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.
Journal Reference:
- Badreddin Edris, Kipp Weiskopf, Anne K. Volkmer, Jens-Peter Volkmer, Stephen B. Willingham, Humberto Contreras-Trujillo, Jie Liu, Ravindra Majeti, Robert B. West, Jonathan A. Fletcher, Andrew H. Beck, Irving L. Weissman, and Matt van de Rijn. Antibody therapy targeting the CD47 protein is effective in a model of aggressive metastatic leiomyosarcoma. Proceedings of the National Academy of Sciences, March 26, 2012 DOI: 10.1073/pnas.1121629109
Courtesy: ScienceDaily
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