A New Modified Molecule Helps to Tailor Effective Anti-Cancer Response

A mouse study published in Cell Chemical Biology reveals that a new version of the foreign fat molecule alpha-galactosylceramide (a-GalCer) is very successful at inducing inflammatory and anti-tumor responses in humans. The results of this study may be helpful in creating treatments that will prevent the spread of cancer.

Past studies have shown that synthetic-GalCer, or different variants of it, can successfully stimulate anti-cancer immune responses in mice by inciting their natural killer T-cells (NKT). NKT cells are a subtype of T-cells that search the body for stressed or irregular cells, so they are crucial in encouraging immune responses in the body, especially anti-tumor responses. These cells work either to directly destroy cancer cells or to trigger other immune cells. The immune responses of these cells become active when they identify foreign fat molecules. The cells quickly produce a large number of cytokines, molecules that help arrange communication between immune system cells.

Scientists have found that a-GalCer molecules are very powerful stimulators of these NKT cells with anti-cancer responses, which allow them to be successful in treating cancer through cell-targeted immunotherapy. Although studies have shown that aGalCer and its variants have been successful in stimulating anti-cancer immune responses in mice, there have been very few responses in human patients. Researchers attribute those results to the particular compounds that are stimulating NKT cells: they believe that the compounds produce cytokines with inconsistent effects in the body, sometimes being pro-inflammatory and sometimes anti-inflammatory, and that creates the unsuccessful and irregular immune responses. Thus, researchers have developed an improved a-GalCer compound, AH10-7, that creates a specific type of pro-inflammatory cytokines, Th1 cytokines, that produce effective anti-tumor immune responses.

Researchers made changes to the chemical make up of an a-GalCer molecule, which ultimately made the molecule more secure, developed its ability to be recognized by NKT cells, and prompted a more precise anti-tumor response. Amy Howell, PhD, a chemistry professor at the University of Connecticut, says that the team’s goal was to determine compounds that create a more nuanced response from NKT cells, and they were successful in being able to do that with AH10-7.

The team tested AH10-7 in mice with melanoma, and one of the mouse models was partially “humanized,” which means it had been genetically modified to simulate human NKT cell response. AH10-7 effectively stopped the growth and spread of melanoma cells in both the normal and the “humanized” mice, which means that the changes the team made to the A-GalCer compound could have promising results in human cancer therapies. Using innovative 3-D computer technology, the team was able to clearly interpret the effects of the modifications they made to create AH10-7. This approach could potentially help to develop other new and better NKT cell-activator compounds.

José Gascón, PhD, a specialist in quantum and molecular mechanics at UConn, says that the team is hoping to “[provide] protocols so that other scientists can rationally design related molecules that elicit desired responses from iNKT cells.”