The discovery of a rare human antibody has pointed to a way of getting leukemia cells to kill each other, according to research published in Proceedings of the National Academy of Sciences.
Scientists at The Scripps Research Institute (TSRI) say the surprise finding, which involves changing leukemia cells into leukemia-killing immune cells, could lead to a powerful new therapy for leukemia and possibly other cancers.
Senior investigator Prof. Richard A. Lerner describes it as a “totally new approach to cancer.” He says the team is working to test it in human patients as soon as possible.
The Lerner laboratory has pioneered techniques to generate and screen very large libraries of antibodies (immune system molecules), in a search for therapeutic antibodies that bind to a desired target or activate a desired receptor on cells.
The team has been searching for therapies for people with certain immune cell or blood factor deficiencies.
They were searching for antibodies that activate growth-factor receptors on immature bone marrow cells, which might induce these bone marrow cells to mature into specific blood cell types.
They say some receptor-activating antibodies have unexpected effects on marrow cells, causing them to mature into radically different cell types, such as neural cells.
Turning cancerous cells into non-cancerous cells
Without knowing why this happens, the team speculated that they could also use the same method to convert cancerous marrow cells (leukemia cells) into non-cancerous cells.
Fast facts about leukemia
- About 52,380 Americans were expected to be diagnosed with leukemia in 2014
- An estimated 327,520 people live with leukemia in the US.
- From 2004-10, the survival rate was 70% overall and 91.8% for children under 15 years.
Lerner and his team were testing 20 recently discovered receptor-activating antibodies against acute myeloid leukemia cells from human patients, when one of these antibodies had an extraordinary impact on the acute myeloid leukemia cells.
A high percentage of acute myeloid leukemia cells express the thrombopoietin (TPO) receptor. The antibody in question was a highly potent and selective activator of this receptor on marrow cells.
When the antibody was applied to healthy, immature marrow cells, it caused them to mature into blood-platelet-producing cells called megakaryocytes.
However, when the antibody was applied to acute myeloid leukemia cells, they matured into very different cells known as dendritic cells, which are key support cells in the immune system. With longer exposure and certain other conditions, the induced dendritic cells developed further, into cells that closely resembled natural killer (NK) cells.
NK cells kill 15% of cancer cells in 24 hours
NK cells form one of the immune system’s rapid-reaction forces. They can fight viruses, bacteria and even cancer cells, without prior exposure.
When these induced NK cells were examined with electron microscopy, many were found to have extended tendrils through the outer membranes of neighboring leukemic cells, cells that had previously been their “siblings.”
In lab tests, a modest number of these NK cells wiped out about 15% of the surrounding acute myeloid leukemia cell population in just 24 hours.
Curiously, the induced NK cells only appear to kill “sibling” cells. Unrelated breast cancer cells did not die off in large numbers in the presence of the NK cells.
Why the induced NK cells appear to target only closely related cells is not yet known. However, it is thought that other antibodies may be able to turn other cancerous cell types into fratricidal NK cells.
There are several advantages to such fratricidal therapies, or “fratricidins,” as Prof. Lerner calls them. First, if they are antibodies, they could be clinically useful with little or no further modification.
Second, the likelihood of adverse side effects would be reduced, making them much more tolerable than existingchemotherapy. This would be due to their high specificity for their target receptors and the resulting NK cells’ specificity for related cancer cells.
Finally, if every cancerous cell is potentially convertible to a cancer-killing NK cell, it might not just reduce the targeted cancer-cell population in a patient, but also it could potentially eliminate cancer altogether.