T Cell Homing Receptor Modification for Reduced Tissue Toxicity
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Solution Overview
Problem
Current cancer therapies using T cells often face challenges with unintended trafficking to normal cells, leading to side effects, as these cells express adhesion molecules and chemokines that direct them to tissues expressing similar ligands, causing damage to healthy tissues alongside cancerous ones.
Innovation Solution
Genetic modifications are introduced into T cells to inhibit the expression or activity of proteins like α4β7 integrin and CCR9, which are involved in trafficking, allowing these cells to specifically target cancer cells while minimizing interaction with normal cells by blocking their homing to intestinal or CNS sites.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T cells are used to target cancer cells expressing specific antigens, then therapeutic efficacy is improved, but unintended trafficking to normal cells expressing the same antigens causes toxicity to healthy tissues
Solution Approach 1:
The patent applies local quality by making the T cells heterogeneous in their trafficking properties. Specifically, the T cell population includes cells with different expression levels of homing receptors (such as α4β7 integrin and CCR9), creating subpopulations with different tissue tropism. This allows the therapy to target cancer cells while reducing unintended accumulation in specific normal tissues that express the corresponding ligands (MAdCAM-1 in gut, CCL25 in gut and CNS), thereby reducing local toxicity while maintaining overall therapeutic efficacy
Solution Approach 2:
The patent employs parameter changes by modifying the expression levels of homing receptors on T cells through genetic engineering. By altering the expression parameters of molecules like α4β7 integrin and CCR9, the patent changes the trafficking behavior of T cells. This parameter modification allows control over which tissues the T cells home to, enabling optimization of therapeutic effect while minimizing toxicity to specific healthy tissues that would otherwise be damaged by unintended homing
2Measurement precision
If T cells express homing receptors to target specific tissues, then tissue-specific targeting is improved, but accumulation in normal tissues expressing ligands causes side effects
Solution Approach 1:
The patent applies partial action by creating a T cell population where not all cells express homing receptors at high levels. Instead of uniformly equipping all T cells with strong homing capabilities (excessive action), the patent uses a mixed population where some cells have reduced or modified homing receptor expression. This partial approach maintains sufficient targeting capability for cancer cells while reducing excessive accumulation in normal tissues, thereby minimizing side effects
Solution Approach 2:
The patent makes the T cell population heterogeneous with different local qualities in terms of homing receptor expression. This creates subpopulations with different trafficking preferences, allowing some cells to target cancer cells effectively while others have reduced tendency to accumulate in specific normal tissues. This local quality variation reduces side effects while preserving tissue-specific targeting capability
Data Source
AI summary
Isolated pluralities of T cells which recognize at least one epitope of an intestinal cancer antigen or CNS cancer antigen and pharmaceutical compositions comprising the same are disclosed. Methods of making a plurality of T cells that recognize at least one epitope of an intestinal cancer antigen or CNS cancer antigen are also disclosed. Methods of treating an individual who has been diagnosed with cancer of a mucosal tissue or preventing such cancer in an individual at elevated risk are disclosed as are nucleic acid molecules that comprise a nucleotide sequence that encode proteins that recognize at least one epitope of an intestinal cancer antigen or CNS cancer antigen and T cells comprising such nucleic acid molecules.