minimizing immune responses against infused cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If allogeneic therapeutic cells are infused to treat cancer, then the therapeutic effect is improved, but host-versus-graft disease occurs causing graft rejection
Solution Approach 1:
The patent introduces immune checkpoint ligands (PD-L1, CD155, CD112, FGL1, galectin-9, CD47, B7H3, or B7H4) as intermediary molecules expressed on the surface of allogeneic therapeutic cells. These ligands act as mediators that bind to corresponding receptors on host immune cells, delivering inhibitory signals that prevent harmful immune recognition and rejection while allowing the therapeutic cells to function. This intermediary mechanism resolves the contradiction by enabling the therapeutic cells to coexist with the host immune system without eliminating it.
Solution Approach 2:
The patent changes the immunological parameters of the therapeutic cells by genetically modifying them to overexpress specific immune checkpoint ligands. This parameter change (increased expression levels of inhibitory ligands) transforms the cells from being highly immunogenic targets of host rejection to being protected from immune attack, thereby maintaining their therapeutic function while reducing graft rejection.
2Object-affected harmful factors
If lymphodepletion is used as pre-treatment to reduce immune response, then graft rejection is reduced, but severe side effects occur due to immune system damage
Solution Approach 1:
The patent converts the harmful immunogenicity of allogeneic cells into a beneficial therapeutic mechanism by engineering them to express immune checkpoint ligands. Instead of trying to eliminate the host immune response through destructive lymphodepletion, the modified cells actively engage and regulate the host immune system through checkpoint ligand-receptor interactions, transforming potential harm into controlled immune modulation that protects the graft while preserving immune function.
Solution Approach 2:
The patent applies preliminary genetic modification to the therapeutic cells before infusion, equipping them with immune checkpoint ligands in advance. This preliminary action prepares the cells to actively prevent rejection upon contact with host immune cells, eliminating the need for subsequent aggressive lymphodepletion procedures and their associated side effects.
3Object-affected harmful factors
If genome editing is used to knockout TCR genes to reduce graft-versus-host disease, then GvHD is reduced, but immunogenicity of edited cells increases leading to NK cell-mediated rejection
Solution Approach 1:
The patent applies local quality modification by specifically targeting and modifying only the necessary genes (TCR genes for GvHD prevention, B2M for MHC class I reduction) while preserving other essential cell functions and characteristics. This localized genetic modification approach maintains cell identity and therapeutic function while reducing specific harmful interactions, and the additional expression of immune checkpoint ligands provides localized protection against NK cell recognition of the edited cells.
Data Source
AI summary
Provided are modified therapeutic cells that overexpress an immune checkpoint ligand such as PD-L1, CD155, CD112, FGL1, galectin-9, CD47, B7H3 and B7H4, while expressing one or more Major Histocompatibility Complex (MHC) molecules. Also provided are methods of treatment using the modified therapeutic cells.