The antibody eradicates leukemia stem cells

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UCLA slide

UCLA

Dr. John Chute

The introduction of the drug imatinib in 2001 revolutionized the treatment of a type of cancer called chronic myelogenous leukemia. In over 80% of people with CML who received the drug, the disease went into complete remission.

However, in most people with chronic myeloid leukemia, cancer stem cells remain in the body for years after their cancer has entered remission. If treatment with imatinib or another similar drug is stopped – and in some cases, even while treatment continues – leukemia stem cells can cause cancer to recur.

Now, in experiments on mice and isolated human cancer cells, UCLA researchers have discovered a way to eliminate CML stem cells. Their approach uses an antibody to block a protein on which stem cells rely to grow. The advance, described in a study published in the Journal of Clinical Investigation, it could possibly help to treat not only chronic myeloid leukemia but also other cancers.

Imatinib, commonly marketed under the Gleevec brand, is an inhibitor of tyrosine kinases; acts by targeting the genetic anomaly that causes chronic myeloid leukemia.

"Our results suggest that it may be possible to eradicate CML stem cells by combining this new targeted therapy with a tyrosine kinase inhibitor," he said. Dr. John Chute, senior author of the study and member of Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. "This could lead to a day on the road where people with CML might not need to take a tyrosine kinase inhibitor for the rest of their lives."

Chronic myeloid leukemia causes the bone marrow to produce too many white blood cells. More than 95% of all cases are caused by the same genetic change – a mashup of two genes that are normally found on different chromosomes. Imatinib targets that "fusion gene".

However, Imatinib is not a permanent cure in most cases.

"In most people, CML stem cells are still there," said Chute, who is also a professor of radiation medicine and oncology at David Geffen School of Medicine at UCLA and a member of UCLA Jonsson Comprehensive Cancer Center.

Several studies have shown that even after years of treatment with imatinib, when people stop treatment, their cancer has a significant chance of relapse.

In the last decade, Chute and his colleagues have shown that a molecule called pleiotrophin, produced by the bone marrow, supports the normal growth of blood stem cells and recovery from stress. They wondered if pleiotropin could also play a role in the survival of chronic myeloid leukemia stem cells.

To find out, the team studied mice that had the fusion gene that causes CML. Normally, these mice rapidly develop symptoms of chronic myeloid leukemia and live on average only three to four months. But mice with the gene that causes CML lacking the pleiotropin gene had normal white blood cell levels and survived for almost twice as much.

The scientists then transplanted blood stem cells from the group of mice with the gene that causes CML in previously healthy mice and the new mice contracted chronic myelogenous leukemia. When the researchers tried the same experiment using blood stem cells from mice lacking pleiotrophin, transplant patients showed little evidence of leukemia and their carcinogenic gene levels were lower than 1% of the levels found in the group of control of mice.

When Chute's team isolated CML stem cells from humans with cancer, they found that the cells had levels 100 times higher pleiotrophin found in healthy blood stem cells. Further experiments revealed that CML cells were producing their own pleiotropin as well as reacting to the pleiotropin that is normally found in the body.

"This provides an example of cancer stem cells that are perpetuating the growth of their disease by hijacking a protein that normally supports healthy blood stem cell growth," said Chute.

When the researchers used an anti-pleiotropin antibody to block pleiotropin in isolated human cancer cells, CML stem cells started to die. Further experiments revealed that in CML stem cells, pleiotropin works by triggering a known mechanism that keeps cells alive. When pleiotropin is blocked by antibodies, it cannot activate this mechanism and CML stem cells die.

"Normal cells can proliferate and survive without pleiotropin," Chute said. "But human CML stem cells are relatively pleiotropin-dependent and do not survive well without it."

To assess its therapeutic potential, Chute's group tested the effect of the combination of imatinib and anti-pleiotropin antibody. Together, the drugs virtually eliminated the human CML cells that had been transplanted into mice.

The anti-pleiotropin antibody has only been used in preclinical studies and has not been tested in humans or approved by the FDA as safe and effective for use in humans.

According to Chute, the researchers are now working on the modification of the anti-pleiotropin antibody to make it more similar to the antibodies produced by humans, which would make their rejection by the human immune system less likely.

The study was funded by the National Institutes of Health, the California Institute for Regenerative Medicine, the Tower Cancer Research Foundation and the Damon Runyon Cancer Research Foundation.

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