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1228 | CANCER DISCOVERY�DECEMBER 2015 www.aacrjournals.org
NEWS IN BRIEF
First Immunotherapy Combo Approved for Cancer
The FDA has granted acceler-
ated approval to the combination of
Bristol-Myers Squibb’s PD-1 inhibi-
tor nivolumab (Opdivo) and CTLA-4
inhibitor ipilimumab (Yervoy) to treat
advanced melanoma, the fi rst approval
of an immunotherapy combination to
treat cancer.
The agency approved the combination
for patients with BRAF V600 wild-type
unresectable or metastatic melanoma,
based on the pivotal phase II CheckMate
069 trial (N Engl J Med 2015;372:2006–
17). In that study, patients with BRAF
wild-type melanoma had objective
response rates (ORR) of 61% with the
combination therapy versus 11% with
ipilimumab alone.
Later results from the phase III
CheckMate 067 study, which will be
taken into account for fi nal approval,
suggest that the combination may be
an option for all melanoma patients
with advanced disease (N Engl J Med
2015;373:23–34). Researchers enrolled
945 patients with untreated advanced
melanoma regardless of mutation status
and found that the nivolumab–ipilimu-
mab combination extended progression-
free survival (PFS) and improved ORR
compared with either drug alone.
“This is a very exciting development
for melanoma patients,” says Patrick
Ott, MD, PhD, clinical director of the
Melanoma Center and the Center for
Immuno-Oncology at Dana-Farber
Cancer Institute in Boston, MA.
“Although the response rate of 60% with
the combination compared to 40% with
nivolumab alone seen in both the phase II
and phase III trials comes at a price for
these patients because the toxicity is sub-
stantially higher with the combination
compared to anti–PD-1 therapy alone.”
In the phase III study, about 36% of
patients in the combination therapy
group dropped out due to side effects,
compared with about 8% in the
nivolumab group and 15% in the ipilimu-
mab group. The most common adverse
events were diarrhea and colitis.
When looking at response based on
PD-L1 status, researchers in the phase
III study noted that the greatest benefi t
with the combination of nivolumab
and ipilimumab versus nivolumab
alone may occur in the context of neg-
ative PD-L1 tumor expression, as the
PFS was similar between combination
therapy and monotherapy in patients
with PD-L1–positive tumors. Expres-
sion of PD-L1 has been associated with
increased response rates in previous
studies using PD-1 inhibition alone.
“At Dana-Farber, we are offering the
combination to most patients who we
think can tolerate the toxicity, regard-
less of PD-L1 status,” says Ott, who
has been treating patients for the past
8 months on an extended-access pro-
tocol. “Patients face a choice between
taking a PD-1 inhibitor alone with
lower toxicity or the combination with
higher toxicity, but a better overall
chance of response.” ■
HPV Vaccine Triggers Regression of Precancers
A DNA vaccine that targets strains
of the human papillomavirus (HPV)
causes cervical lesions to regress or
disappear, a phase IIb trial shows.
In most women who are infected
with HPV, the immune system attacks
and eliminates the virus. The two
approved HPV vaccines, Gardasil and
Cervarix, help protect against new
infections with HPV-16 and HPV-18,
the strains responsible for 70% of cer-
vical cancers, but they don’t clear the
virus from already-infected patients.
HPV infection can trigger a precancer-
ous lesion known as cervical intraepi-
thelial neoplasia (CIN).
Doctors can’t predict which lesions
will progress to cervical cancer, so the
standard treatment is to have them
excised. However, more than one proce-
dure is often necessary, and deep exci-
sions can increase the risk of premature
birth. Researchers are working on sev-
eral less invasive alternatives, including
therapeutic vaccines, to induce immune
responses that would eliminate HPV.
Cornelia Trimble, MD, of the Johns
Hopkins School of Medicine in Bal-
timore, MD, and colleagues tested an
investigational therapeutic DNA vac-
cine, VGX-3100, developed by Inovio
Pharmaceuticals (Plymouth Meeting,
PA). VGX-3100 contains plasmids that
target two key HPV proteins, E6 and
PEOPLE
Charles S. Abrams, MD, a professor of medicine, pathology, and laboratory medi-cine; vice chair for research and chief scientific officer of the Department of
Medicine at the University of Pennsyl-vania; and director of the Blood Center for Patient Care and Discovery at the University of Pennsylvania and Children’s Hospital of Philadelphia, will become president of the American Society of Hematology on December 8. Serving a 1-year term, he will succeed David A. Williams, MD.
A graduate of Johns Hopkins Univer-sity in Baltimore, MD, and Yale Univer-sity School of Medicine in New Haven, CT, Abrams’s research interests include platelet activation, platelet disorders, and production of megakaryocytes. In particular, his lab focuses on phospho-lipid signaling in platelets and its con-tribution to inappropriate platelet activation.
Nobel laureate Venkatraman “Venki” Ramakrishnan, PhD, became president of the Royal Society, the United Kingdom’s preeminent scientific institution, on
December 1. He replaces geneticist Paul Nurse, PhD, who held the position for the past 5 years. Nurse will continue his role as director and chief executive of the London, UK–based Francis Crick Institute, a biomedical research center.
Most recently, Ramakrishnan served as deputy director of the Medical Research Council Laboratory for Molecular Biology in Cambridge, UK. He was awarded a share of the Nobel Prize in Chemistry in 2009 for his work on the structure and function of ribosomes.
The Royal Society was founded in 1660. As the organization’s president, Ramakrishnan will wield influence over and be able to speak out on science pol-icy, as well as the government’s research budget, which has flagged significantly in purchasing power since 2010.
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on August 2, 2020. © 2015 American Association for Cancer Research. cancerdiscovery.aacrjournals.org Downloaded from
Published OnlineFirst October 20, 2015; DOI: 10.1158/2159-8290.CD-NB2015-143
NEWS IN BRIEF
DECEMBER 2015�CANCER DISCOVERY | 1229
could be an effective way to protect
from cancer, instead of taking a
chance that the DNA damage will be
incompletely repaired and escape into
future populations.”
An editorial accompanying this study
allowed the plausibility of elephants
owing “their relatively cancer-free lon-
gevity to the acquisition… of extra copies
of TP53” (JAMA 2015;314:1806–7).
The authors added, though, that “it
is perhaps unlikely that the p53 gene
deserves all the credit,” noting that
other animals—for instance, bowhead
whales and naked mole rats—have
evolved different ways to resist cancer.
They also pointed out that most
human cancers are linked to lifestyles
“not found among animals.”
“Our cancer risk is artifi cially
higher because of smoking, drinking,
and other bad habits,” Schiffman
agrees. “However, there are inher-
ent biological differences between
human and elephant cells that can’t
be explained by lifestyle or environ-
mental factors.”
The researchers aren’t directly con-
necting an elephant’s low likelihood
of cancer to its additional copies of
TP53, Schiffman stresses—“we think
there’s a relationship here, but we
have to further explore this mecha-
nism.” They’re now closely analyzing
individual TP53 retrogenes, each being
distinctly different; and exploring
the potential involvement of other
molecular pathways in elephants’
robust apoptotic response to
DNA damage.
“In comparative oncology, we’ve
learned a lot about human cancer
from cancer-prone animals,” Schiff-
man observes. “By shifting the focus
to understanding why some animals
are naturally cancer-resistant, we could
learn still more.” ■
E7. After receiving a dose of the vac-
cine, which is injected into the arm,
patients receive a mild electrical pulse
at the injection site. This increases the
permeability of the cell membrane,
allowing cells to absorb the plasmids.
Trimble and colleagues reported the
results of a trial of the vaccine in women
with CIN2 or CIN3 lesions (Lancet 2015
Sep 16 [Epub ahead of print]). In 49.5%
of the 107 women who received all three
planned doses of the vaccine, the lesions
vanished or regressed. In contrast, lesions
disappeared or regressed in 30.6% of the
36 women who received three placebo
injections. In these patients, the immune
system attacked HPV without stimula-
tion from the vaccine.
The scientists also confi rmed that
the vaccine triggered a response by the
immune system. Compared with the
control group, patients who received
VGX-3100 produced more HPV-target-
ing CD8+ T cells that make perforin, a
protein that helps kill infected cervical
cells. In addition, 81% of the vaccinated
women whose CINs regressed showed
no trace of the virus, versus 45% of the
subjects who received the placebo. “The
study proves that it’s possible to pro-
duce a T-cell response in people with
existing disease, and that this T-cell
response works,” says Trimble.
“The amount of viral clearance they
had in this study was quite impressive,”
says Henry Kitchener, MD, of the Univer-
sity of Manchester in the United
Kingdom, who wasn’t connected to the
research. Eliminating the virus is cru-
cial, he says, because “if you don’t clear
the virus, it’s highly likely [the lesions]
will recur” and cancer could develop.
Kitchener adds that he wants to see
long-term studies to confi rm that the
lesions don’t return.
Trimble notes that VGX-3100 isn’t
as effective as surgery, which can
eliminate the lesions in up to 90% of
patients. That’s why the researchers
are working to increase its ability to
stimulate the immune system. ■
Illuminating Cancer Resistance in Elephants
Elephants are perhaps best known
for their remarkably good memory
and long life span—60 years on aver-
age. They also have an unusually
generous share of the tumor sup-
pressor gene TP53 and seldom develop
cancer, which may contribute to their
longevity (JAMA 2015;314:1850–60).
Joshua Schiffman, MD, a pediatric
oncologist at the University of Utah’s
Huntsman Cancer Institute in Salt
Lake City and one of the study’s senior
authors, fi rst learned 3 years ago that
co–senior author Carlo Maley, PhD, an
evolutionary biologist at Arizona State
University in Tempe, had found at
least 20 copies of TP53 in both African
and Asian elephants. Whole-genome
sequencing revealed that one was an
ancestral copy comparable to TP53 in
other mammals, including the much
smaller hyrax, the elephant’s closest
living relative. The rest were retrogenes,
or modifi ed duplicates, that emerged
after the evolutionary split between
hyrax and elephant. This fascinated
Schiffman, because “it suggested
a natural protection, evolved over
millions of years, against diseases like
cancer.”
Schiffman and Maley analyzed 36
mammalian species, from striped grass
mice to elephants, and showed that
the probability of carcinogenesis did
not increase with body size and life
span. Combing through 644 deaths in
the Elephant Encyclopedia database,
the researchers estimated the elephant
cancer mortality rate to be 4.81%. In
contrast, human cancer mortality
rates range from 11% to 25%.
The team then assessed DNA damage
repair in elephant cells, healthy human
cells, and cells from patients with Li-
Fraumeni syndrome (LFS)—who have
a compromised copy of TP53 with one
functional allele instead of two, making
them highly cancer-prone—by bombard-
ing the cells with ionizing radiation
and doxorubicin, which induce DNA
double-strand breaks.
“We expected that DNA damage
repair in elephant cells would be more
effi cient than human cells, and quite
off the charts compared to LFS cells,”
Schiffman says, “so we were disap-
pointed to fi nd that double-strand
breaks weren’t repaired any faster in
elephant versus human cells.” Instead,
the researchers found that elephant
cells had higher rates of apoptosis:
twice that of healthy human cells, and
fi ve times that of LFS cells. “Thinking
about it, this made sense,” Schiff-
man says. “Eliminating damaged cells
Un
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f U
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He
alth
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Joshua Schiffman led a study that could explain why elephants rarely get cancer.
on August 2, 2020. © 2015 American Association for Cancer Research. cancerdiscovery.aacrjournals.org Downloaded from
Published OnlineFirst October 20, 2015; DOI: 10.1158/2159-8290.CD-NB2015-143
2015;5:1228-1229. Published OnlineFirst October 20, 2015.Cancer Discov HPV Vaccine Triggers Regression of Precancers
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