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Highly Efficient Generation of Transgenically Augmented CAR NK Cells Overexpressing CXCR4
Arezoo Jamali1,2,3, Jamshid Hadjati4, Zahra Madjd1,5
1Faculty of Advanced Technologies in Medicine, Department of Molecular Medicine, Iran University of Medical Sciences, Tehran, Iran.
Abstract:
Natural killer (NK) cells are a noteworthy lymphocyte subset in cancer adoptive cell therapy. NK cells initiate innate immune responses against infections and malignancies with natural cytotoxicity, which is independent of foreign antigen recognition. Based on these substantive features, genetically modifying NK cells is among the prime goals in immunotherapy but is currently difficult to achieve. Recently, we reported a fully human CAR19 construct (huCAR19) with remarkable function in gene-modified T-cells. Here, we show efficient and stable gene delivery of huCAR19 to primary human NK cells using lentiviral vectors with transduction efficiencies comparable to those achieved with NK cell lines. These huCAR19 NK cells display specific and potent cytotoxic activity against target cells. To improve homing of NK cells to the bone marrow, we augmented huCAR19 NK cells with the human CXCR4 gene, resulting in transgenically augmented CAR NK cells (TRACKs). Compared to conventional CAR NK cells, TRACKs exhibit enhanced migration capacity in response to recombinant SDF-1 or bone marrow stromal cells while retaining functional and cytolytic activity against target cells. Based on these promising findings, TRACKs may become a novel candidate for immunotherapeutic strategies in clinical applications.
Insights
Genetically engineered natural killer (NK) cells expressing a chimeric antigen receptor (CAR) show potent anti-cancer activity. Augmenting these CAR NK cells with CXCR4 improves their bone marrow homing, creating TRACKS for enhanced cancer immunotherapy.
Area of Science:
- Immunology
- Cell Biology
- Cancer Research
Background:
- Natural killer (NK) cells are crucial lymphocytes for innate immunity against cancer.
- Genetically modifying NK cells for adoptive cell therapy is challenging but highly desirable.
- A fully human CAR19 construct (huCAR19) demonstrated efficacy in T-cells.
Purpose of the Study:
- To achieve efficient and stable gene delivery of huCAR19 to primary human NK cells.
- To evaluate the anti-cancer activity of genetically modified NK cells.
- To enhance NK cell homing to the bone marrow by incorporating the CXCR4 gene.
Main Methods:
- Lentiviral vectors were used for gene delivery of huCAR19 to primary human NK cells.
- Transduction efficiencies were compared between NK cell lines and primary NK cells.
- The migration capacity of modified NK cells was assessed using recombinant SDF-1 and bone marrow stromal cells.
Main Results:
- Efficient and stable gene delivery of huCAR19 to primary human NK cells was achieved.
- huCAR19 NK cells exhibited specific and potent cytotoxic activity against target cells.
- Transgenically augmented CAR NK cells (TRACKs), incorporating CXCR4, showed enhanced migration to bone marrow and retained cytotoxic function.
Conclusions:
- Genetically engineered NK cells, particularly TRACKS, represent a promising strategy for cancer immunotherapy.
- The enhanced homing capacity of TRACKS may improve their efficacy in clinical applications.
- TRACKS offer a novel candidate for immunotherapeutic approaches in cancer treatment.
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