[LINK] O/t cancer breakthrough?

[stephen at melbpc.org.au]

"Single antibody shrinks variety of human tumors transplanted into mice"

KRISTA CONGER, 26/3/2012  http://med.stanford.edu/ism/2012/march/cd47.html


Human tumors transplanted into laboratory mice disappeared or shrank when 
scientists treated the animals with a single antibody, according to a new 
study from the Stanford University School of Medicine. 

The antibody works by masking a protein flag on cancer cells that protects 
them from cells in the immune system. 

The scientists achieved the findings with human breast, ovarian, colon, 
bladder, brain, liver and prostate cancer samples.

It is the first antibody treatment shown to be broadly effective against a 
variety of human solid tumors, and the dramatic response — including some 
overt cures in the laboratory animals — has the investigators eager to 
begin human clinical trials within the next two years.

“Blocking this ‘don’t-eat-me’ signal inhibits the growth in mice of nearly 
every human cancer we tested, with minimal toxicity,” said professor of 
pathology Irving Weissman, MD, who directs Stanford’s Institute of Stem 
Cell Biology and Regenerative Medicine and the Ludwig Center for Cancer 
Stem Cell Research and Medicine at Stanford. 

“This shows conclusively that this protein, CD47, is a legitimate and 
promising target for human cancer therapy.”

The antibody treatment also significantly inhibited the ability of the 
tumors to metastasize throughout the animals’ bodies.

“This is exciting work and will surely trigger a worldwide wave of research 
designed to convert this strategy into useful therapies,” said Robert 
Weinberg, PhD, a professor of biology at the Whitehead Institute for 
Biomedical Research in Massachusetts who was not involved in the research. 

“Mobilizing the immune system to attack solid tumors has been a 
longstanding goal of many cancer researchers for decades.”

The research was published online March 26 in the Proceedings of the 
National Academy of Sciences. Weissman, who is the Virginia & D.K. Ludwig 
Professor for Clinical Investigation in Cancer Research at Stanford and a 
member of the Stanford Cancer Institute, is the senior author of the 
research. Postdoctoral scholars Stephen Willingham, PhD, and Jens-Peter 
Volkmer, MD, are the co-first authors of the study.

Previous work in Weissman’s lab has shown that CD47 is normally expressed 
on the surfaces of circulating blood stem cells to protect them from immune 
cells called macrophages. 

Macrophages patrol the body looking for signs of trouble in the form of 
invaders or rogue cells, but they sometimes latch onto the wrong targets. 
CD47 prompts them to release cells they’ve grabbed by mistake.

Weissman and his colleagues also showed previously that some types of 
cancer cells — particularly those of blood cancers such as leukemia and 
lymphoma — have figured out a way to game the system and use this “don’t-
eat-me signal” to their advantage by expressing CD47 on their own surfaces. 

In 2010, they found that blocking CD47 with a specific antibody (plus 
adding another to further stimulate the macrophages’ killing instinct) can 
cure some cases of human non-Hodgkin’s lymphoma in mice. But it wasn’t 
known until now how widespread or clinically important the phenomenon would 
be in human solid tumors.

In the current study, Willingham and Volkmer collected surgical samples of 
a variety of human tumors, including ovarian, breast, colon, bladder, 
brain, liver and prostate. To do so, they enlisted the help of clinical 
experts from across the School of Medicine, including those specializing in 
oncology, urology, obstetrics and gynecology, radiation oncology, 
neurosurgery, hematology, pathology, otolaryngology and hepatology.

They showed that nearly every human cancer cell they examined expressed 
CD47 — usually at higher levels (on average, about three times more) than 
did non-cancerous cells. 

Furthermore, people whose cancer cells express a lot of CD47 tend to have 
shorter life spans than people with similar cancers that express less CD47. 

This suggests that an analysis of the levels of CD47 expression in some 
types of tumors could be a valuable prognostic tool for patients and their 
doctors.

Willingham and Volkmer then implanted the different human tumor cells into 
matching locations in the bodies of mice — breast cancer tumors into the 
mammary fat pads, and ovarian cancer tumors into the abdomen, for example. 

Once the tumors were well-established (after two weeks or more), they 
treated the animals with the anti-CD47 antibody.

The researchers saw that most of the established tumors begin to shrink and 
even, in some cases, disappear within weeks of treatment with the antibody. 
In one case, antibody treatment cured five mice injected with the same 
human breast cancer cells. When the tumor was gone, the treatment was 
discontinued; the mice were monitored for four months with no signs of 
recurrence.

“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,” concluded the authors.

“If the tumor was highly aggressive,” said Weissman, “the 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.” The innate immune system is the body’s first line of 
defense against pathogens like bacteria and viruses. Unlike the adaptive 
immunity conferred by antibodies and T cells that recognize and battle 
specific molecules, cells of the innate immune system, like macrophages, 
respond non-specifically to a variety of threats.

The researchers’ approach didn’t work in every animal, though. A set of 
mice with breast cancer cells from one human patient experienced no benefit 
from antibody treatment. “There’s certainly more to learn,” said Weissman. 

“We need to learn more about the relationship between macrophages and tumor 
cells, and how to draw more macrophages to the tumors.” He suggested that 
reducing the size of a tumor with surgery or radiotherapy before antibody 
treatment could make the treatment more effective. Another option, he 
added, would be to use a second antibody in addition to CD47 that would 
further stimulate the ability of the macrophages or other immune cells to 
kill the cancer cells.

 While treatment modifications may be beneficial, the findings about the 
effect of the single antibody are promising in their own right and set the 
stage for advancing the research. “We believe these results show that we 
should move forward quickly but cautiously into human clinical trials for 
many types of solid tumors,” Weissman said.
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Cheers,
Stephen