At the end of June this year, the CAR-NK cell, a new immune cell, was reported as the third CAR cell to fight against cancer after CAR-T cells and CAR-macrophage cells.
The NK-CAR-iPSC-NK cells, developed by researchers from the University of California San Diego School of Medicine (UCSD) and the University of Minnesota, are both economical and exceptional, which can effectively fight off ovarian cancer without toxic side effects similar to CAR-T cells. The research report was published in Cell Stem Cell within the same period.
In the cancer immunotherapy field, CAR-T cell therapy and PD-1 inhibitors are two hot stars that both focus on T cells. As a matter of fact, NK cells rather than T cells act as the best fighters against tumors in our body. NK cells born with the ability to identify abnormal cells can kill tumors without advance exposure or activation compared to T cells. When encountering cancer cells, NK cells have already rushed to cancer cells and pave the way to fight back while other cells still remain in resting state. Therefore, NK cells are also called the first defense line against cancers in our body.
1 iPSC-NK cell
Then scientists have also turned their attention to NK cells during the cancer research process. The researchers in this experiment used genetic engineering to transform somatic cells into induced pluripotent stem cells (iPSC) by introducing foreign genes into somatic cells. iPSC is equivalent to a production workshop and raw materials that make it executable to continuously develop NK cells and apply to a majority of patients not limited to a single one.
At the same time, NK cells therapy eliminates the time-consuming and costly process like T cells therapy that extracts immune cells from patients and expands them in vitro. In comparison with CAR-T treatment’s hundreds of thousands of dollars costs, the NK cell therapy made in this way is equipped with both high efficiency and superior quality at a low price.
2 NK-CAR-iPSC-NK
However, iPSC-NK cells alone are not enough to defeat the cunning cancer cells. Like T cells, there also exists a control switch on the surface of NK cells that, once opened, prevents NK cells attacking other cells. The switch, familiar to cancer cells, will be opened to enormously reduce the vitality of NK cells.
Therefore, the researchers found an NK92 cell born without this switch. Based on it, the chimeric antigen receptor CAR4 that specifically recognizes tumors is loaded to further enhance the ability to recognize and kill cancer cells. In this way, with the NK92 cells differentiated by iPSC and the carefully selected CAR4, the NK-CAR-iPSC-NK cells (CAR-NK cells for short) are eventually accomplished.
CAR4-NK cells have the strongest antitumor activity
3 CRS and Neurotoxicity
As for the in vivo animal testing, the researchers prepared a group of mice models with ovarian cancer xenografts to test the anti-tumor activity and side effects of CAR-NK cells, other NK cells and CAR-T cells. The results showed that CAR-NK cells overwhelmingly completed the testing as well as one might expect compared with other NK cells. During the 49-day experiment, tumor load was significantly reduced in four mice injected with CAR-NK cells. On the 7th day of the injection, the tumor load of the first mouse was almost invisible.The red and blue blocks in the figure are tumor burdens of ovarian cancer in mice labeled with fluorescence. The smaller the tumor load, the stronger the antitumor activity of the cells.
The red and blue blocks in the figure are tumor burdens of ovarian cancer in mice labeled with fluorescence. The smaller the tumor load, the stronger the antitumor activity of the cells.
In terms of survival rate, other NK cells showed a significant decrease on the 80th day and even the 40th day while CAR-NK cells did not disappear until the 100th day.
At the same time, CAR-NK not only succeeds in drawing level with CAR-T cells in the aspect of antitumor activity but also is superior to CAR-T with almost no toxic side effects.
Although the specific mechanism is still under investigation, it is reported that elevated cytokines IL-6, TNF, and IFN are associated with severe cytokine storms and neurotoxicity of CAR-T.
In this experiment, cytokines in mice using CAR-T showed different degrees of increase, reaching a relatively high level on the 20th day. While CAR-NK cells showed a transient increase on the second day after injection, the cytokines decreased a lot on the 10th day, and on the 20th day, there were almost no CAR-NK cells in the mice body.
Cytokine storms and neurotoxicity have been two difficult challenges all the time that are too severe and even lead to death. So, FDA also approved the drug to treat cytokine storm when it approved the listing of CAR-T products.
The CAR-NK cells not just eliminated these two fatal side effects but also ensured the same efficacy as CAR-T. Even more surprising is that the preparation process of CAR-NK is shorter and faster. And the iPSC helps to apply CAR-NK to various people without boundaries. We all look forward to the entry of this cheap and safe therapy into clinical trials as soon as possible for the benefit of cancer patients.
Reference
- Ye Li, David L. Hermanson 4, Branden S. Moriarity, et al. Human iPSC-Derived Natural Killer Cells Engineered with Chimeric Antigen Receptors Enhance Anti-tumor Activity, Cell Stem Cell (2018)