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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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

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Joshua Schiffman led a study that could explain why elephants rarely get cancer.

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2015;5:1228-1229. Published OnlineFirst October 20, 2015.Cancer Discov     HPV Vaccine Triggers Regression of Precancers

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