Universal CAR Platform Targeting LOH Alleles
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Solution Overview
Problem
Current cancer immunotherapy approaches face challenges in identifying suitable targets for genetically redirected killer cells due to the need for precise antigen recognition to avoid off-tumor toxicity and the limitations of shared antigens between tumor and normal tissues, particularly in cancers with low mutational load and high intratumoral heterogeneity.
Innovation Solution
The development of inhibitory chimeric antigen receptors (iCARs) and protective chimeric antigen receptors (pCARs) that target specific allelic variants of polymorphic cell surface epitopes lost in tumor cells due to loss of heterozygosity (LOH), allowing for safe and effective tumor cell killing while sparing normal cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If shared antigens between tumor and normal tissues are used as targets for CAR therapy, then tumor cells can be recognized and killed, but off-tumor toxicity occurs due to antigen expression on healthy tissue
Solution Approach 1:
The patent divides the antigen recognition task into two separate CARs: one targeting the shared antigen and another targeting the LOH-specific allele. This segmentation allows the immune system to distinguish tumor cells (expressing only one allele due to LOH) from normal cells (expressing both alleles), thereby resolving the contradiction between tumor recognition and off-tumor toxicity
Solution Approach 2:
The patent applies local quality by making each CAR highly specific to a particular allelic variant. The first CAR recognizes the shared antigen while the second CAR recognizes the specific LOH allele, creating localized specificity at the molecular level that enables precise tumor targeting without affecting normal tissues
2Reliability
If pre-selected antigens are used for CAR-T cell therapy, then clinical response can be predicted, but the range of targetable tumors is limited due to lack of suitable targets
Solution Approach 1:
The patent creates a universal platform that can be applied across multiple tumor types by targeting LOH events, which are a fundamental characteristic of cancer biology. This multi-functional approach allows the same CAR-T strategy to be adapted to various cancers regardless of their specific mutations, thereby expanding the range of targetable tumors while maintaining predictability
Solution Approach 2:
The patent changes the targeting parameter from specific tumor mutations to the more universal LOH parameter. Since LOH is a common event across diverse cancer types, this parameter change enables broader applicability while LOH-specific antigens still provide the necessary predictability for clinical response
3Productivity
If conventional CARs targeting shared antigens are used, then tumor cells are killed effectively, but normal cells expressing the same antigen are also damaged
Solution Approach 1:
The patent inverts the conventional approach by instead of trying to find antigens unique to tumors, it targets the absence of one allele (LOH) in tumor cells while normal cells retain both alleles. This inversion strategy allows effective tumor killing while sparing normal cells through the protective CAR that recognizes the missing allele
Data Source
AI summary
The present invention provides a method of identifying a target for preparing an inhibitory chimeric antigen receptor (iCAR) or a protective chimeric antigen receptor (pCAR) capable of preventing or attenuating undesired activation of an effector immune cell. Also provided are a list of iCAR targets, as well as vectors and transduced effector immune cells comprising the nucleic acid molecule and methods for treatment of cancer comprising administering the transduced effector immune cells are further provided.