Chimeric Antigen Receptor Therapy, but Using Natural Killer Cells

Adding chimeric antigen receptors to T cells (CAR-T), causing them to aggressively target cancer cells, has proven to be a fruitful approach to the treatment of cancer. Like most immunotherapies, it can result in potentially severe side-effects related to excessive immune activation, but it is also quite effective. Treatment of forms of leukemia in particular has produced good results in a large fraction of patients who have trialed the therapy. In the research reported here, scientists extend the chimeric antigen receptor approach to natural killer cells rather than T cells, noting that this may prove to be both safer and logistically easier to deploy to large numbers of patients.

Genetically engineered T cells that destroy cancer cells have proven to be promising options when other treatments fail. However, there's currently no one-size-fits-all CAR T, and each patient needs his own bespoke intervention. Now, researchers report that natural killer cells, grown from human induced pluripotent stem (IPS) cells and modified in a similar way to CAR-T cells, are effective against ovarian cancer in a mouse model. The result paves the way for developing an "off the shelf" immunotherapy that doesn't need to be personalized for each patient. Natural killer (NK) cells, which play an important role in tumor surveillance, offer a key advantage over T cells in that they kill some cancer cells without requiring tumor-specific cell-surface receptors, meaning they can work in many patients.

CAR-T cell therapies are built by harvesting a patient's T cells and genetically modifying them to produce so-called chimeric antigen receptors (CARs) that direct them to destroy cancer cells. Two such immunotherapies were approved last year. Unmodified NK cells isolated from peripheral blood or umbilical cord blood have also been shown to be effective against acute myelogenous leukemia in several clinical trials, and a few trials testing NK cells equipped with CARs in other forms of blood cancer have begun. But developing a means of deriving NK cells from stem cells would allow researchers to generate hundreds of thousands of doses that are standardized.

The team created the mouse models by transplanting human ovarian cancer cells into mice whose immune systems had been suppressed to prevent them from rejecting the human cells. The scientists then infused the CAR-NK cells into the animals, and for comparison, did the same for CAR-T cells. They noted that the mice treated with the iPSC-derived CAR-NK cells and those treated with CAR-T cells both had shrunken tumors after 21 days. The researchers were surprised to find that, compared to the mice treated with CAR NKs, the animals that had received the CAR-T cell treatment appeared to be in worse shape: they had damage in organs such as the liver, lungs, and kidneys and an increase in inflammatory cytokines. "The mice that got the CAR-T cells actually wound up getting sick, losing weight, and getting these toxicities, whereas the CAR-NK-cell-treated mice didn't."



"Beatriz Martín Antonio, a postdoc at Josep Carreras Institute and the August Pi i Sunyer Biomedical Research Institute in Spain, isn't convinced the results suggest that CAR NKs are safer. She suggests that the toxicities could have been due to the human T cells attacking the mouse immune system, because of species-specific differences. The same experiments ought to be repeated with CAR-expressing cells engineered from mice, she adds."

So the experiment needs to be repeated, but if the results hold up with mouse IPS derived CAR NK cells then this could be great news.

Posted by: Jim at July 9th, 2018 7:15 AM

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