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Natural killer cells: the making of cancer cell assassins

Researchers have engineered natural killer cells to target HER2-expressing cancer cells, which they have found to be a potent and safe form of immunotherapy against solid tumours.

Chimeric antigen receptor (CAR) T cells are one of the main drivers of cancer immunotherapy. This approach equips a patient’s T cells with genetically engineered receptors that recognise and bind to a specific antigen. As a result, CAR-T cells are directed to attack antigen-expressing tumour cells.

CAR-T cell therapy exhibits remarkable clinical efficacy against haematological malignancies. However, their use against solid tumours has been much more limited and often results in life-threatening side effects. This is mostly because CAR-T cells indiscriminately attack cells expressing their target antigen, including healthy cells with low expression levels.

There is an ongoing effort to develop safe alternatives for CAR-based immunotherapies against solid tumours. One promising approach harnesses natural killer (NK) cells. These cells have an innate ability to distinguish healthy from malignant cells and are central in tumour immunosurveillance. However, previous attempts at adoptive NK cell therapy against solid malignancies have been limited by the immunosuppressive tumour microenvironment.

Natural killer cells against solid tumours

In this study published in iScience, researchers at McMaster University have generated CAR-NK cells targeting human epidermal growth factor receptor 2 (HER2). This antigen is overexpressed in epithelial carcinomas, such as breast, ovarian and gastric cancers. In some normal tissues, HER2 retains basal levels of expression.

The engineered HER2 CAR-NK cells displayed elevated cytotoxicity and inflammatory cytokine production against human HER2-expressing cancer cells in vitro. This demonstrated that CAR expression can redirect NK cells and elicit a potent cytotoxic attack against specific solid tumours.

A killer advantage to other cancer immunotherapies

Strikingly, the researchers observed that HER2 CAR-NK cells exhibited higher cytotoxicity against breast cancer cells than HER2 CAR-T cells in vitro. More promisingly, HER2 CAR-NK cells did not exert unwanted cytotoxic effects or cytokine production against non-malignant, HER2-expressing lung epithelial cells. In contrast, HER2 CAR-T cells exhibited uncontrolled activation against healthy epithelial cells.

These CAR-NK cells may also overcome challenges faced in adoptive NK cell therapy. This approach had previously faltered due to the abundance of immunosuppressive factors in the solid tumour microenvironment. These factors, such as TGF- and PGE2, downregulate the anti-tumour functions of NK cells. Impressively, the HER2 CAR-NK cells generated in this study maintained cytotoxicity even after exposure to TGF- and PGE2.

Further in vivo work is necessary to confirm the anti-tumour efficacy, persistence and safety of HER2 CAR-NK cells. Nevertheless, this study demonstrated the superior potency and safety of CAR-NK cells over other immunotherapies in the context of solid tumours. Expanding this work to target other tumour-specific antigens may finally allow for efficacious treatments against solid tumours to be developed.

Image credit: National Cancer Institute – Unsplash

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Cancer / CAR-T Cell / Immunotherapy