Gene-Regulating Compositions for Enhanced Immune Cell Proliferation
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Solution Overview
Problem
Adoptive cell therapies, such as CAR-T cell treatments, have limited efficacy against solid malignancies and face challenges like reduced T cell proliferation, survival, and function due to tumor environment factors, leading to suboptimal responses in patients with melanoma, renal cell carcinoma, and colorectal cancer.
Innovation Solution
Modified immune effector cells with reduced expression or function of specific endogenous target genes, such as IKZF1, IKZF3, and PTPN2, using gene-regulating systems like siRNA, shRNA, or CRISPR-Cas, to enhance proliferation, infiltration, persistence, and resistance to exhaustion, thereby improving anti-tumor activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T cells are used to treat solid malignancies, then some anti-tumor activity is achieved, but the efficacy is limited due to reduced T cell proliferation, survival, and function
Solution Approach 1:
The patent removes suppressive elements from the T cell system by knocking out genes that inhibit T cell function (TOX, NFATC1, IKZF1, IKZF3, PTPN2). This extraction of harmful genetic factors allows T cells to overcome tumor-induced suppression and maintain proliferative capacity, directly addressing the contradiction between limited efficacy and reduced proliferation.
Solution Approach 2:
The patent fundamentally changes the genetic parameters of T cells by introducing multiple gene knockouts that alter cellular behavior. These parameter changes (gene expression levels) transform T cells from a state of tumor-induced exhaustion to a state of enhanced persistence and function, resolving the contradiction between anti-tumor efficacy and T cell productivity.
2Reliability
If CAR-T cells are transferred to patients, then immune response is activated, but T cell function is inhibited by factors secreted by host immune cells and cancer cells
Solution Approach 1:
The patent applies preliminary anti-action by pre-equipping T cells with genetic modifications (knockouts of TOX, NFATC1, IKZF1, IKZF3, PTPN2) that counteract inhibitory factors before they can suppress T cell function. This preemptive genetic engineering allows T cells to resist tumor-derived suppression and maintain immune response efficacy.
Solution Approach 2:
The patent converts the harmful effect of inhibitory factors into a benefit by selecting and modifying T cells that are genetically resistant to these factors. The very presence of tumor-derived suppressors serves to select for enhanced T cell variants with improved resistance mechanisms, turning the harmful environment into a selective advantage.
3Productivity
If T cells proliferate extensively during manufacturing and after transfer, then adequate cell numbers are achieved, but immune cell exhaustion occurs
Solution Approach 1:
The patent extracts the exhaustion phenotype from proliferating T cells by knocking out genes (TOX, NFATC1, IKZF1, IKZF3, PTPN2) that are responsible for functional decline. This allows T cells to maintain high proliferation capacity during manufacturing and after transfer without suffering from exhaustion, resolving the contradiction between cell numbers and function.
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.