CAR-NK Cell Therapy: Safer Choice to Treat Tumors

Posted by Candy Swift on February 13th, 2020

Chimeric antigen receptor T cell (CAR-T) therapy that use genetically modified T cells to kill cancer cells has proven to be a promising method to treat various diseases. However, there is currently no CAR-T cell therapy suitable for all patients, which means each patient needs to customize their own CAR-T cells.

It has reported that researchers from the University of California, San Diego, and the University of Minnesota cultured natural killer cells (NK cells) using human induced pluripotent stem cells (iPS cells) and modified in a manner similar to CAR-T cells, which are highly effective to treat ovarian cancer in mouse models. An additional trial conducted in Europe in 2019 tested CAR NK cell therapy in patients with brain cancer glioblastoma. Patients with B-cell lymphoma will receive stem cell transplantation and chemotherapy before CAR NK cell formation to remove residual cancer cells. So, what are NK cells?

NK cells are mainly derived from bone marrow CD34+ lymphocytes, which can identify and lyse virus-infected cells and tumor cells and produce immunomodulatory cytokines. It is an important non-specific immunoregulatory cell for anti-infection and prevention of malignant transformation of cells in the human body, and is mainly distributed in the blood, liver, spleen, bone marrow and other parts of the human body. Degranulation, cytokine release, and cell killing function of NK cells are regulated by a variety of receptors that are mainly divided into NK cell inhibitory receptors (KIR) and activating receptors (KAR).

There are three main steps for NK cells to kill tumor cells. Firstly, NK cell secrets cellular plasmids, which contain cytotoxic granules such as perforin and granzyme. Then, it expresses tumor necrosis factors, such as Fas ligand and tumor necrosis factor-related inducing ligand (TRAIL), to induce apoptosis. At last, it binds to the Fc segment of tumor antigen-specific antibodies by expressing FcγRIII (CD16) to mediate antibody-dependent cell-mediated cytotoxicity (ADCC).

Similar to T cells, PD-1 and CTLA4 are also expressed on the surface of NK cells. It has been shown that blockade with PD-1 and CTLA4 can significantly improve the anti-tumor effect of NK cells. At the same time, NK cells also have their own immune escape mechanism. For example, tumor cells encapsulated by platelets release immunosuppressive factors such as TGFβ. Common tumor cells also secrete substances such as PGE2, Adenosine, and IL10 that inhibit NK cell function.

What are advantages of CAR-NK cell therapy?

First, NK cells can come from a wide range of sources. In addition to the successful clinical translation of NK cells derived from peripheral blood and cord blood, NK cell lines such as NK-92, KHYG-1, NKL, NKG all have excellent anti-tumor efficacy. Compared with primary NK cells, NK-92 cells do not need to be extracted from the patient's blood and are easier to culture and genetically modify in vitro, likely to be applied to allogeneic adoptive transfer.

Apart from convenient preparation and application, CAR-NK is also considered to be safer than common CAR-T. The survival time of primary NK cells in the human body is extremely short, generally a few days to two weeks. NK-92 cells need to be irradiated at a specific dose before injection to ensure that the cells do not proliferate in vivo, but can maintain the cell killing ability before irradiation. CAR-NK can therefore avoid the side effects of CAR-T therapy due to prolonged survival in the circulatory system and targeting to non-tumor cells to some extent.