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Caitlin Turner-Lafving
11/19/2014
Cancer Immunology: The Future of Cancer Treatment Looks Bright
If you get a chance, stand in a crowded space for a few minutes and just look
around. Recent statistics show that almost everyone you see has been affected by cancer
in some way. In 2012, the National Cancer Institute estimated that 1,638,910 new cancer
cases would be diagnosed that year. Another 577,190 Americans were expected to die of
cancer in 2012 alone. That amounts to more than 1,500 lives taken by cancer every
single day (“Cancer Facts,” 1). Those statistics are just one of the many reasons why
advancements in cancer treatments are important to so many people in America and
around the world.
The only good thing about cancer affecting so many people is that scientific
research geared toward cures for cancer has substantially increased. In fact, a very
promising treatment called cancer immunology was named Science’s 2013 Breakthrough
of the Year. This new way of treating cancer is actually the product of twenty years’
worth of discovery and testing, but not until last year did it “cement its potential in
patients and sway even the skeptics,” said Jennifer Couzin-Frankel, author of the 2013
Science Breakthrough article. The specific treatment that initially made cancer
immunology stand out, called ipilimumab, is notable because the results of its clinical
trials were “the first time any treatment had extended life in advanced melanoma in a
randomized trial” (Couzin-Frankel). The 2010 ipilimumab trials went so well that the
FDA approved it in 2011 for use in patients with metastatic melanoma, both as an initial
treatment option and for use after a relapse (Mellman, Coukos & Dranoff, 483).
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So what exactly is cancer immunology? At its most basic level, it involves
unblocking an immune system blocker that prevents the immune system from attacking
cancerous cells or combatting their growth. What makes cancer immunology remarkable
is its “entirely different way of treating cancer,” targeting the immune system rather than
tumors themselves (Couzin-Frankel). Why target the immune system? From a logical
standpoint, if it can fight off infections and wipe out damaged cells, it should be able to
wage war against tumor cells as well (de Visser, Eichten & Coussens, 24). A brief
overview of the immune system will help illustrate why it doesn’t already do this and
what researchers focusing on cancer immunology are doing to change that.
Our immune system provides different responses depending on the agent
detected; the type of agent determines whether it is the innate or adaptive immunity that
responds. Innate immunity distinguishes normal tissues belonging to the body from new
‘non-self’ proteins or cells and attacks what it finds to be ‘non-self.’ Adaptive immunity
is more complex, triggered by intracellular pathogens that are detected by the receptors of
specialized immune cells called T cells. “Both innate and adaptive immunity can
contribute to a response to malignancies,” therefore, uninhibited cancerous growth can be
a consequence of either type of immunity tolerating the cells instead of attacking them
(Bremers and Parmiani, 3).
One significant reason innate immunity does not consistently work against cancer
is that tumors do not express non-self antigens and “are not truly foreign” (Houghton, 1).
When it comes to adaptive immunity, a protein receptor on the surface of T cells, called
cytotoxic T-lymphocyte antigen 4 (CTLA-4), is an antigen that has been found to halt T
cells, preventing them from initiating immune attacks (Couzin-Frankel). Introducing an
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antibody to block this blocker could generate an adaptive immune response to cancer
cells that was previously suppressed; if the antibody was successful, it would allow for
“greater expansion of all T-cell populations, presumably including those with antitumor
reactivity,” says Dr. Finn of the Department of Immunology at the University Of
Pittsburgh School Of Medicine (Finn, 2710). It is this specific branch of cancer treatment
– developing antigens to counteract immune system antibodies currently preventing an
immune response – that landed cancer immunology Science’s Breakthrough of the Year
award.
Why is cancer immunology such a new approach to cancer treatment? For
starters, the first blocker to be discovered – CTLA-4 – was only found in 1987 by French
researchers who were not focused on cancer (Couzin-Frankel). However, American
cancer immunologist James Allison recognized the potential implications of CTLA-4,
hypothesizing that blocking this blocker could leave the immune system free to eradicate
cancer cells (Couzin-Frankel). In 1996, Allison’s trials on mice demonstrated that
blocking CTLA-4 did, in fact, induce an antitumor immune response (Samelson and
Klausner, 149).
Fourteen years later, in 2010, results from clinical trials using Allison’s CTLA-4
specific antibody in human patients with metastatic melanoma cemented the potential of
cancer immunotherapy. The company running the trials reported that patients with
metastatic melanoma “lived an average of 10 months on the antibody, compared with 6
months without it” and “nearly a quarter of participants survived at least 2 years”
(Couzin-Frankel). As Drew Pardoll, Professor of Oncology, Medicine, Pathology and
Molecular Biology and Genetics at the Johns Hopkins University School of Medicine
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acknowledges, this is significant because it “was the first therapy to demonstrate a
survival benefit for patients with metastatic melanoma” (Pardoll, 255). Then, in 2013,
the company reported even better statistics, showing that 22% of the 1800 melanoma
patients treated with the antibody were alive three years later (Couzin-Frankel). This
successful anti-CTLA-4 antibody is now an FDA-approved treatment for metastatic
melanoma – ipilimumab!
Another blocker, called programmed cell death protein 1 (PD-1), was discovered
in the early 1990’s. PD-1 functions differently than CTLA-4; it regulates the activity of
T cells in tissue and tumors, while CTLA-4 regulates the activation of T cells (Pardoll,
256). Many types of cancers – particularly most melanoma, ovarian and lung cancer
samples – have been found to upregulate PD-1 expression, which decreases the activity
of T cells and therefore limits the adaptive immune response to cancer (Pardoll, 258).
Because of this, the anti-PD-1 antibody performs a different function than ipilimumab
does to get the immune system to fight cancer. By blocking PD-1, it enhances the
antitumor efforts of T cells within tumors (Pardoll, 257).
The clinical trial process for PD-1 antibodies began years after those for CTLA-4,
so there are not as many results. However, what results are available seem very
promising. In 2012, a trial began that included 296 patients and five different types of
cancer – advanced melanoma, non-small-cell lung cancer, castration-resistant prostate
cancer, and renal-cell cancer. Of the 236 patients whose responses could be evaluated,
successful responses, either complete or partial, were found in “approximately one in four
to one in five patients with non-small-cell lung cancer, melanoma, or renal-cell cancer”
(Topalian et al).
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Multiple additional T cell antigens have been identified very recently, but are not
far enough through the clinical stages to have results yet. Each antibody is specific to an
individual antigen that regulates the immune responses at different levels and in different
ways. This makes the process of developing each antigen-specific antibody complex.
However, there are many antibodies for the newly discovered antigens already under
development (Pardoll, 253).
Although cancer immunology treatments have proven to positively affect some
types of cancer, it’s important to know that there are potential negative side effects.
There is a level of immune toxicity that comes with these treatments. The first antiCTLA-4 treatment tested on mice, tremelimumab, created levels of immune toxicity too
high to be safe (Pardoll, 260). However, the toxicity that comes with ipilimumab is much
lower, which is why it was certified by the FDA (Pardoll, 260). Fortunately, the anti-PD1 treatment results in even less immune toxicity than ipilimumab (Pardoll, 260). Horror
stories from early clinical trials of other cancer immunotherapies during which severe
toxicities and death occurred have demonstrated “the power of the immune system and
the need for extreme care and a conservative trial design when using any immune
activator” (Mellman, Coukos & Dranoff, 485). Toxicity is now something closely
monitored by researchers and developers working on cancer immunotherapies, so it
should not be a problem in the future.
Looking toward the future, researchers have begun experimenting with combining
immunology treatments that have been proven to work. One hope is that the combination
will successfully treat some patients who were not positively affected by just one.
Another hope is that patients whose immune systems were incited to attack the cancer
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will remain in remission, if not by the one treatment, then by the combination. According
to Phillip Darcy, head of the Cancer Immunotherapy laboratory at the Peter MacCallum
Cancer Centre, and his co-head, David Ritchie, the results of melanoma patients using the
combination of anti-CTLA-4 with anti-PD-1 treatments “is an exciting advance” and
suggests that other similar combinations “may lead to expanding therapeutic options”
(Darcy and Ritchie, 2).
Especially after being named Science’s Breakthrough of the Year, cancer
immunology has proven its potential as a cancer treatment of the future. Progress will be
slow due to the specificity of each antibody made to target each specific, newly identified
antigen, but the success rates of the immunotherapies already developed prove that
further research in the field is worthwhile. Probably the most exciting part of cancer
immunology is simply the ingenuity behind using the immune system for cancer
treatment. It raises questions about what other life-changing discoveries in medicine are
yet to be designed in the twenty-first century.
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Works Cited
American Cancer Society. Cancer Facts & Figures 2012. Atlanta: American Cancer
Society; 2012.
Bremers, Andreas JA, and Giorgio Parmiani. "Immunology and Immunotherapy of
Human Cancer: Present Concepts and Clinical Developments." Critical reviews in
oncology/hematology 34.1 (2000): 1-25.
Couzin-Frankel, Jennifer. "Cancer Immunotherapy." Science 342.6165 (2013): 14321433.
Darcy P., Ritchie D. “Editorial overview: Tumor Immunology: New frontiers in Cancer
Immunotherapy.” Current Opinion in Immunology 27 (2014): vii-x.
de Visser, Karin E., Alexandra Eichten, and Lisa M. Coussens. "Paradoxical Roles of the
Immune System During Cancer Development." Nature reviews cancer 6.1 (2006):
24-37.
Finn, Olivera J. “Molecular Origins of Cancer Immunology.” The New England Journal
of Medicine 358 (2008): 2704-2715.
Houghton, Alan N. "Cancer Antigens: Immune Recognition of Self and Altered
Self." The Journal of experimental medicine 180.1 (1994): 1-4.
Mellman, Ira, George Coukos, and Glenn Dranoff. "Cancer Immunotherapy Comes of
Age." Nature 480.7378 (2011): 480-489.
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Pardoll, Drew M. "The Blockade of Immune Checkpoints in Cancer
Immunotherapy." Nature Reviews Cancer 12.4 (2012): 252-264.
Samelson, Larry, and Richard Klausner. "Immunotherapy: It Takes a Village." Science
344.6180 (2014):149.
Topalian, Suzanne L. et al. “Safety, Activity, and Immune Correlates of Anti–PD-1
Antibody in Cancer.” The New England journal of medicine 366.26 (2012):
2443–2454. PMC. Web. 10 Nov. 2014.