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 macrophages and other 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 phase-1 and -2
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 a 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.
Luis Liz Marzán
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