CAR T Cell Combinatorial Antigen Recognition Logic
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Solution Overview
Problem
Current CAR T cell therapies face challenges in specifically targeting solid tumors due to cross-reactivity with normal tissues, as many tumor-associated antigens are also expressed in healthy tissues, leading to toxicity and reduced therapeutic efficacy.
Innovation Solution
Engineering immune cells to produce multiple antigen-triggered polypeptides that recognize specific combinations of cell surface antigens using Boolean logic gates, such as AND and NOT gates, to improve tumor selectivity and reduce off-target toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If single antigen recognition is used in CAR T cells, then the device complexity is low, but the measurement precision of tumor detection is insufficient due to cross-reactivity with normal tissues
Solution Approach 1:
The patent divides the antigen recognition function into multiple independent CAR components, each recognizing a different antigen. Instead of using a single complex CAR, the system employs multiple simpler CARs that work together through logical operations (AND gates) to achieve high-specificity tumor detection while maintaining individual CAR structural simplicity
Solution Approach 2:
The patent creates CAR T cells with multi-functionality by equipping them with multiple CARs that can recognize different antigens. These CARs collectively perform both detection and discrimination functions, allowing the system to achieve high measurement precision through combinatorial antigen recognition patterns unique to tumor cells
2Productivity
If tumor-associated antigens are targeted, then the productivity of tumor cell killing is high, but the object-affected harmful factors increase due to cross-reactivity with normal tissues
Solution Approach 1:
The patent applies local quality by making the activation state of CAR T cells location-specific. Through AND gate logic requiring multiple antigens to be present simultaneously, the system ensures that T cells are activated only in the local tumor microenvironment where the specific antigen combination exists, while remaining inactive in normal tissues, thereby eliminating off-target toxicity while maintaining high tumor cell killing efficiency
Solution Approach 2:
The system implements feedback control through logical integration of multiple antigen signals. The CAR T cell activation is determined by the combined input from multiple antigen recognition events, creating a feedback mechanism that confirms tumor presence through pattern recognition before triggering the killing response, thus preventing premature or incorrect activation that would cause toxicity
Data Source
AI summary
The present disclosure provides immune cells genetically modified to produce two antigen-triggered polypeptides, each recognizing a different cell surface antigen, wherein the two different cell surface antigens employed are selected from those pairs described herein. The present disclosure further provides systems comprising two antigen-triggered polypeptides (or nucleic acids encoding same), each recognizing a different cell surface antigen, wherein the two different cell surface antigens employed are selected from those pairs described herein. Also provided are method of killing a target cancer cell, using the described genetically modified immune cells and/or systems. The present disclosure also provides polyspecific-immune inducing polypeptides including first and second antigen binding domains specific for first and second antigens, respectively, present on the surface of a target cancer cell.