Gene-Edited Immune Cells for Solid Tumor Infiltration
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Solution Overview
Problem
Current adoptive cell therapies for cancer treatment, such as CAR-T cell therapies, have limited efficacy against solid malignancies and are hindered by issues like reduced T cell proliferation, survival, and function due to tumor environment factors and immune cell exhaustion.
Innovation Solution
Modification of immune effector cells to reduce expression or function of specific endogenous genes like ZC3H12A, BCL2L11, and others using CRISPR/Cas systems, siRNA/shRNA, and antibodies, enhancing proliferation, infiltration, persistence, and resistance to exhaustion, thereby improving anti-tumor efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T cell therapy is used to treat hematological malignancies, then patient response rate is improved, but efficacy against solid malignancies deteriorates
Solution Approach 1:
The patent modifies the functional parameters of T cells by reducing expression of endogenous genes that limit T cell function. Specific genes targeted include ZC3H12A (which regulates T cell proliferation and survival), BCL2L11 (which controls apoptosis), and other genes involved in T cell exhaustion. By changing the molecular parameters of the T cells through gene editing, the therapy achieves improved efficacy across both hematological and solid malignancies
Solution Approach 2:
The patent extracts and removes the limiting factors (specific endogenous genes) that prevent T cells from functioning effectively against solid tumors. By using CRISPR/Cas systems and other gene editing tools to knock out or reduce expression of genes like ZC3H12A, BCL2L11, and others, the therapy removes the biological constraints that previously limited adaptability to different cancer types
2Reliability
If T cells are adoptively transferred to treat cancer, then anti-tumor activity is improved, but T cell proliferation and survival deteriorate due to tumor environment factors
Solution Approach 1:
The patent applies preliminary anti-action by pre-modifying T cells ex vivo to resist the harmful effects of the tumor microenvironment before transfer. The T cells are genetically engineered to reduce expression of genes that make them vulnerable to exhaustion and apoptosis, such as ZC3H12A (which promotes T cell death) and BCL2L11 (which regulates apoptosis). This preliminary modification protects the T cells from the adverse tumor environment, enabling sustained proliferation and long-term anti-tumor activity
Solution Approach 2:
The patent performs preliminary actions on T cells during the manufacturing process by editing their genome to enhance survival capabilities. Genes involved in metabolic pathways, exhaustion markers, and apoptosis regulation are modified before the cells are activated and expanded. This preliminary genetic conditioning ensures that the adoptively transferred cells are pre-equipped to withstand the challenging tumor environment and maintain function over extended periods
3Quantity of substance
If T cells are activated and expanded ex vivo, then cell numbers are improved, but cell function deteriorates due to exhaustion during manufacturing
Solution Approach 1:
The patent applies preliminary genetic modification to T cells before activation and expansion to prevent exhaustion during the manufacturing process. By knocking out or reducing expression of exhaustion-associated genes (such as ZC3H12A, PD-1, and other inhibitory receptors) prior to culture expansion, the T cells maintain their functional potential throughout the manufacturing process. This allows for robust cell number expansion without the typical loss of cytotoxic function that occurs in conventional protocols
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.