Gene-Regulating Compositions for Enhanced Immune Cell Efficacy
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Solution Overview
Problem
Current adoptive cell therapies, particularly CAR-T cell therapies, have limited efficacy in treating solid malignancies and exhibit relapses due to diminished T cell function and exhaustion.
Innovation Solution
Modified immune effector cells with reduced expression and/or function of specific endogenous target genes, such as BCL2L11, SOCS1, and ANKRD11, using gene-regulating systems like siRNA, shRNA, or guide RNA molecules, to enhance effector functions like proliferation, infiltration, persistence, and resistance to exhaustion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T cell therapy is used to treat solid malignancies, then some anti-tumor response may be achieved, but therapeutic efficacy is limited and relapses occur due to diminished T cell function
Solution Approach 1:
The patent applies preliminary action by modifying T cells ex vivo before infusion to preemptively address functional limitations. Specifically, the T cells are engineered to express inhibitory receptor modulators that prevent exhaustion and enhance persistence before the cells are administered to the patient, thereby preparing them to maintain functional activity throughout the treatment course and beyond.
Solution Approach 2:
The patent changes key parameters of T cell function by modulating the expression levels of inhibitory receptors (such as PD-1, CTLA-4, LAG-3, TIGIT) through gene editing or transduction. This parameter modification enables the T cells to overcome inhibitory signals from the tumor microenvironment, thereby extending their functional duration and improving therapeutic efficacy in solid malignancies.
2Productivity
If adoptive cell transfer is performed, then anti-tumor activity may be generated, but cell proliferation is limited following transfer
Solution Approach 1:
The patent applies preliminary action by pre-modifying T cells ex vivo to enhance their proliferative capacity before infusion. The cells are engineered with genetic modifications or transduced with vectors that promote cell cycle progression and prevent apoptosis, enabling them to expand rapidly upon administration and generate sufficient anti-tumor activity.
Solution Approach 2:
The patent changes proliferative parameters of T cells by modifying expression of cell cycle regulators, survival factors, and metabolic genes. This parameter modification enables the cells to undergo robust proliferation following transfer, thereby increasing the magnitude of the anti-tumor response.
3Reliability
If T cells are transferred to treat cancer, then initial anti-tumor response may be achieved, but cell survival is reduced due to induction of apoptosis by tumor environment factors
Solution Approach 1:
The patent applies preliminary action by pre-engineering T cells with enhanced survival mechanisms before infusion. The cells are modified to express anti-apoptotic proteins, cytokine producers, or metabolic enzymes that protect them from tumor-induced apoptosis, thereby ensuring their survival and persistence in the host.
Solution Approach 2:
The patent changes survival parameters of T cells by modifying expression of BCL-2 family members, death receptor ligands, and metabolic pathways. This parameter modification confers resistance to apoptosis induced by tumor microenvironment factors, thereby extending T cell survival and maintaining anti-tumor response.
4Power
If T cells are used for immunotherapy, then cytotoxic function may be exerted, but cell function is inhibited by inhibitory factors secreted by host immune cells and cancer cells
Solution Approach 1:
The patent converts the harmful inhibitory signals from the tumor microenvironment into beneficial effects by engineering T cells to express inhibitory receptor modulators. These modulators bind to inhibitory receptors (PD-1, CTLA-4, etc.) and prevent their interaction with ligands, thereby transforming the inhibitory environment into a permissive one that enhances cytotoxic function.
Solution Approach 2:
The patent changes the functional parameters of T cells by modulating the expression and activity of inhibitory receptors. This parameter modification alters the cell's response to inhibitory factors, enabling maintained or enhanced cytotoxic function despite the presence of suppressive signals from host immune cells and cancer cells.
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 modified immune cells demonstrate enhanced anti-tumor effects by improving cell proliferation, infiltration, persistence, and function, leading to increased therapeutic efficacy against both hematological and solid malignancies.
Implementation Method 1
The disclosure relates to methods, compositions, and components for editing a target nucleic acid sequence, or modulating expression of a target nucleic acid sequence
Implementation Method 2
using guide RNA molecules to enhance effector functions
Implementation Method 3
using gene-regulating systems like siRNA, shRNA, or guide RNA molecules
Implementation Method 4
using gene-regulating systems like siRNA, shRNA, or guide RNA molecules
Data Source
AI summary
The present disclosure provides methods and compositions related to the modification of immune effector cells to increase therapeutic efficacy. In some embodiments, immune effector cells modified to reduce expression of one or more endogenous target genes, or to reduce one or more functions of an endogenous protein to enhance effector functions of the immune cells are provided. In some embodiments, immune effector cells further modified by introduction of transgenes conferring antigen specificity, such as exogenous T cell receptors (TCRs) or chimeric antigen receptors (CARs) are provided. Methods of treating a cell proliferative disorder, such as a cancer, using the modified immune effector cells described herein are also provided.