Engineered Hematopoietic Cells to Prevent CAR T Fratricide
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Solution Overview
Problem
Current targeted immunotherapies, particularly CAR T cell therapies, face challenges due to the lack of suitable target antigens and often result in side-effects such as on-target off-tumor toxicity and fratricide, limiting their application to a wider range of cancers.
Innovation Solution
A combination immunotherapy approach using antigen-recognizing receptors in combination with hematopoietic cells resistant to recognition by these receptors, either through natural polymorphisms or genetic modification, to reduce side-effects and enable the use of alternative target antigens.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR T cell therapy targets an antigen that is also expressed on hematopoietic cells, then tumor recognition and destruction is achieved, but hematopoietic cells are destroyed causing fratricide and side-effects
Solution Approach 1:
The patent applies local quality by creating different versions of the target antigen with distinct properties: a wild-type antigen on tumor cells that is recognized by CAR T cells, and a modified antigen on hematopoietic cells that resists CAR T cell recognition. This allows spatial differentiation of antigen recognition, enabling tumor targeting while protecting hematopoietic cells from fratricide.
Solution Approach 2:
The patent employs asymmetry by introducing asymmetric modifications to the antigen structure. The antigen on hematopoietic cells contains specific mutations (e.g., in the extracellular domain) that create asymmetric binding properties, allowing it to escape recognition by the CAR T cell receptor while maintaining its functional role on the cell surface.
2Adaptability or versatility
If a broad range of antigens is used for immunotherapy, then treatment versatility is improved, but the risk of targeting healthy cells increases
Solution Approach 1:
The patent applies parameter changes by modifying the antigen's molecular parameters (amino acid sequence, glycosylation patterns, or other post-translational modifications) to alter its recognition properties. This allows the same antigen to serve different functions: recognized by CAR T cells on tumor cells, but resistant to recognition on healthy hematopoietic cells, thereby expanding safe antigen choices for therapy.
Data Source
AI summary
This disclosure provides a system for preventing or reducing side effects in a patent undergoing immunotherapy to remove diseased cells that express a target antigen: for example, by CAR T cell therapy. Side effects can ensue from concurrent depletion of hematopoietic cells bearing the same target antigen. A population of engineered hematopoietic cells is prepared by obtaining healthy hematopoietic cells from the patient or a third party donor, and using them to produce engineered hematopoietic cells. The engineered cells either do not express the target antigen, express it at a lower density, or express it in a modified form. The engineered hematopoietic cells are formulated for administration to the patient, whereupon they reconstitute hematopoietic cell function, thereby preventing or reducing the side effects.