The Birth of CAR-NK: a “Sword” turned “Missile”

As an essential component of the human immune system, Natural Killer (NK) cells are capable of eliminating a variety of immunological enemies such as bacteria, viruses, and parasites from the body. NK cells were first noticed for their ability to kill tumor cells without any priming or prior activation and are best known for killing virally infected cells, as well as for detecting and controlling early signs of cancer.

As a variation on the comparatively more established CAR-T cell therapies, CAR-NK cell therapies promise better toxicity characteristics against cancer cells, while also promising reduced side effects in patients receiving treatment.

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Now, with the continuous development of gene and cell therapy technology, this “guard with a sword,” trained in genetic engineering methods, has evolved into a modern “special force” equipped with “precision-guided missiles,” targeting human tumors, CAR-NK.

The birth of CAR-NK: the “first sigh”

The earliest CAR-T cells were born in the 1980s. Researchers at the time extracted T cells from patients and genetically modified them to express Chimeric Antigen Receptors (CARs) specific for cancer-related antigens so that the T cells infused into the patient could better recognize and kill cancer cells.

Since then, CAR-T research has mainly focused on improving the efficacy of CAR-T cell therapy for cancer. To this end, the researchers used methods such as adding costimulatory signals and cytokine secretion to cells. The second-generation and third-generation CAR-T produced after further genetic modification have successfully alleviated the symptoms of some patients, but failed to fully address remaining side effects such as Cytokine Release Syndrome (CRS) and neurotoxicity.

As a result, many researchers have turned their attention to natural killer cells with their innate tumor-killing capabilities. Compared with CAR-T, CAR-NK has better toxicity characteristics to cancer cells, while also reducing the often distressing side effects experienced by patients receiving treatment. Another consideration that gets side-stepped by the use of NK cells as a base instead of T cells, is the need to “match” the patient’s genes with the CAR-modified T cell to avoid development of graft versus host disease. Moreover, as a result of prolonged combat with cancer, many patients suffer from immunosuppression, resulting in host T cells that lack the immunological “combat power” that they would otherwise have if taken from a healthy host patient.  When the patient’s T cells cannot be used, a complex gene editing process is required to generate allogeneic CAR-T cells, which takes a great deal of time and effort to produce. In contrast, there is no such requirement for allogeneic CAR-NK cell therapy, thus making it far more versatile and applicable to various therapeutic situations. Currently, researchers are actively conducting various clinical studies on CAR-NK cells, including on their use for treating hematological tumors and solid tumor cancers.

Examples of preclinical studies of CAR-NK

T follicular helper cells (TFH) can interact with B cells to induce differentiation of B cells and produce high-affinity antibodies that provide long-term immunity to the human body after infection and vaccination. However, the dysregulation of TFH cells is closely related to the formation and development of various autoimmune diseases and T cell malignancies, and the frequency of TFH in peripheral blood is a characteristic indicator of the degree of disease progression. Therefore, TFH cells have become one of the main points of focus for developing novel therapies as a key target for regulating the aforementioned diseases and disorders.

In an article published in the Cell Reports Medicine, Dr. Seth Reighard and collaborators, showed that CAR-NK cells could reduce the expression of the human programmed cell death protein 1 (PD-1), a cardinal feature of follicular T cells [1]. This method could effectively reduce or eliminate TFH cells in peripheral blood and provides an exciting theoretical basis for using CAR-NK cells to treat TFH-driven diseases. To test the role of CAR-NK-92 cells in the body, the researchers constructed a humanized mouse model of lupus-like disease. They reported that CAR NK cells selectively eliminated PD-1+ T cells in vivo

In the same study, researchers found CAR NK-92 cells in the spleen and liver of the recipient humanized mice. However, to treat autoimmune diseases by reducing TFH cells, CAR-NK cells may have to enter areas such as follicular tissues and germinal centers. Subsequent clinical application research will need to test this promising strategy on human cells and verify the migration of CAR-NK cells to these important targets, which may require further genetic modification of CAR-NK cells.

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[1] Reighard, Seth D., et al. “Therapeutic targeting of follicular T cells with chimeric antigen receptor-expressing natural killer cells.” Cell Reports Medicine 1.1 (2020): 100003.