Scientists at Scripps Research have unveiled a promising new strategy for treating lymphomas, a group of cancers that start in the fighting cells of the immune system called lymphocytes.
The new method uses cancer-targeted natural immune cells, called natural killer cells, that have been modified to selectively target lymphoma. As described in their study, published in the journal Cemie Angewandte, the altered natural killer cells resulted in a significant reduction of lymphoma in a mouse.
“We found a way to achieve selectivity in targeting lymphoma cells, which is an important departure from existing treatments,” says co-author Peng Wu, PhD, associate professor in the Department of Molecular Medicine at Scripps Research.
Wu and his laboratory in the study collaborated with the laboratory of lead author James Paulson, PhD, Professor Cecil H. and Ida Green and Chair of the Department of Molecular Medicine at Scripps Research.
More than 20,000 people in the United States die from lymphomas each year, while about 85,000 people recover from it. Most lymphomas arise from B cells, an important type of lymphocyte that has a primary role in producing antibodies.
Some existing lymphoma treatments, including B-cell killing antibodies and so-called CAR-T cell therapies, work by targeting B cells unequally, sending them virtually out. However, this strategy has many side effects, including months of immunosuppression due to low antibody levels.
Wu, Paulson and their teams have developed a more specific approach using natural killer cells, which are immune cells that normally circulate blood flow and nappies, seeking and destroying cells with virus or cancer.
These immune system heroes, also known as NK cells, are able to tell some story surface molecules that indicate severe damage or malignancy within a cell; they can kill that target cell through a variety of means, including by hiding proteins that punch holes in the outer part of the cell.
Creating a full-power NK cell
In the early 1990s, Canadian researchers developed a specific type of NK cell, NK-92, from a patient with rare NK-cell cancer. NK-92 cells are relatively easy to grow and multiply in the laboratory, compared to normal NK cells found in human blood.
The researchers from Canada and others have since shown that NK-92 cells are good at killing different types of cancer cells, and that they give amazing results in some patients, with very few side effects. NK-92MI cells, an easier-to-multiply version of NK-92 cells, are now being studied for use against a variety of cancers.
By themselves, NK-92MI cells may not be particularly suitable cancer fighters, especially not for advanced malignancies, partly because they are scattered throughout the body when taken. into the bloodstream. In the new study, however, Wu and his team used chemistry techniques to modify NK-92MI cells to target their cancer-fighting power against lymphoma.
Directs powerful cells where they are most needed
In an initial set of experiments, Scripps Research scientists reconstructed NK-92MI cells to incorporate a surface molecule that binds to a surface B cell receptor called CD22, which is commonly abundance of lymphoma cells derived from B cells. Thus, in principle, the NK-92MI cells would selectively recognize cancerous B cells.
In cell culture experiments, the mutation significantly improved the ability of NK cells to kill lymphoma cells, and these killer cells did not harm healthy cells. In a mouse model of lymphoma, however, the strategy did not work as well, apparently because the NK cells were still not going where they were needed.
We found that, after injection, these NK cells are found in the lungs and throughout the bloodstream – but only in this mouse model and in human lymphoma patients. , lymphoma cells are mainly in bone marrow, “
Peng Wu, PhD, Associate Professor, Department of Molecular Medicine, Scripps Research Institute
The team then added their new molecular NK cells called Sialyl-Lewis X, which caused the cells to accumulate in bone marrow among the lymphoma cells. This caused a significant delay in the development of lymphoma in the mice. With this promising result, Wu and his laboratory are now continuing to develop this and related strategies for clinical use.
Wu and Paulson are skeptical, in general, that the addition of dating molecules such as Sialyl-Lewis X to cell-based anticancer therapies enhances the killing power of cancer at the cancer site, and may be a key mechanism for the future success of these treatments – especially against hard tumors and other local cancers.
Wu notes, too, that Sialyl-Lewis X, which caused the NK-92MI cells to accumulate in bone marrow, as well as the CD22 binding molecule that directed the cells to malignant B cells, both as sugar-like “glycan” molecules. Although such molecules are found on almost all cells, and often have essential biological functions as well as vital functions in disease, they are difficult to study and have therefore been largely neglected.
“People are just beginning to understand the importance of glycans,” said Senlian Hong, PhD, the study’s first author and a postdoctoral research associate in Wu’s lab at Scripps Research.
Scripps Research Institute
Hong, S., et al. (2020) Glycoengineering of NK cells with glycan ligands of CD22 and selectins for B-cell lymphoma therapy. Cemie Angewandte. doi.