CAR-T Cell RINF Knockdown for Longer In Vivo Persistence
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current CAR T-cell therapies for cancer treatment suffer from limited persistence and efficacy, particularly in solid malignancies, due to the lack of in vivo persistence of CAR-T cells, and there is a need for safer strategies that do not increase the risk of transformation into T-cell lymphoma/leukemia.
Innovation Solution
Inhibition or knockdown of the Retinoid-Inducible Nuclear Factor (RINF) gene in CAR-T cells using a lentiviral vector approach to enhance T-cell proliferation and persistence, applicable to both cancer and non-cancer diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T cells are used to treat cancer, then tumor eradication efficacy is improved, but in vivo persistence of CAR-T cells is insufficient
Solution Approach 1:
The patent applies parameter changes by targeting and modulating the expression level of the RINF gene in CAR-T cells. By reducing RINF expression through methods such as shRNA-mediated knockdown or CRISPR/Cas9 gene editing, the patent alters a molecular parameter that controls T-cell persistence and proliferation, thereby extending the duration of action of CAR-T cells in vivo while maintaining tumor eradication efficacy
2Duration of action of stationary object
If epigenetic factors are targeted to improve T-cell persistence, then long-term persistence is enhanced, but risk of transformation into T-cell lymphoma/leukemia increases
Solution Approach 1:
The patent applies the extraction principle by identifying and isolating RINF as a specific molecular target that mediates T-cell persistence without being involved in oncogenic transformation. By extracting and targeting RINF specifically, the patent achieves long-term persistence enhancement while avoiding the harmful effects associated with targeting broader epigenetic factors or tumor suppressor genes that could lead to transformation into T-cell lymphoma/leukemia
3Duration of action of stationary object
If RINF expression is reduced in CAR-T cells, then persistence and proliferation are improved, but gene silencing mechanism complexity increases
Solution Approach 1:
The patent applies the disposable principle by utilizing transient, non-integrating RNA interference mechanisms (such as shRNA expressed from plasmids or viral vectors that do not integrate into the host genome) to achieve RINF knockdown. This approach provides sufficient persistence enhancement without requiring complex, permanent genetic modifications, thereby reducing the long-term complexity of the gene silencing mechanism while maintaining therapeutic efficacy
Data Source
AI summary
The present invention relates to the adoptive therapy using notably CAR-T cells. Here the inventors used a lentiviral vector approach to silence RINF expression in a shRNA-dependent manner and evaluate the consequences of RINF silencing on human CAR-T cells proliferation ex vivo and their functionality and capacity to eradicate tumor cells in vivo. More, the proposed methodology to improve CAR-T cells persistence and efficacy by disrupting RINF/CXXC5 is not restricted to patients suffering from hematological or solid cancers (anti-CD19, anti-EGFR, anti-BCMA . . . ) but could be also used to improve the efficacy of ACT in non-cancer diseases by such as lupus (1), cardiac fibrosis (2) or aging related-disorders (3). Thus, the present invention relates to an immune cell characterized in that it is defective for RINF.