Deploying the Body’s Army

Using patients’ own immune systems to fight cancer
BY JAMIE GREEN AND CHARLOTTE ARIYAN

More than a century ago, American bone surgeon William
Coley came across the case of Fred Stein, whose
aggressive cheek sarcoma had disappeared after he
suffered a Streptococcus pyogenes infection following surgery to
remove part of the large tumor. Seven years later, Coley tracked
Stein down and found him alive, with no evidence of cancer.
Amazed, Coley speculated that the immune response to the bacterial
infection had played an integral role in fighting the disease,
and the doctor went on to inoculate more than 10 other patients
suffering from inoperable tumors with Streptococcus bacteria.
Sure enough, several of those who survived the infection—and
one who did not—experienced tumor reduction.1
Coley subsequently developed and tested the effect of injecting
dead bacteria into tumors, hoping to stimulate an immune
response without risking fatal infection, and found that he was
able to cause complete regression of cancer in some patients with
sarcoma, a type of malignant tumor often arising from bone, muscle,
or fat. Unfortunately, with the increasing use of radiation
treatments and the advent of systemic chemotherapy, much of
Coley’s work was abandoned by the time he died in 1936.
Today, however, the use of immune modulation to treat cancer
is finally receiving its due. Unlike chemotherapy and radiation
treatments, which directly attack cancer cells, immunotherapy
agents augment the body’s normal immune machinery,
increasing its ability to fight tumors. This strategy involves either
introducing compounds that directly stimulate the immune cells
to work harder, or introducing synthetic proteins that mimic
the components of the normal immune response, thereby
increasing the body’s entire immune reaction. Last year, cancer
immunotherapy was named “Breakthrough of the Year” by
the journal Science, placing it in the company of the first cloned
mammal and the complete sequencing of the human genome.
With a handful of therapies already on the market, and dozens
more showing promise in all stages of clinical development,
these treatments are poised to forever change the way that we
approach cancer management.
The power of the immune response
The human immune system orchestrates processes that continuously
survey the host environment and protect it from infection.
The two main components of the human immune system, the
innate and adaptive arms, work together to fight infection and,
importantly, to remember which pathogens the host has encountered
in the past. Alerted by danger signals in the form of common
microbial peptides, surface molecules, or gene sequences,
innate immune cells such as macrophages and neutrophils
invoke broad mechanisms to quickly fight foreign invaders. At
the same time, B cells of the adaptive immune system generate
a highly specific response, creating antibodies that can recognize
and clear the pathogens. Antigen-specific T cells, activated
by innate immune cells that have ingested the pathogen, further
boost the body’s response. These B and T cells have lasting memory,
allowing them to generate faster and stronger responses on
subsequent exposures.

USING THE IMMUNE SYSTEM TO BATTLE CANCER
Researchers are now developing tumor-specific vaccines that present the body’s own immune cells with tumor-associated antigens in order
to elicit an immune response that specifically targets cancerous cells. There is currently one such vaccine on the market—Sipuleucel-T (below,
left), which is made by Seattle-based cancer research company Dendreon and was approved in 2010 as a last-resort treatment for metastatic
prostate cancer. Similar treatments for some other cancers are now in late-stage clinical trials.
Other strategies aim to maintain T cells in an active state so they can continue the fight against cancer. One approach is to block the
inhibitory pathways known as immune checkpoints that halt the immune response using drugs that block these inhibitory signals (box, right).
The FDA approved the humanized monoclonal antibody ipilimumab (marketed by Bristol-Myers
Squibb as Yervoy) for the treatment of advanced melanoma in 2011, and researchers are now
testing the drug in patients with other cancers, as well as developing similar immune checkpoint
blockade therapies.
A third immunotherapy currently under development is known as adoptive T-cell transfer.
This treatment involves isolating T cells from a patient; expanding them in the lab, where they
can be trained to more effectively target the cancer; then reinfusing them
into the body. To increase the efficacy of the method, researchers
are genetically engineering patients’ T cells to express receptors
specific for the tumor.

VACCINATING CANCER
Most cancer vaccines in development involve an
injection containing a component of a tumor-specific
antigen, with the goal of increasing the immune system’s
tumor-specific activity. Others, such as Sipuleucel-T,
involve the extraction of a patient’s antigen-presenting
cells (APCs), which are cultured with antigens from the
patient’s tumor along with immune-stimulating factors
to prime the APCs to activate T cells in the body.

DON’T STOP FIGHTING
Immune checkpoint blockade therapies work by preventing the
immune response from turning off when it normally would. By
blocking these immune checkpoints using molecules that bind T-cell
surface proteins such as cytotoxic T-lymphocyte antigen 4 (CTLA-
4) or programmed death-1 receptor (PD-1), which are expressed on
activated T-cells and normally dampen the immune response, the
treatments are able to maintain an active immune attack.

In the 1960s and ’70s, Lloyd Old of the Ludwig Institute for
Cancer Research at Memorial Sloan Kettering Cancer Center
(MSKCC) helped rekindle interest in cancer immunotherapy
research, finding, among other things, that tumor cells display
different surface antigens than healthy cells. These socalled
tumor-associated antigens serve as the basis for developing
cancer treatment vaccines, which attempt to stimulate
a tumor-specific immune response. Old’s discoveries were followed
in the 1980s by the work of Steven Rosenberg at the
National Institutes of Health. Rosenberg studied the use of
cytokines, which normally act to stimulate the immune system,
to treat cancer.
More recently, the advent of immune checkpoint blockade
approaches pioneered by James Allison, formerly of MSKCC and
current chair of the University of Texas MD Anderson Cancer
Center, has written immunotherapy into the oncologist’s playbook.
To ensure that the immune system does not become overactive,
causing tissue damage or attacking the body, regulatory
T cells (or Tregs) and myeloid-derived suppressor cells secrete
anti-inflammatory proteins or directly inhibit pro-inflammatory
immune cells. Additionally, immune checkpoint proteins
expressed on the surface of activated immune cells serve
to neutralize the immune response. Tumors may in fact exploit
these very anti-inflammatory pathways, perhaps by stimulating
an increase in Tregs or increased immune-checkpoint protein
expression, to evade recognition by the immune system. Allison
is now pioneering techniques to block these checkpoints, allowing
the immune response to continue to fight the tumor unhindered.
(See illustration at left.)
These exciting new therapies are able to prolong life in
patients whose cancers were previously deemed fatal, with kidney
cancer and malignant melanoma leading the pack.
Vaccinating to treat cancer
Localized injection of Bacillus Calmette-Guérin (BCG), an antituberculosis
vaccine made from attenuated live Mycobacterium
bovis, was approved for the treatment of bladder cancer in 1990.
It was the first immunotherapy approved by the US Food and
Drug Administration (FDA) for the treatment of cancer. The idea
that tuberculosis or BCG infection could have a role in fighting
cancer was first posited in 1929 by Johns Hopkins biogerontologist
Raymond Pearl, who noted a reduced incidence of cancer
among patients with active tuberculosis at the time of autopsy.2
Old went on to demonstrate in the late 1950s that BCG injections
in animal models could reduce tumor growth. Subsequent clinical
work in the 1970s and ’80s found that the treatment caused
regression of bladder cancers in patients given regular intralesional
BCG injections and a 12-fold reduction in bladder tumor
recurrence, along with decreased progression and improved survival.
Twenty years after its approval, BCG remains the most effective
therapy available for the treatment of non-muscle invasive
bladder cancer, resulting in the eradication of cancer in 70 percent
of eligible patients.

The attenuated bacteria decrease tumor growth by attaching
to the bladder tumor and surrounding cells and provoking the
infiltration of immune cells, proinflammatory cytokine release,
and eventual phagocytosis of cancerous cells by neutrophils and
macrophages. While this inflammatory response is efficient at
killing tumor tissue, it can also damage the healthy cells of the
bladder lining, resulting in side effects that mimic a urinary tract
infection, including low-grade fever and pain during urination.2
Researchers are now hoping to avoid the side effects of localized
injections by designing novel vaccines that trigger systemic
tumor-specific immune responses by binding to proteins unique
to tumor cells.
Unfortunately, tumor-specific vaccines have rarely demonstrated
significant antitumor activity and survival benefits in
humans. So far, only one vaccine of this type is on the market,
Seattle-based cancer research company Dendreon’s Sipuleucel-
T (or Provenge), approved by the FDA in 2010 as a last-resort
treatment for metastatic prostate cancer. In this case, vaccine production
involves extracting a patient’s own antigen-presenting
cells (APCs), a subset of white blood cells capable of activating T
cells, and reinfusing them several days later. While outside of the
body, the APCs are incubated with immune-stimulating factors
and prostatic acid phosphatase (PAP) antigen, a cell-surface protein
found on 95 percent of prostate cancer cells. The APCs then
reenter circulation armed to elicit an immune response against
the prostate tumor. (See illustration on page 36.) In randomized
controlled trials, the treatment caused a four-month improvement
in overall survival for eligible prostate cancer patients.3
Systemic injections of the PAP antigen and similar antigens
that target other types of cancer—as opposed to treatment of
white blood cells ex vivo as in Sipuleucel-T—have been shown to
elicit an immune response in the tumors. But they have not yet
been proven to increase survival times. Hundreds of vaccine clinical
trials of all stages, including Phase 3 trials for breast cancer,
lung cancer, kidney cancer, and melanoma, are now underway to
evaluate whether these therapies can indeed boost the cancerspecific
immune response and help patients.
Blocking immune inhibition
Another exciting and rapidly expanding category of immunotherapy
is immune checkpoint blockade. Immune checkpoints
are inhibitory pathways that help prevent overstimulation of the
immune system. Proteins on the surface of activated immune cells
turn off those cells when an immune battle is perceived to be over.
The cytotoxic T-lymphocyte antigen 4 (CTLA-4), for example, is
normally located inside T cells, but when expressed on the surface,
it functions as a “brake” signal to the immune system.
In the mid-1990s, Allison hypothesized that temporary interruption
of CTLA-4’s inhibitory effects could augment the immune
system and fight tumors. In preclinical models, he demonstrated
that treatment with an anti–CTLA-4 antibody was able to cure
mice of colon tumors, which can be made to form on the surface
of the body by injecting transplantable mouse colon cancer cells
subcutaneously.4 Early clinical studies in patients with malignant
melanoma demonstrated the treatment’s safety and hinted
at its efficacy. In 2010, a large Phase 3 trial showed that blocking
CTLA-4 with a humanized monoclonal antibody called ipilimumab
(or Yervoy, as marketed by Bristol-Myers Squibb) improved
overall survival in patients with late-stage melanoma.5
While the response rate was low, with only about 10 percent of
patients showing decreased tumor size after therapy and 18 percent
showing stable disease, ipilimumab was the first agent that
improved survival in these patients, who typically live only six
to nine months from diagnosis when treated with conventional
chemotherapy agents. Moreover, the majority of patients who
did respond to ipilimumab showed improvement lasting more
than two years. The FDA approved the drug for the treatment of
advanced melanoma in 2011, and follow-up studies of early trial
participants are showing that some patients live up to 10 years
after their initial ipilimumab treatment.6 Phase 2 and 3 trials are
now testing ipilimumab treatment for numerous other types of
cancer, including non–small cell lung cancer, prostate cancer, kidney
cancer, and ovarian cancer.
The most common adverse events associated with ipilimumab
treatment are immune-related and result from the drug’s
unleashing of the immune system. They include colitis, dermatitis,
and hepatitis, which all result from excessive inflammation.
Given ipilimumab’s low response rate, further work is needed to
improve this therapy.
One option may be to block other immune checkpoints, such
as the interaction between the programmed cell death 1 receptor
(PD-1) on T cells and its ligand (PD-L1) on APCs. Similar
to CTLA-4, PD-1 is expressed on activated T cells, as well as on
“exhausted” T cells that have been shut off despite the persistence
of pathogens. When PD-1 binds to PD-L1, the T-cell response
is attenuated. Interestingly, in addition to expression on APCs,
PD-L1 has also been found on tumor cells, and it is thought to
play a role in how tumors are able to evade the immune response.
Early results have been promising for Bristol-Myers Squibb’s
nivolumab, an anti-PD-1 antibody, in the treatment of malignant
melanoma, non–small cell lung cancer, and kidney cancer, and
Phase 3 trials are currently under way to investigate the potential
survival benefit of this novel agent.7 Similar studies are also being
conducted for PD-L1 inhibitors.
Early research testing the combination of anti–CTLA-4 and
anti–PD-1 medications also point to the benefits of blocking both
immune checkpoints simultaneously. In a study published by one
of us (Ariyan) in the New England Journal of Medicine last July,
more than half of metastatic melanoma patients treated with the
maximum combination dose of nivolumab and ipilimumab had
a greater than 80 percent reduction in tumor mass, and more
than 80 percent of these patients were alive a year after treatment.
8 These promising results for a disease with so few treatment
options show why immune checkpoint blockade is altering
the landscape of cancer therapy.
Transferring T cells
A third way to boost the immune attack on a tumor is to isolate T
cells from a patient, expand them in the laboratory, then reinfuse
them into the body as souped-up cancer-fighting agents. Known
as adoptive T-cell transfer, the procedure was initially performed
using tumor-infiltrating lymphocytes (TIL), a subset of white
blood cells that have left the circulating blood and migrated into
solid tumors, and which can be isolated from excised tumors. (See
“Imagining a Cure,” The Scientist, April 2011.) Unfortunately, disease
progression in some patients is too quick to allow the time
needed for the extensive ex vivo work, which can take up to a
month; but for those who can wait, the therapy may be of some
help. In a Phase 2 trial published in 2010, half of 20 patients with
stage IV melanoma showed noticeable improvement following
treatment, including two complete remissions.9
This strategy is limited, however, in that some patients do not
have a lesion that can be excised, or the excised tumor does not
have any TILs that grow or that demonstrate antitumor reactivity
in vitro. To circumvent these hurdles, researchers have developed
chimeric antigen receptors (CARs) as a method of genetically
modifying a patient’s circulating T cells to make them target
tumor cells. CARs include an antigen-recognition domain, or
modified antibody segment, which is able to recognize a specific
protein on the surface of tumor cells, and an intracellular domain
that activates the T cell and stimulates in vivo proliferation.10
Researchers have designed CARs to treat a variety of cancers,
including chronic lymphoid leukemia (CLL). In one case, they isolated
T cells from a CLL patient’s blood and engineered them to
express a CD19-targeting CAR. CD19 is a protein that is expressed
on the surface of normal B cells, as well as on malignant B cells.
After expanding the modified B cells in vitro, researchers reinfused
them into the patient, who had failed to respond to all previously
available treatment regimens. Following treatment, this
patient, and now numerous others, was found to be cancer free.11
(See “Commander of an Immune Flotilla” on page 56.)
While there are currently no FDA-approved therapies involving
such T-cell manipulations, numerous Phase 1 and 2 trials are
underway to determine safety profiles on a larger scale as well as
effects on survival for a variety of different cancer types, including
leukemia, lymphoma, pancreatic cancer, breast cancer, prostate
cancer, and melanoma.
The future of immunotherapy
Immunotherapy is quickly proving itself as a powerful weapon in
the fight against cancer, and research continues to further improve
the effectiveness of this approach and to broaden the number of
patients that are able to benefit from it. Many researchers are currently
studying the effects of combining multiple immunotherapy
methods, such as immune checkpoint blockade and adoptive
T-cell transfer, or cancer treatment vaccines and cytokine administration.
In the coming years, it will be exciting to see the profound
effects that immunotherapy agents are expected to have on
human survival as the hundreds of clinical trials currently interrogating
this breakthrough begin to bear fruit. 􀁊
Jamie Green is a general surgery resident at New York Presbyterian
Hospital-Weill Cornell Medical College and is currently
completing a Surgery Research Fellowship at Memorial Sloan
Kettering Cancer Center, where Charlotte Ariyan is an assistant
attending who is conducting clinical trials on ipilimumab.
References
1. S.A. Cann et al., “Dr William Coley and tumour regression: a place in history
or in the future,” Postrgrad Med J, 79:672-80, 2003.
2. N.M. Gandhi et al., “Bacillus Calmette-Guerin immunotherapy for
genitourinary cancer,” BJU Int, 112:288-97, 2013.
3. P.W. Kantoff et al., “Sipuleucel-T immunotherapy for castration-resistant
prostate cancer,” N Engl J Med, 363:411-22, 2010.
4. D.R. Leach et al., “Enhancement of antitumor immunity by CTLA-4 blockade,”
Science, 271:1734-36, 1996.
5. F.S. Hodi et al., “Improved survival with ipilimumab
in patients with metastatic melanoma,” N Engl J Med,
363:711-23, 2010.
6. Z. Chustecka, “Some melanoma patients living for
up to 10 years after ipilimumab,” Medscape Medical
News, Sept 2013.
7. S.L. Topalian et al., “Safety, activity and immune
correlates of anti–PD-1 antibody in cancer, ” N Engl J
Med, 366:2443-54, 2012.
8. J.D. Wolchok et al., “Nivolumab plus ipilimumab in
advanced melanoma, ” N Engl J Med, 369:122-33,
2013.
9. M. Besser et al., “Clinical responses in a phase II
study using adoptive
transfer of shortterm
cultured tumor
infiltration lymphocytes
in metastatic melanoma
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Res, 16:2646-55, 2010.
10. N.P. Restifo et
al., “Adoptive
immunotherapy for
cancer: harnessing the
T cell response,” Nat
Rev Immunol, 12:269-
81, 2012.
11. D.L. Porter et al.,
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