PS-Targeted CAR-T Cells Killing Apoptosis-Resistant Tumor Cells
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Solution Overview
Problem
Current cancer therapies assume that phosphatidylserine (PS)-expressing tumor cells will undergo apoptosis, but these cells may survive the activation of the apoptosis cascade, leading to an unmet medical need for ensuring complete cell death of PS-expressing tumor cells.
Innovation Solution
Development of a chimeric antigen receptor (CAR) specific for phosphatidylserine (PS), comprising a signal peptide, an antigen binding domain, a hinge domain, a transmembrane domain, and an intracellular domain with immunoreceptor tyrosine-based activation domains (ITAMs) and/or co-stimulatory domains, to target and eliminate PS-expressing tumor cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional cancer therapies target phosphatidylserine-expressing tumor cells to induce apoptosis, then tumor cell death is achieved, but some tumor cells survive the apoptosis cascade activation
Solution Approach 1:
The patent introduces an intermediary mechanism (CAR-T cells with granzyme B and perforin) to mediate tumor cell killing. Instead of relying solely on apoptosis induction, the CAR-T cells directly kill PS-expressing tumor cells through cytotoxic granule release, ensuring complete elimination of target cells including those that resist apoptosis
Solution Approach 2:
The patent changes the killing mechanism parameter from apoptosis induction to direct cytotoxicity. By equipping CAR-T cells with granzyme B and perforin, the system switches from a biochemical apoptosis pathway to a physical pore-forming mechanism that directly lyses tumor cells, bypassing apoptosis resistance
2Measurement precision
If phosphatidylserine is used as a target marker for tumor cells, then specific targeting is achieved, but the ability to ensure complete cell death is compromised
Solution Approach 1:
The patent merges two functions into a single CAR-T cell system: (1) specific targeting of PS-expressing tumor cells through the CAR's antigen binding domain, and (2) direct cytotoxic killing through granzyme B and perforin. This combination ensures both high targeting specificity and complete cell death by eliminating reliance on apoptosis alone
Data Source
AI summary
Disclosed herein are compositions comprising a chimeric antigen receptor targeting phosphatidylserine on the surface of cancer cells and methods of using the compositions to treat a cancer in a subject.