CAR T Cell Persistence via Anti-Phagocytic Signal Modulation
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Solution Overview
Problem
Current CAR T cell therapies face challenges in solid tumors due to immune clearance by macrophages, which reduces their efficacy, and there is a need for compositions and methods to modulate the activity and persistence of engineered T cells.
Innovation Solution
Engineered lymphocytes overexpressing anti-phagocytic signaling proteins, such as CD47, to inhibit immune clearance and enhance persistence and efficacy, and a method to deplete engineered T cells by blocking these signals when toxicity occurs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR T cells are administered to treat solid tumors, then antitumor activity is induced, but immune clearance by macrophages reduces their persistence and efficacy
Solution Approach 1:
The patent applies preliminary anti-action by pre-equipping CAR T cells with anti-phagocytic signals (such as CD47 overexpression) before administration. This pre-established protective mechanism prevents macrophage-mediated phagocytosis from the outset, allowing CAR T cells to persist longer in the tumor microenvironment and maintain antitumor efficacy without being rapidly cleared by macrophages.
2Reliability
If CAR T cells are administered to treat solid tumors, then antitumor activity is induced, but immune clearance by macrophages reduces their expansion
Solution Approach 1:
The patent applies preliminary anti-action by pre-equipping CAR T cells with anti-phagocytic signals (such as CD47 overexpression) before administration. This pre-established protective mechanism prevents macrophage-mediated phagocytosis from the outset, allowing CAR T cells to persist longer in the tumor microenvironment and maintain antitumor efficacy without being rapidly cleared by macrophages.
3Duration of action of moving object
If anti-phagocytic signals are overexpressed on CAR T cells, then persistence and expansion are improved, but ability to control or deplete cells is reduced
Solution Approach 1:
The patent applies dynamics by making the anti-phagocytic signal expression controllable and adjustable. The system can dynamically switch between high expression (to protect and persist) and low or no expression (to allow depletion when needed). This dynamic control enables the same CAR T cell product to adapt to different therapeutic requirements, including both persistence enhancement and safety-controlled depletion.
Solution Approach 2:
The patent applies parameter changes by modifying the expression level of anti-phagocytic signals as a controllable parameter. By adjusting this parameter (from high expression for protection to low or zero expression for depletion), the system can achieve different therapeutic outcomes. This parameter control allows clinicians to optimize CAR T cell persistence when needed while maintaining the ability to deplete cells for safety management.
4Duration of action of moving object
If macrophage interaction with T cells is reduced, then CAR T cell clearance is decreased, but immune response modulation is limited
Solution Approach 1:
The patent applies local quality by differentiating the macrophage interaction mechanism: anti-phagocytic signals (like CD47) are localized to prevent phagocytosis and protect CAR T cells from clearance, while other macrophage interaction pathways (such as MHC-TCR dependent activation) remain intact to enable immune response modulation. This spatial and functional differentiation allows simultaneous protection from clearance and maintenance of immune modulatory capabilities.
Data Source
AI summary
Provided herein are engineered lymphocytes which overexpress one or more anti-phagocytic signaling proteins, and methods of using same to induce an immune response against cancer cells by inhibiting immune clearance of the engineered T cells. Also provided is a method of depleting engineered T cells in a subject by administering to the subject an agent that inhibits the activity of one or more anti-phagocytic signaling proteins expressed by the engineered T cells.