Blocking CARs for Selective Immune Cell Activation
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Solution Overview
Problem
Current CAR T cell therapies face challenges in achieving antigenic selectivity, leading to potential damage to non-tumor tissues due to the lack of tumor-associated antigens that are uniquely expressed by cancer cells without being present in healthy tissues, resulting in on-target off-tumor toxicity.
Innovation Solution
Development of novel blocking chimeric antigen receptors (bCARs) that prevent undesired activation of immune cells by specifically binding to epitopes on normal tissues, thereby allowing selective activation only upon interaction with target cells, such as tumor cells, through the use of extracellular domains longer than 20 nm, single-chain binding domains, and intracellular domains capable of dephosphorylating ITAMs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional CAR T cell therapies are used to treat cancer, then immune cells can be activated to attack tumor cells, but immune cells may also be activated against normal tissues causing on-target off-tumor toxicity
Solution Approach 1:
The CAR structure is segmented into distinct functional domains: an extracellular binding domain that recognizes tumor-specific antigens, a transmembrane domain, and an intracellular signaling domain. This segmentation allows the CAR to distinguish between tumor cells and normal cells by requiring specific antigen recognition before activation, thereby improving selectivity and reducing off-tumor toxicity.
Solution Approach 2:
The patent introduces modular signaling domains with different activation thresholds and signaling strengths at specific locations within the CAR structure. By localizing specific signaling components (such as co-stimulatory domains like CD28 or 4-1BB) to particular positions, the CAR achieves differentiated response characteristics that enhance tumor selectivity while sparing normal tissues.
2Productivity
If CAR T cell therapies are designed to activate immune cells broadly against cancer antigens, then treatment efficacy is improved, but the risk of damaging essential healthy tissue increases
Solution Approach 1:
The CAR is pre-configured with specific binding domains that are engineered to recognize tumor-associated antigens with high affinity and specificity. This preliminary design ensures that immune cells are activated only when they encounter the correct tumor antigens, maintaining high treatment efficacy while preventing activation against healthy tissues that do not express these specific antigens.
Solution Approach 2:
The patent employs systematic variation of CAR parameters including binding affinity, antigen density thresholds, and signaling domain composition to optimize the activation profile. By adjusting these parameters, the CAR achieves a therapeutic window where sufficient activation occurs against tumor cells while activation against normal tissues remains below harmful thresholds.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The bCARs effectively inhibit undesired activation of immune cells against normal tissues, ensuring selective activation only on target cells, thereby reducing toxicity and enhancing the safety and efficacy of CAR T cell therapies.
Implementation Method 1
The binding domain specifically binds to a cell surface epitope present on normal mammalian tissue
Implementation Method 2
a protease cleavage site capable of being cleaved by a protease
Implementation Method 3
an intracellular domain includes a full or partial intracellular domain of a membrane phosphatase capable of dephosphorylating phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs)
Data Source
AI summary
Provided herein are novel blocking chimeric antigen receptors (“bCARs”) and immune cells (e.g., effector and regulatory immune cells) that express such bCARs. Such blocking CARs prevent undesired activation of the immune cells, particularly undesired activation of the immune cells against normal tissue in therapeutic applications. Thus, such bCARs advantageously allow for selective immune cell activation only upon interaction with specific target cells (e.g., tumor cell).