by Heidi Ledford
13 April 2016
(pictured here, dried
adriamycin viewed under a microscope)
might work better
when paired with immunotherapies.
The next frontier in cancer
lies in combining it with other
Scientists are trying to get
the mix just right.
In cancer research, no success is more revered than the huge
reduction in deaths from childhood leukemia.
From the 1960s to the 2000s, researchers
boosted the number of children who survived acute lymphoblastic
leukemia from roughly 1 in 10 to around 9 in 10.
What is sometimes overlooked, however, is that these dramatic gains
against the most common form of childhood cancer were made not
through the invention of new drugs or technologies, but rather
through a reassessment of the tools in hand:
a dogged analysis of the relative
gains from different medicines and careful strategizing over how
best to apply them side by side as combination therapies.
"It wasn't just about pounding
drugs together," says Jedd Wolchok, a medical oncologist at
Memorial Sloan Kettering Cancer Center in New York City.
"It was about understanding the
mechanism and figuring out what should be given when."
That lesson has particular relevance in
cancer research today.
A new class of immunotherapies - which
turn the body's immune system against cancerous cells - is
elevating hopes about combination therapies again. The drugs, called
checkpoint inhibitors, have already generated great
excitement in medicine when applied on their own.
Now there are scores of trials mixing
these immune-boosting drugs with one another, with radiation, with
chemotherapies, with cancer-fighting viruses, with cell treatments
"The field is exploding," says
Crystal Mackall, who leads the pediatric cancer immunotherapy
program at Stanford University in California.
Fast-moving trends in cancer biology
often fail to meet expectations, and little is yet known about how
these drugs work together.
Some observers warn that the
combinations being tested are simply marriages of convenience -
making use of readily available compounds or capitalizing on
"In many cases, we're moving forward
without a rationale," says Alfred Zippelius, an oncologist at
the University of Basel in Switzerland.
"I suspect we'll see some
disappointment in the next few years with respect to
But many clinicians argue that delay is
not an option as their patients queue up for the next available
"Right now I have more patients that
could benefit from combinations than there are combinations
being tested," says Antoni Ribas, an oncologist at the
University of California, Los Angeles.
"We're always waiting on the next
Lying in wait
Immunotherapies have been more than a
century in the making, starting when physicians first noticed
mysterious remissions in a few people with cancer who contracted a
The observations led to a hypothesis:
perhaps the immune system is able to kill tumors when made hypervigilant by an infection.
The concept has vast appeal. What
to beat a fast-evolving biological system such as a tumor than
with a fast-evolving biological immune system?
But it took decades for researchers to
turn that observation into something useful.
Part of the trouble, they eventually
learned, is that tumors suppress the immune response. T cells, the
immune system's weapon of choice against cancer, would sometimes
gather at the edge of a tumor and then just stop.
It turned out that a class of molecules
called inhibitory checkpoint proteins was holding those T cells at
bay. These proteins normally protect the human body from unwarranted
attack and autoimmunity, but they were also limiting the immune
system's ability to detect and fight tumors.
In 1996, immunologist James Allison,
now at the University of Texas MD Anderson Cancer Center in Houston,
showed that switching off a checkpoint protein called CTLA-4 helped
mice to fend off tumors. 1
The discovery suggested that there was a
way to re-mobilize T cells and beat cancer.
In 2011, the US Food and Drug
approved the first checkpoint inhibitor - a drug, called
ipilimumab, that inhibits CTLA-4 - to treat advanced melanoma.
The improvements were modest:
of patients benefited from ipilimumab, and the survival gain was
less than four months on average. 2
But a handful of recipients are still
alive a decade after starting the therapy - a stark contrast with
most new cancer drugs, which often benefit more patients in the
short term, but don't have a durable response.
Ipilimumab was at the leading edge of a
flood of checkpoint inhibitors to enter clinical trials.
The drug's developer, Bristol-Myers
Squibb of New York, followed up with the approval of
nivolumab, which inhibits the protein PD-1.
And a host of other companies have
jumped into the immunotherapy fray, as have academics such as
Edward Garon at the University of California, Los Angeles.
"Our group gladly shifted into
this," says Garon, who began focusing on checkpoint inhibitors
in 2012. "It was very clear this was going to have a major
But even as the family of checkpoint
inhibitors was rapidly expanding, the drugs were running up against
the same frustrating wall: only a minority of patients experienced
And some cancers - such as prostate and
pancreatic - responded poorly, if at all, to the drugs.
Further research revealed a possible
explanation: many people who were not responding well to the drugs
were starting the
treatment without that phalanx of T cells waiting at the margins
of their tumors (in the lingo of the field, their tumors were not
Researchers reasoned that if they could
raise this T-cell response first, and recruit the cells to the edges
of the tumor, they might get a better result with the checkpoint
That realization fuelled a
rush to test combinations of drugs. Radiation and some
chemotherapies kill enough tumor cells to release proteins that the
immune system might then recognize as foreign and attack.
Vaccines containing these proteins,
called antigens, could have a similar effect.
"On some level, one can make an
argument for almost any drug combining well with an
immunotherapy," says Garon. "And obviously we know not all of
Mixing it up
One of the first combinations to be
tested was made up of two immunotherapies - ipilimumab and
- at once.
Although the targets of these drugs both
do the same job, silencing T cells, they do so in different ways:
CTLA-4 prevents the activation of T cells; PD-1 blocks the cells
once they have infiltrated the tumor and its environment.
And treating mice with compounds that
block both proteins yielded a more-inflamed tumor as well. 3
"There was reason to think that if
you block both, the T cells will be even more ready to kill the
tumors," says Michael Postow, an oncologist at Memorial Sloan
Together, ipilimumab and nivolumab boost
response rates in people with advanced melanoma from 19% with just
ipilimumab to 58% with the combination. 4
The combination also produces
more-dangerous side effects than using either drug alone, but
physicians are learning how to treat immunotherapy reactions, says
Ipilimumab generally doesn't help people
with lung cancer when given on its own, but researchers are now
testing it with nivolumab.
Normally, they would not have bothered
to investigate a combination involving a drug that had failed on its
own, Garon says.
The new approach is grounded in
immunology, but some researchers worry that the effort could be
wasted, he adds. Researchers are also testing inhibitors of other
checkpoint proteins, including TIM-3 and LAG-3, in combination with
those that block PD-1.
The combination approach is breathing
life into drugs that had been shelved. For example, a protein called
CD40 stimulates immune responses and has shown promise against
cancer in animals. But in the wake of disappointing early clinical
trials, some companies put their CD40 drugs to the side.
Years later, mouse studies showed that
combining CD40 drugs with a checkpoint inhibitor could boost their
Now, at least seven companies are
developing them. Cancer immunologists have listed the protein as one
of the targets they are most interested in studying, says Mac
Cheever, a cancer immunologist at the Fred Hutchinson Cancer
Research Center in Seattle, Washington.
Cancer vaccines - long pursued by
researchers but burdened by repeated failures in clinical trials -
may also see a renaissance. There are now more than two dozen trials
of cancer vaccines that make use of a checkpoint inhibitor.
Some promising combinations have been
uncovered by serendipitous clinical observations.
Researchers at Johns Hopkins University
in Baltimore, Maryland, were conducting trials of epigenetic drugs,
which alter the chemical tags on chromosomes. They shifted a handful
of people with lung cancer who had not responded to the drugs to a
clinical trial of nivolumab. Five of them responded - a much higher
proportion than expected.
The discovery became the seed for an
ongoing clinical trial launched in 2013 to study combinations of
epigenetic drugs and immunotherapies.
Preclinical work has now provided
evidence that epigenetic drugs can affect aspects of the immune
Riding the wave
These chance observations could lead to
real advances, says Jedd Wolchok.
"We're riding the wave of
But extracting the most from these
combinations will require more well-designed preclinical studies to
support the human ones.
Just as attention to combinations of
chemotherapies fuelled advances in treating pediatric leukemias, the
current combinatorial craze will require careful planning to work
out the right pairings and timing of therapies.
Another class of drug, known as targeted
therapies, could also receive a significant boost from
These drugs, which target proteins
bearing specific mutations, generate a high response rate when given
to patients with those mutations,
but the tumors often develop resistance to the drugs and come
Coupling targeted therapies with a
checkpoint inhibitor, researchers reason, could yield both high
response rates and durable remissions.
One of the first targeted therapies for
melanoma was an inhibitor that is specific to certain mutations in
BRAF proteins that can drive tumor growth. However, an early attempt
to combine this drug with ipilimumab was aborted when trial
participants showed signs of possible liver damage. 5
No one was injured, but for some it was
an important reminder that combinations can yield unanticipated side
"It was a good lesson for us to
learn," says Wolchok. "It will not be as simple as we imagined."
Paying careful attention to sample
collection during clinical trials would help researchers to catch
toxicity problems early, says Jennifer Wargo, a cancer
researcher at MD Anderson.
"We're making mistakes by looking
just at clinical endpoints," she adds. "We need to be smarter
about how we run these trials."
In one of his latest trials, Wolchok
wants to combine immunotherapy with a drug that targets a cellular
pathway that some cancer cells use to maintain their rapid division.
Cancers with mutations in this pathway,
which is regulated by the protein MEK, can be extraordinarily
difficult to treat.
But the pathway is also important for
T-cell development, so Wolchok is working to determine the right
timing for the treatment. One approach could be to use a MEK
inhibitor to quiet tumors in mice and to release tumor antigens.
He would then wait for the T-cell
response to rejuvenate before adding the immunotherapy.
"You want to make sure you're not
trying to activate the immune system at the same time you're
turning off that signaling," he says.
Garon is watching such trials with
optimism, but he's aware that there may be a limit to how well
combinations will perform. He sees a cautionary tale in a drug from
an earlier era that works mainly in people with a mutation in the
Researchers spent a decade trying to
find drugs that could turn a non-responding patient into a
"It is now clear that there probably
is no such agent," he says. "I'm hopeful we won't be repeating
that same response, but we have to watch our data cautiously."
Researchers are so ravenous for those
data that the results are being unveiled at major meetings at an
earlier stage than in the past, he adds.
"People are getting up and
presenting response rates when the number treated is five,"
Garon says. "We generally have had a higher threshold than
He worries that presenting such early
data could prompt community physicians in the audience to start
making decisions on treatments before they are appropriately
The excitement is also fuelling a frenzy
of clinical trials that are often based on speed rather than
"Right now I'm kidding myself if I
say I'm picking a combination because I have a scientific reason
to pick it," says Mackall. "It's likely to just be what was
The strategy may still produce some
"There is plenty of opportunity
for serendipity now," says Robert Vonderheide, who studies
CD40 at the University of Pennsylvania in Philadelphia.
But as the field matures, he says,
this could give way to a more-systematic approach, similar to
the careful planning and testing of variables used for pediatric
Despite his concerns, Garon is
excited to be a part of the immunotherapy wave.
Last autumn, he and his colleagues
held a banquet for the patients who had been enrolled in his
first immunotherapy trials three years earlier. These were the
lucky survivors - the few who had shown a dramatic response.
As he looked around the table at the
guests of honor, he marveled at their recovery. All had been
diagnosed with advanced lung cancer, and many had been too weak
Now they were talking about their
families, re-embarking on careers and taking up old hobbies such
as golf and running.
"We've never been able to hold a
banquet like that before," he says. "I would love to hold
Leach, D. R., Krummel, M. F. & Allison, J. P. Science 271, 1734–1736
Enhancement of Antitumor Immunity by
Hodi, F. S. et al. N. Engl. J. Med. 363, 711–723 (2010)
Improved Survival with Ipilimumab in
Patients with Metastatic Melanoma
Curran, M. A., Montalvo, W., Yagita, H. & Allison, J. P. Proc. Natl
Acad. Sci. USA 107, 4275–4280 (2010) -
PD-1 and CTLA-4 combination blockade
expands infiltrating T cells and reduces regulatory T and
myeloid cells within B16 melanoma tumors
Larkin, J. et al. N. Engl. J. Med. 373, 23–34 (2015)
Combined Nivolumab and Ipilimumab or
Monotherapy in Untreated Melanoma
Ribas, A., Hodi, F. S., Callahan, M., Konto, C. & Wolchok, J. N.
Engl. J. Med. 368, 1365–1366 (2013) -
Hepatotoxicity with Combination of
Vemurafenib and Ipilimumab