Download game changer for cancer

42 — FEATURE
Issue 69
GAME
CHANGER
FOR CANCER
At last: the immune system is being
recruited in the war against cancer.
DYANI LEWIS investigates.
IMMUNE RESPONSE: T-cells attack a cancer cell.
COSMOS
FEATURE — 43
01
44 — FEATURE
Issue 69
RON WALKER has never been one to shy
from a challenge. But at 72, the former
lord mayor of Melbourne was thrown
a curveball. A pea-sized lump on his
forehead turned out to be a melanoma.
THE IMMUNE
SYSTEM IS A
SMART ARMY,
DESIGNED
BY NATURE
TO IDENTIFY
AND DESTROY
ONLY ENEMY
CELLS, AND
TO KEEP ON
DESTROYING
THEM.
ONCE REMOVED , and with the lymph nodes
showing all clear, his surgeon was optimistic.
Within a year tumours blossomed in his lungs,
bones and brain.
Walker was given a few months to live.
In a last-ditch attempt, he travelled to Los Angeles
to enrol in a trial of a new drug, Keytruda. Every
three weeks, Walker watched drug-laced fluid
drain from the drip into his arm. After just four
treatments, his tumours began shrinking. A year
and a half later, his cancer was nowhere to be seen.
Similar stories of survival against the odds
are found across the globe, given prominence by
celebrity recipients such as former US President
Jimmy Carter, who used the drug to great effect in
his fight against melanoma.
Keytruda and similar drugs are heralded as
game-changers in the cancer community. “It’s
absolutely profoundly changed the way we think
about cancer treatment,” says Grant McArthur,
Walker’s oncologist at the Peter MacCallum Cancer
Centre in Melbourne.
Unlike most cancer treatments, these new
drugs do not kill cancer cells. Rather, they unleash
the formidable forces of the immune system. The
approach is dubbed “cancer immunotherapy”.
Science magazine, normally conservative with its
calls, crowned it the 2013 breakthrough of the year.
Pharmaceutical companies are spending billions on
the new drugs, some already approved and others
being fast-tracked through the regulatory pipeline.
So is it time to sound the victory call in the war
on cancer? Well, no.
Victories like those of Walker or Carter are still
exceptions. About 40% of melanoma patients show
little response to Keytruda. And for other types of
cancer, the figures are worse. These are deflating
statistics for desperate patients and their battleweary oncologists. “What we’ve seen so far are
the stand-outs – the cancers which are clearly very,
very sensitive to immunotherapy,” says Hui Gan,
a brain cancer specialist at the Joint Austin Ludwig
Oncology Unit in Melbourne. Why, then, is cancer
immunotherapy exalted as a breakthrough?
Because the war on cancer, first declared by US
president Nixon in 1970, has been fought long and
hard. Until now the dominant strategy has been
slash, burn and poison – surgery, radiation and
chemotherapy.
This scorched-earth approach destroys tumours
but also causes a lot of collateral damage. And the
tumour often returns. By contrast, the immune
system is a smart army, designed by nature to
identify and destroy only enemy cells, and to keep
on destroying them.
What researchers now have in their sights
is commanding this army, with its numerous
divisions, communications systems and
sophisticated weaponry. That’s why, even with the
treatment’s limitations, hopes are so high.
“People use words like ‘game-changer’ – well it
is a game-changer,” says Jonathan Cebon, medical
director of Melbourne’s Olivia Newton-John
Cancer Research Institute. “A lot of incurable
cancers are now coming under control, often
long‑term. It’s something that we’ve never seen
before in the history of oncology.”
NOT SO LONG AGO , medical wisdom held that the
immune system could not be marshalled against
cancer. It’s an army exquisitely trained to recognise
foreigners like bacteria or viruses. It is also welltrained not to attack our own cells. And cancer cells
are our own cells.
Yet there have long been hints that the immune
system might be recruited to the cause.
In 1890 an astute young American surgeon
by the name of William Coley noticed that in
FEATURE — 45
COSMOS
some patients, cancers melted away after a severe
bacterial infection. He tried to replicate the effect
by injecting patients with a bacterial brew known as
Coley’s toxins. Despite some success the technique
did not take hold, largely because there was no clear
understanding of what the toxins were doing. Were
they especially deadly to cancer cells or did they
work some other way?
In more recent times, hints came from cancer
patients who’d received bone marrow transplants.
Bone marrow is one of those tissues that suffers
huge collateral damage after cancer therapy.
Cancer patients can’t survive long without the
constant stream of fresh red and white blood cells
that the transplanted bone marrow provides.
But occasionally the transplant itself was deadly,
turning on the patient’s tissues, a scenario known
as graft-versus-host disease. To avoid it, doctors
removed the most aggressive of the foreign bone
marrow cells, white blood cells known as T-cells.
They successfully reduced the risk of graft-versushost disease; they also reduced the efficacy of the
cancer treatment. It seems the foreign T-cells were
obliterating the cancer cells.
Another major clue came from the AIDS
epidemic. Patients’ immune systems were
obliterated by the HIV virus. One of the first
symptoms of their disease was tumours. And in
some cancer patients, there was a compelling
but perplexing finding: their tumours were often
infiltrated with T-cells –evidence that the immune
system had answered the call to battle. But clearly
that wasn’t enough.
THROUGHOUT THE 1980S researchers tried to
boost the immune system in the time-honoured
fashion – by developing a vaccine. For instance, the
measles vaccine is made by taking a fragment of the
virus, an “antigen”, and mixing it with an irritating
chemical called an “adjuvant”. The adjuvant
recruits the immune forces, which are trained to
recognise the antigen – rather like teaching troops
to recognise the stripes on an enemy uniform. These
troops stand ready and waiting to nip any future
incursion of the measles virus in the bud.
Thierry Boon and colleagues at the Brussels
branch of the Ludwig Institute for Cancer Research
took a similar approach to train an immune army
against melanoma. They used a protein unique to
melanoma cells as the antigen in a vaccine to boost
immunity against the cancer.
“Overall the results were disappointing,” recalls
Cebon, who devoted over 20 years of his career to
pursuing a melanoma vaccine. The dismal story
was repeated over and over for vaccines against
different cancers. In the war against cancer, it was
not a proud moment for the immunology brigade.
But some researchers were not ready to give up.
They turned their attention to where there had been
a flicker of promise: those T-cells found camped
inside tumours. These T-cells had clearly recognised
the enemy, yet failed to vanquish it. Were they just
outnumbered? Steven Rosenberg, a surgeon at the
US National Cancer Institute near Washington DC,
decided to send in reinforcements.
From the tumours he had removed from his
patients, he extracted T-cells and stimulated
their growth with a natural booster called IL-2.
The cells multiplied into an army of billions of
tumour-recognizing T-cells, which Rosenberg
returned to his patients. The technique, termed
“adoptive cell therapy”, worked. In a 2011 trial of
patients with advanced melanoma, more than half
of the participants saw their tumours shrink; 40%
underwent complete remission and some remained
cancer-free for more than four years.
02
Ron Walker lobbied for Keytruda to be approved
by the government after he had success with it.
Meanwhile another group of researchers took
a different tack. Harking back to the T-cells camped
around the tumours, it seems there was more to
their wimpiness than simply being outnumbered.
T-cells are formidable killers that specialise in
destroying cells infected by viruses. Once the viral
infection is contained, it’s crucial to deactivate
them lest they fire on innocent cells. So T-cells come
with molecular muzzles to keep them in check.
(In the jargon they are known as “checkpoints”.)
46 — FEATURE
Issue 69
Those muzzles have to be locked into place. Usually
that’s the job of regulatory cells that act like military
police. Astoundingly, cancer cells – consummate
survivors that they are – have also learnt how to
lock down the muzzles.
IN 1997, IMMUNOLOGIST James Allison, now at the
University of Texas MD Anderson Cancer Centre,
identified the first of these muzzles, called CTLA-4.
Working in mice, he experimented with drugs that
unmuzzled CTLA-4. “All we’d have to do was just
give one, maybe two injections and the tumours
would disappear,” he says. Another muzzle goes
by the name of PD-1.
Certain contingents of the immune system
possessed keys capable of locking down the muzzles
on the T-cells. For instance, one of the keys for
muzzling T-cells is known as PD-L1. Lieping Chen,
now at Yale University, discovered some tumours
possessed this same key. In other words, a tumour
can direct T-cells to lay down their arms. Cracking
these communication codes offered a whole new
strategy for unleashing the immune system. Drugs
(engineered antibodies) could be designed to
interfere with the muzzling of T-cells by clogging
up the CTLA-4 and PD-1 locks or the PD-L1 key.
Yervoy, the first drug to unmuzzle CTLA-4,
yielded striking results in advanced melanoma
patients. Eleven per cent of patients who received
the drug saw some tumour shrinkage compared
to 1.5% in the group who received a different
treatment.
But the real excitement was the long survival
tail. With previous melanoma treatments, the
number of long-term survivors would drop to
5-10% of those treated. With Yervoy, 20% of
patients shifted into the tail. Some of the first
trial participants are alive today, 14 years after
treatment.
Unlocking the PD-1 muzzle has produced
even more impressive results. The miracle drug
Keytruda, acts this way. In one head-to-head
comparison published in the New England Journal
of Medicine last year, 74% of melanoma patients
on Keytruda were still alive after a year, compared
with 58% on Yervoy. (Without immunotherapies,
as few as 25% survive this long.) A small trial of
Opdivo (another drug that unlocks PD-1)
in patients with relapsed Hodgkin’s lymphoma
saw a stunning 87% response rate.
Keytruda may have the edge over Yervoy
because it strikes a better balance between
unleashing killer cells while minimising collateral
damage.
Drugs that block PD-L1, the key carried by
tumour cells, are also being developed. Small trials
suggest they are about as effective as those that
unmuzzle PD-1 with similar rates of side effects.
Keytruda and Opdivo were initially approved in
the US in 2014 to treat advanced melanoma, but in
2015, both drugs were approved for use in advanced
non-small cell lung cancer and kidney cancer, where
the response rates are about 25%.
Approvals are also in the pipeline for head
and neck cancer, bladder cancer, and Merkel
cell carcinoma, says Thomas Gajewski, a cancer
immunologist at the University of Chicago who
has pioneered immunotherapy trials. Small trials
of 20-40 patients are also showing responses with
gastric cancer, triple negative breast cancer, ovarian
cancer, oesophageal cancer, mesothelioma and
bladder cancer. “It’s not just a melanoma story,”
says Cebon. “And it’s not just a matter of a couple
of extra months. Some patients get complete
remissions which last for years.”
Nevertheless, while some patients see their
cancers melt away, others have tumours that
stubbornly persist, meaning most trials show only
a modest few months of life extension on average.
And for the common types of breast and colon
cancer, responses are rare, says Cebon. So can these
resistant cancers be tackled by the immune system?
Yes, believes Gajewski. He points out that
T-cells are straitjacketed through multiple locks.
The hope lies in steadily identifying them, and
unpicking them. For instance a recent advance
came from identifying another muzzle called IDO.
A trial where both PD-1 and IDO were unmuzzled,
saw the response rate to melanoma climb over 50%.
“These developments are occurring at breathtaking
speed compared to the sloth-like pace of typical
oncology drug development,” says Gajewski.
WHILE ONE GROUP of researchers was busy
learning how to unleash T-cells, another was trying
to develop an immune special ops force. If the
search and destroy capability of T-cells is limited,
why not give them tailor‑made guidance systems
and sustained blast power? When Michel Sadelain
at the Memorial Sloan Kettering Cancer Centre in
New York mooted the concept in the 1980s, he says,
“It was perceived as … science fiction”. But it’s an
idea whose time has come.
The guidance on a T-cell comes from a T-cell
receptor, which can be genetically engineered to
recognise antigens on the surface of specific types
of cancer cells. Alternatively, a completely artificial
receptor known as a chimeric antigen receptor
FEATURE — 47
COSMOS
A
CLOSER
LOOK
MOBILISING T-CELLS
FOR BATTLE
VACCINES
ADOPTIVE CELL THERAPY
ENGINEERED T-CELLS
Inject tumour antigen
into patient
T-cells surround a patient’s
tumour but do nothing
Isolate T-cells from
patient’s blood cells
Antigen activates T-cells
to recognise tumour cells
Isolate T-cells
Engineer T-cells to produce
molecules that recognise
cancer cells
Activated / engineered T-cells
attack the cancer cell
Multiply T-cells in culture
Multiply engineered
T-cells in culture
Infuse multiplied
T-cells into patient
Infuse engineered
T-cells into patient
48 — FEATURE
A
CLOSER
LOOK
Issue 69
HOW CHECKPOINT INHIBITOR
DRUGS WORK
Regulatory cell
The T-cell is locked into an “off”
state via its PD-1 and CTLA-4
locks. Regulatory cells possess the
key to engage these locks. So do
tumour cells.
Tumour cell
CTLA-4 lock
T-cell off
PD-1 lock
To liberate cancer-killing T-cells,
the locks and keys are gummed up
with checkpoint inhibitors.
PD-L1 key
Anti-CTLA-4 ipilimumab (Yervoy)
T-cell on
Anti-PD-1 pembrolizumab (Keytruda)
Anti-PD-L1 durvalumab (MEDI4736)
FEATURE — 49
COSMOS
(CAR) can be engineered. The destructive power
of these receptors can also be enhanced by adding
modules that ensure T-cells stay switched on.
To deliver these engineered receptors into T-cells,
the cells are removed from a patient and infected
with a virus that carries the receptor DNA. The
engineered T-cells are called CAR T-cells.
Between 2011 and 2013, promising results
in a handful of leukaemia patients silenced the
sceptics. In most cases, the leukaemia melted
away after a single infusion of the engineered cells,
followed by complete remission in just three weeks.
“There’s no doubt that when these cells go into
the body, they mean business,” says Sadelain,
who refers to them as “living drugs”.
The great promise of these cells is that they
can be engineered to attack cancers that normally
fly under the radar of the immune system. Clinical
trials of T-cells engineered to attack brain, breast,
liver, ovarian, pancreatic and ovarian cancers are
already underway.
But there’s a rub. If any non-cancerous
tissue contains the same antigens recognised by
the modified T-cells, it too will be marked for
destruction. Finding targets specific to each cancer
is key. But sometimes researchers have been fooled.
In a tragic 2011 case of a 39 year old woman with
colon cancer, CAR T-cells were targeted at an
antigen – ERBB2 – known to be abundant on the
surface of colon cancer cells. But it also turned out
to be present at low levels in her lung tissue. Within
15 minutes of being infused with the suped-up cells,
she went into severe respiratory distress and died
five days later. Clinicians are now on high alert to
an immune system going haywire, and can usually
keep things under control using corticosteroids
and other drugs.
The other challenge in using CAR T-cells is
to make the technology accessible on a large scale,
given that each patient needs their own batch of
T-cells engineered, a process that takes several
weeks. Companies are rising to both challenges.
Immunocore in Abingdon, UK, is using gene
databases to screen cancer targets to ensure they
do not appear in vital tissues. Sadelain believes
robotics could speed up the engineering of patients’
T-cells and co-founded a biotech start-up, Juno
Therapeutics, to commercialise CAR therapies.
In an illustration of the frenzy that surrounds this
field, Juno went public in 2014 and within a month
was valued at a record US$4.7 billion.
In Australia, Alan Trounson, former president
of the California Institute of Regenerative Medicine
has founded a cancer immunotherapy start-up,
Cartherics Pty Ltd, based at the Monash Health
Translation Precinct in Melbourne. Rather
than engineering T-cells for individual patients,
the company aims to make broadly compatible
“off‑the‑shelf” CAR T-cells. The idea is to start with
donors whose blood cell types represent about half
the population.
AS WITH ANY WAR , the winning strategy for
immunotherapy will be one that coordinates the
different elements of the immune army: the regular
fighting forces and special ops, the communication
codes, the weaponry. To that end, trials that involve
a mind-boggling number of combinations of the old
and new are underway. For instance, radiotherapy
which rouses the immune system (what we call
inflammation) is being combined with cancer
vaccines. Other trials are combining Keytruda
and Yervoy, or adding in vaccines or battalions
of T-cells.
Tailoring the treatment to each patient is
crucial, because each cancer, in effect, requires a
different type of battle plan. “We are just scratching
the surface of what can be achieved,” says Cebon.
CANCER IMMUNOTHERAPY does not yet mean
a cure-for-all, but there’s no doubt researchers have
begun an entirely new type of war against cancer.
And as they master the command of the immune
forces, many are confident that a lasting victory may
be within reach.
David Bowtell, a geneticist at the Peter
McCallum Cancer Centre, sums up the views of
many: “The history of cancer medicine has been one
of excitement subsequently tempered by reality.
We’ve been hampered because what occurs in
one cancer doesn’t necessarily apply to the many.
However, medicine is also characterised by gaining
a ‘beachhead’ and then ‘invading inland’. My money
would be on this being a D-Day rather than a
Gallipoli experience.”
DYANI LEWIS is a freelance science journalist
based in Hobart.
IMAGES
01 Maurizio De Angelis / Science Photo Library / Getty Images
02 Michael Clayton-Jones / Fairfax
ILLUSTRATIONS
Ellen Porteus / Jacky Winter Group
THERE’S
NO DOUBT
THAT WHEN
THESE CELLS
GO INTO
THE BODY,
THEY MEAN
BUSINESS.