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In what could be a big step forward for immunotherapy, ”unprecedented NK [natural killer] cell-engaging Nanodrones” that can selectively target specific cancer cells have been developed, by researchers at Ulsan National Institute of Science and Technology (UNIST). This approach, the researchers suggest, could be used to address types of cancers that have been out of reach from immunotherapy so far. 

The study was led by Sebyung Kang and Sung Ho Park in the Department of Biological Sciences at UNIST. Their paper appears in Nanotoday.

Natural killer (NK) cells are a specific type of lymphocyte that is essential for tumor immunosurveillance. These cells prevent early tumor, metastasis, and minimal residual disease. They can directly kill cancer cells by releasing cytotoxic granules containing perforin and granzymes, and cytokines, which recruit other immune cells to the site of the tumor. One of NK cells’ key features is that they do not require the need of antigen processing and presentation. Also, unlike T cells, which must be genetically altered before they are infused to avoid graft vs host disease, HLA mismatched NK cells can be delivered without GVHD risk, which makes them good prospects as off-the-shelf products.

While NK cells have delivered positive responses in hematologic cancers, infusion of these cells in patients with solid tumors have not been encouraging. Preclinical and clinical data suggest that their efficacy in solid tumors is hampered by factors that include inadequate tumor infiltration and factors in characteristics of the tumor microenvironment (TME).

Numerous cancer immunotherapies have been developed to overcome the immune system’s evasion mechanisms and reactivate the human immune system against malignancy. These approaches have largely focused on the adaptive immune system, including T cell-based cancer immunotherapies, such as immune checkpoint inhibitors and chimeric antigen receptor-T cell (CAR-T) therapies.

The cancer immunotherapy market is estimated at over $120B, but only between 20%-to-40% of patients actually respond to them.

Could new NK-based strategies offer a new avenue?

“… recent studies suggest that innate immune cells, including natural killer (NK) cells, are also crucial for successful cancer immunotherapy,” the UNIST team writes.

The team has designed and created NK cell-engaging nanodrones, referred to as NKeNDs, using AaLS protein cage nanoparticles. These NKeNDs simultaneously display cancer-targeting ligands, such as HER2Afb or EGFRAfb, and an NK cell-recruiting ligand, aCD16Nb, on the surface of the AaLS through the group’s SpyCatcher/SpyTag protein ligation system. 

The dual ligand-displaying NKeNDs, dubbed HER2 @NKeND and EGFR@NKeND, selectively bind to HER2-overexpressing SK-OV-3 cells and EGFR-overexpressing MDA-MB-468 cells, respectively, as well as human NK cells.

Engaging the human NK cells with the target cancer cells activates them to eliminate the target cancer cells. In SK-OV-3 tumor-bearing mice, the administration of HER2 @NKeNDs along with human PBMCs facilitates the infiltration of activated human NK cells into the tumor sites. As a result, tumor growth was significantly suppressed without causing noticeable side effects.

Kang said, “This research presents new possibilities for immune treatment through NK cell delivery nanodrones, overcoming challenges such as the movement and survival of NK cells. We aim to provide new opportunities for customized treatments that selectively address various types of cancer through further research, including cancer-specific immune cell induction.”

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