A single antibody caused tumors from seven different human cancers transplanted into mice to shrink or disappear, according to a new study led by Stanford University School of Medicine in the US. The researchers hope to repeat this dramatic finding with tests in humans within the next two years.
Senior author Dr Irving Weissman, professor of pathology at Stanford, and colleagues, write about their success in treating bladder, brain, breast, colon, liver, ovarian, and prostate cancertumors in this week's online ahead of print issue of the Proceedings of the National Academy of Sciences.
They say the antibody blocks a protein known as CD47, that sends "don't eat me" signals that cancer cells use to stop macrophages and other cells of the immune system from gobbling them up.
Anti-CD47 is the first antibody treatment to work against a variety of human solid tumors. The investigators said they are now eager to get started with phase 1 and phase 2 clinical trials in humans within the next two years.
The treatment also significantly reduced the ability of the tumors to spread (metastasize) to other parts of the mice's bodies, and in some cases, the animals appeared to be "cured".
Weissman, who directs the Institute of Stem Cell Biology and Regenerative Medicine and the Ludwig Center for Cancer Stem Cell Research and Medicine, both at Stanford, told the press their findings show "conclusively" that CD47 is a "a legitimate and promising target for human cancer therapy":
"Blocking this 'don't eat me' signal inhibits the growth in mice of nearly every human cancer we tested, with minimal toxicity," said Weissman.
Dr Robert Weinberg is a professor of biology at the Whitehead Institute for Biomedical Research in Massachusetts and was not involved in the research. He describes the findings as "exciting work" that is bound to cause a worldwide rush to translate these findings into useful therapies.
"Mobilizing the immune system to attack solid tumors has been a longstanding goal of many cancer researchers for decades," said Weinberg.
Weissman's lab had already discovered that CD47 is normally expressed on the surfaces of circulating blood stem cells as a way to stop them being attacked by macrophages, clean-up cells of the immune system that go around looking for rogue cells to eliminate, but sometimes get it wrong.
A CD47 signal prompts the macrophage to release a snared cell.
Weissman and colleagues had also previously discovered that some types of cancer cells, such as those of leukemia and lymphoma, have also found a way to express CD47 on their surfaces to send the "don't eat me" signal and avoid being eaten by macrophages.
They found that by giving mice with human non-Hodgkin's lymphoma an antibody that blocks CD47, together with an agent that boosts the macrophages' killing instinct, cured some of them.
But what they didn't know then was this tactic was also used by many other human cancers, and thus how clinically important this potential treatment might be.
This latest study involved experts from many fields including, oncology, urology, obstetrics and gynecology, radiation oncology, neurosurgery, hematology, pathology, otolaryngology and hepatology. This was to collect samples from a range of human cancers.
The researchers found that nearly every human cancer cell they investigated expressed CD47, on average, about three times as strongly as non-cancerous cells.
They also found that people whose cancer cells express a lot of CD47 tend not to live as long as those with similar cancers but whose cancer cells express less CD47. This feature could be a very useful tool in cancer prognosis.
Once they obtained the human tumor samples, the researchers implanted them in the matching parts of the bodies of prepared lab mice: for instance breast tumors into mammary fat pads, and ovarian tumors into the abdomen.
Two weeks later, once the tumors were well established, they began treating the mice with the antibody that blocks CD47.
The researchers observed that within weeks, most of the tumors began to shrink, and in some cases even disappear.
In the case of five mice transplanted with cells from the same human breast cancer tumor, when the tumors disappeared, the researchers stopped the treatment.
The mice were still cancer-free four months later.
The researchers conclude:
"These results indicate that anti-CD47 antibodies can dramatically inhibit the growth of human solid tumors by blocking the ability of CD47 to transmit the 'don't eat me' signal to macrophages."
Weissman said that if the tumor was highly aggressive, the CD47 antibody also blocked metastasis.
"It's becoming very clear that, in order for a cancer to survive in the body, it has to find some way to evade the cells of the innate immune system," he explained.
The innate immune system is the first line of defence against invading pathogens like viruses and bacteria. Its response is more generalized that the fine-tuned responses of the adaptive immune system that has antibodies and T cells able to recognize and attack specific molecules.
However, in some cases, the CD47 antibody treatment did not work. A group of mice transplanted with human breast cancer cells from one specific patient showed no response at all.
Weissman said there was still a lot to learn.
"We need to learn more about the relationship between macrophages and tumor cells, and how to draw more macrophages to the tumors," he explained.
Perhaps reducing tumor size with surgery or radiotherapy before the antibody treatment could help, or even use it with another antibody to stimulate the immune cells to kill the cancer cells, he said.
In the meantime, the researchers believe their findings are sufficient to show this single antibody holds promise, and sets the stage for advancing research.
Weissman said they need to move forward "quickly but cautiously".