Fratricide-Resistant CAR Immune Cells via CD2 Base Editing
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Solution Overview
Problem
Current methods for generating chimeric antigen receptor (CAR)-modified immune cells, such as CAR-T cells, face challenges in achieving efficient neoplasia treatment due to fratricide and genomic instability, which can be exacerbated by existing gene editing techniques.
Innovation Solution
Development of genetically modified immune cells, including specific CAR constructs with CD2 signaling domains and targeted nucleobase modifications to inactivate the endogenous CD2 gene, reducing fratricide and enhancing anti-neoplasia activity while minimizing genomic rearrangements.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current gene editing methods are used to modify CAR-T cells, then CAR-T cell function is enhanced, but genomic rearrangements are induced which negatively impact efficacy
Solution Approach 1:
The patent replaces traditional mechanical gene editing methods (CRISPR-Cas9 nucleases, TALENs) with base editing technology. Base editors use engineered deaminases to directly convert one nucleobase to another without creating double-strand breaks, thereby substituting the mechanical cutting-and-pasting mechanism with a more precise chemical conversion mechanism that avoids genomic rearrangements
Solution Approach 2:
The patent changes the fundamental parameter of gene editing from creating double-strand breaks to performing single-base conversions. This parameter change in the editing mechanism allows for precise modification of the CD2 gene to reduce fratricide while maintaining genomic stability and avoiding the chromosomal rearrangements associated with traditional editing methods
2Reliability
If gene editing is performed to create fratricide resistance, then CAR-T cell survival is improved, but off-target effects increase
Solution Approach 1:
The patent substitutes traditional gene editing mechanisms that create double-strand breaks with base editing technology. This replacement eliminates the need for non-homologous end joining or homology-directed repair pathways, thereby reducing off-target effects while achieving fratricide resistance through precise CD2 gene modification
Solution Approach 2:
The patent uses base editors that replicate the natural base pairing rules to introduce precise nucleotide changes. The base editing process copies the desired nucleotide conversion (e.g., C to T or A to G) at the target site without creating random mutations elsewhere in the genome, thereby reducing off-target effects
3Power
If shared expression of target antigens on healthy immune cells occurs, then CAR-T cell activation is enhanced, but fratricide increases
Solution Approach 1:
The patent converts the harmful effect of CD2 expression on healthy CAR-T cells (fratricide) into a beneficial outcome by using base editing to precisely modify the CD2 gene. The modification eliminates fratricide while preserving the ability of CAR-T cells to recognize and kill neoplastic cells expressing the target antigen, thereby transforming a harmful interaction into a therapeutic advantage
Data Source
AI summary
The present invention features fratricide resistant modified immune cells (e.g., T- or NK-cells) having enhanced anti-neoplasia activity and methods for producing and using the same. Methods of treating neoplasia (e.g., T- or NK-cell malignancies) using fratricide resistant modified immune cells are also provided.