Scientists show promising strategies for treating lymphoma

Scripps Research scientists have demonstrated a promising new strategy for treating lymphoma, a group of cancers that begin with cells that fight infections of the immune system called lymphocytes.

The new approach uses immune cells that target natural cancer, known as natural killer cells, that have been modified to selectively target lymphoma.Published in the journal, as explained in their study Applied ChemistryModified natural killer cells resulted in a dramatic reduction in mouse lymphoma.

“We have found a way to achieve selectivity for targeting lymphoma cells, which is an important departure from existing therapies,” said Peng Wu, an associate professor of molecular medicine at Scripps Research and co-author. The doctor says.

Wu and his lab collaborated with co-lead authors Dr. James Paulson, Professor Cecil H. & Ida Green, and Scripps Research’s Dean of Molecular Medicine.

More than 20,000 people die of lymphoma each year in the United States, and about 85,000 are newly diagnosed. Most lymphomas arise from B cells, an important type of lymphocyte whose primary function is to make antibodies.

Treatment of some existing lymphomas, including B cell killing antibodies and so-called CAR-T cells Therapies work by indiscriminately targeting B cells and most of them being wiped out. However, this strategy has many harmful side effects, including months of immunosuppression due to low antibody levels.

Wu, Paulson and his team have developed a more specific approach using natural killer cells. Natural killer cells are immune cells that normally patrol the bloodstream and tissues to find and destroy virus-infected and cancerous cells.

These immune system warriors, also known as NK cells, can recognize surface molecules in specific stories that indicate severe intracellular damage or malignancy. The target cell can then be killed in a variety of ways, including by secreting a protein that punctures the outer membrane of the cell.

Creation of super-strong NK cells

In the early 1990s, Canadian researchers developed a special type of NK cell NK-92 from patients with rare NK cell cancers. NK-92 cells grow and proliferate relatively easily in the laboratory compared to the normal NK cells found in human blood.

Researchers in Canada show that NK-92 cells are good at killing different types of cancer cells, with minimal side effects and dramatic results in some patients. I am. A proliferative version of NK-92 cells, NK-92MI cells are currently being extensively studied for use in a variety of cancers.

By itself, NK-92MI cells may not be the ideal gunfighter, especially for advanced malignancies, as they disperse systemically when injected into the bloodstream. However, in a new study, Wu and his team used chemical techniques to modify NK-92MI cells to focus their fight against cancer against lymphoma.

Operate powerful cells where they are most needed

In the first series of experiments, Scripps Research scientists redesigned NK-92MI cells to include a surface molecule that binds to a B cell surface receptor called CD22. CD22 is usually abundant in B cell-derived lymphoma cells. Therefore, as a general rule, NK-92MI cells selectively recognize cancerous B cells.

In cell culture tests, this modification significantly improved the ability of NK cells to kill lymphoma cells, and these killer cells did not harm healthy cells. However, in a mouse model of lymphoma, the strategy did not work very well because the NK cells did not yet move where they were needed.

After injection, these NK cells were found to tend to be found throughout the lungs and bloodstream. On the other hand, in this mouse model and patients with human lymphoma, lymphoma cells are predominantly in the bone marrow. “

Dr. Peng Wu, Associate Professor, Department of Molecular Medicine, Scripps Research Institute

Next, the team added a new molecule called Sialyl-Lewis X to NK cells. This causes the cells to collect in the bone marrow among the lymphoma cells. This dramatically delayed the onset of lymphoma in mice. With this promising result, Wu and his lab are now continuing to develop related strategies for clinical use.

Wu and Paulson generally say that adding homing molecules such as Sialyl-Lewis X to cell-based anticancer therapies increases their ability to kill cancer at the cancer site and may be key to the future success of these therapies. I think there is sex. For solid tumors and other highly localized cancers.

Wu also states that Sialyl-Lewix X, which collects NK-92MI cells in the bone marrow, and the CD22-binding molecule, which directs cells to malignant B cells, are both sugar chain-like “glycan” molecules. Such molecules are found in virtually every cell and often have important biological functions and important roles in disease, but are relatively neglected due to their difficulty in studying. It was.

“People are just beginning to recognize the importance of glycans,” said Dr. Senlian Hong, the first author of the study and a postdoctoral fellow in the Wu lab at Scripps Research.