Scripps Research study uses modified ‘killer cells’ to defeat lymphoma while sparing healthy cells

Hodgkin's lymphoma, one of a group of cancers that begin in infection-fighting cells of the immune system called lymphocytes.

Scientists at Scripps Research in La Jolla have demonstrated a promising new strategy for treating lymphomas, a
group of cancers that begin in infection-fighting cells of the immune system called lymphocytes.

The new approach uses natural cancer-targeting immune cells, known as natural “killer cells,” that have been modified to selectively target lymphoma. As described in the scientists’ study, published in the journal Angewandte Chemie, the modified natural killer cells brought about a dramatic reduction of lymphoma in a mouse.

“We found a way to achieve selectivity in targeting lymphoma cells, which is an important departure from existing therapies,” said co-senior author Peng Wu, an associate professor in the department of molecular medicine at Scripps Research.

Wu and his lab collaborated in the study with the lab of co-senior author James Paulson, chairman of the department of molecular medicine.

More than 20,000 people in the United States die of lymphomas annually, while about 85,000 are newly diagnosed. Most
lymphomas arise from B cells, a type of lymphocyte whose primary function is to make antibodies.

Some existing lymphoma treatments, including B-cell-killing antibodies and so-called CAR-T cell therapies, work by targeting B cells indiscriminately, largely wiping them out. However, that strategy brings many adverse 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 patrol the bloodstream and tissues, seeking and destroying virus-infected or cancerous cells. These immune-system warriors, also known as NK cells, are able to recognize certain tell-tale surface molecules that signify serious damage or malignancy within a cell. They can then kill that target cell through a variety of means, including by secreting proteins that punch holes in the cell’s outer membrane.

Creating a super-powered NK cell

In the early 1990s, Canadian researchers developed a special type of NK cell, NK-92, from a patient with a rare NK-cell cancer. NK-92 cells are relatively easy to grow and multiply in the lab, compared with normal NK cells found in human blood.

The Canadian researchers and others have since shown that NK-92 cells are good at killing different kinds of cancerous cells and can bring about dramatic results in some patients, with minimal side effects.

NK-92MI cells, an easier-to-multiply version of NK-92 cells, are now being widely investigated for use against various cancers.

On their own, NK-92MI cells may not be ideal cancer-fighters, especially not for advanced malignancies — partly because they are dispersed throughout the body when infused into the bloodstream. In the new study, however, Wu and his team used chemistry techniques to modify NK-92MI cells to concentrate their cancer-fighting power against lymphoma.

Steering powerful cells where they’re needed most

In an initial set of experiments, the Scripps Research scientists re-engineered NK-92MI cells to include a surface molecule that binds to a B-cell surface receptor called CD22, which is normally abundant on B-cell-derived lymphoma cells. Thus, in principle, the NK-92MI cells would selectively recognize cancerous B cells.

In cell-culture tests, the modification brought a big improvement in the NK cells’ ability to kill lymphoma cells, and these killer cells did not harm healthy cells. In a mouse model of lymphoma, however, the strategy didn’t work so well, apparently because the NK cells still didn’t go where they were needed.

“We found that after being injected, these NK cells tend to be found in the lungs and throughout the bloodstream, whereas in this mouse model and in human lymphoma patients, the lymphoma cells are mostly in the bone marrow,” Wu said.

The team then added to their NK cells a new molecule called Sialyl-Lewis X, which made the cells gather in bone marrow amid the lymphoma cells. This led to a dramatic delay in the development of lymphoma in the mice. With this result, Wu and his lab now are continuing to develop this and related strategies for clinical use.

Wu and Paulson suspect that in general, adding homing molecules such as Sialyl-Lewis X to cell-based anti-cancer treatments enhances the cancer-killing power at the site of the cancer and may be a key to these treatments’ future success — particularly against solid tumors and other highly localized cancers.

Funding for the study was provided by the National Institutes of Health and the Danish National Research Foundation. ◆