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Immunotherapy: The Road to Legitimacy and
Promising Future

Abigael Gunther

June 16, 2017

Abstract

Cancer is one of the most frightening and notorious diagnoses faced by
humankind to date. Therefore it is imperative to develop efficient and effective
treatment methods for this disease. This paper will review the brief and controversial
history of immunotherapy as a field, the role of the immune system in fighting cancer,
and we will emphasize three current therapies and the challenges they face. A basic
understanding of the immune system is critical in understanding its relationship to
cancer. As a relatively new field, immunotherapy has had a divisive history and faced
a challenging road to legitimacy. We review three main divisions of immunotherapy
including monoclonal antibodies, immune checkpoint inhibitors, and cancer vaccines.
We will emphasize the strengths and weaknesses of the three approaches and
determine the most promising option of cancer treatment to be through monoclonal
antibody techniques. Information has been assimilated from leading experts in the
field and compiled to provide a succinct view on the significance of immunotherapy.
This review encourages the acceptance and financial support of the medical and
scientific communities to further research the scope of cancers that monoclonal
antibody techniques can impact.

Keywords: Adaptive immune response, antigen, antibodies, athymic, B-lymphocytes,
cytotoxicity, host cells, immunosurveillance, immunotherapy, major
histocompatibility response, monoclonal antibodies, natural killer cells, T-
lymphocytes.

Introduction to the Immune System

In a world full of microbes and pathogens, the human body evolved a defense
mechanism to fight off substances that can act as a threat. The immune system
possesses an awesome destructive ability against a broad range of foreign substances
and cells. In order to prevent the destruction of critical healthy host cells, the immune
system has developed self-tolerance. In other words, the growth of mechanisms to
stop reactions against attacking these host, “self-cells”.

The immune system can be divided into two complementary organizations, the
innate and adaptive system (Weinberg, 2014). The innate immune system is
nonspecific; it is the first round of defense that includes aspects like physical barriers
and general chemicals in the blood. The adaptive immune response is more precise
and relies on important leukocytes, called B or T lymphocytes, which target specific
antigens. All cells have a complex system of surface proteins and specific
arrangements that denote their origin of being self or non-self. When a foreign
substance is considered to be an antigen it is identified by its surface proteins to be a
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“non-self” cell and an immune response is triggered. When an antigen is recognized, a
series of B-lymphocytes produce antibodies that lock onto the foreign cells and signal
the T lymphocytes to destroy it. Although the mechanisms of action for the innate and
adaptive systems appear to be fundamentally different, they work synergistically to
form one fully effective and efficient immune system (Chaplin, 2010).

Acceptance of Immunotherapy

Immune system research has been occurring for centuries, with some slow and
some revolutionary breakthroughs. In the late 1800s, William Coley began
questioning whether the immune system could influence cancer treatment and
immunotherapy was born. Immunotherapy is defined as a cancer treatment that takes
advantage of the body’s naturally developed immune system. Interestingly this is a
fairly new field, as evidence for its existence only became overwhelming convincing
in the past 30 years. Coley is widely acknowledged to be “the Father of
Immunotherapy” as he was the first to research, study, and publish findings in 1893
(Parish, 2003). His interest was sparked by the complete remission of a cancer patient
following two incidences of a severe Streptococcus pyogenes bacterial skin infection.
For the next few decades he used an injection of “Coley’s toxin”, or live streptococcal
cultures, on hundreds of patients with different forms of cancer. Coley asserted the
research to be promising, touting significant cases of tumor regression and a 10% cure
rate (Parish, 2003). Despite his personal enthusiasm, this treatment was not widely
accepted by other scientists due to the severe infection that resulted and what they
saw to be very low rate of cures. At this point the majority of immunologists were
unsympathetic and believed that it was not possible for the immune system to play a
role in identifying and reacting to malignant cells. This field was then ignored for
decades.

In 1949, Sir Frank Burnet proposed a theory that was experimentally verified
by Peter Medawar about acquired immune tolerance. This concept enforced the idea
that the immune system cannot distinguish healthy cells from transformed cells
(Fenner, 1987). He asserted that if foreign substances were present during an
embryonic stage prior to immune system development then the material would be
recognized as “self” and no immune response would be initiated upon future
exposure. Roughly 10 years later, Burnet had a change of heart and began advocating
that the immune system did in fact have a significant potential in fighting cancer.
Burnet and his colleague Lewis Thomas coined the term immunosurveillance, or the
belief that the immune system has ways of monitoring and targeting transformed
cells, which is a phrase still relevant today. The reason for Burnet’s change of mind is
not precisely known, but is believed to be related to a colleague’s review about
receptor-presenting lymphocytes and cellular clonal selection concepts (Mackay,
1999). Burnet and Thomas proposed that B and T lymphocytes possess the ability to
recognize and eliminate radically changed host cells through the recognition of tumor-
associated antigens (TAAs) in the process of immunosurveillance (Dunn et al, 2002).

Burnet and Thomas’ favorable theory was short lived and essentially
abandoned for a few decades. This occurred for several reasons: 1) the theoretical
belief that the immune system was not evolved for an immunosurveillant purpose, 2)
world-wide focus changed to acute infections being a more significant disease than
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cancer, and 3) alternative experimental evidence emerged, which took a few years to
be refuted (Parish, 2002). Only in the mid-1980s did evidence supporting
immunosurveillance become progressively convincing. Since then a number of
prominent figures have promoted significant studies that support the belief that the
immune system can play a remarkable role in cancer treatment.

The Immune System and Cancer

In light of the recent immunotherapy resurgence a myriad of new questions
are being examined. The first puzzle to be addressed was how the immune system
possesses the ability to specifically distinguish between “self” and “non-self” agents.
If the immune system is indeed critical in fighting tumor formation, then logically,
organisms with a compromised immune system would have increased cancer rates. In
the 1960s, researchers began working with immunocompromised Nude mice that
lacked proper thymus function. The mice had a deletion in the FOXN1 gene making
them athymic and unable to produce mature T lymphocytes. Results from the Nude
mice trials indicated that there was no significant difference in tumor formation
between the compromised Nude mice and their wild-type littermates. This was
included in evidence refuting the theory of immunosurveillance. It was only years
later that researchers learned, while lacking T lymphocytes immunocompromised
Nude mice still retained other intact components of the immune system, including the
activity of natural killer (NK) cells (Weinberg, 2014). From this, the
immunosurveillance theory was finally widely endorsed.

Only now can we acknowledge the significant role of NK cells in the
identification of antigens that lack major histocompatibility complex (MHC)
expression, which is the strongest method in identifying foreign cells. MHCs are cell
surface proteins, essential to the immune system’s adaptive response, that bind
pathogenic antigens to the cell surface making them recognizable as either self or
non-self (Wu and Lanier, 2003). Human histocompatibility can generally be defined
as having similar alleles in the human leukocyte antigen (HLA) genes. Located on
chromosome 6 each individual inherits two HLA alleles, one paternal and one
maternal. Each allele has six loci that code together for the MHC proteins. The co-
dominant expressions of both maternal and paternal alleles make the MHC proteins
unique for each person. In addition, the level of MHC protein similarity determines
one’s compatibility to another person’s tissues. MHC molecules can also distinguish
self and non-self cells. Natural cytotoxicity receptors (NCRs) stimulate the natural
killer cells to initiate cell-mediated cytotoxicity of the pathogens and viral cells that
display foreign MHC molecules on their cellular surface (Janeway, 2001). Therefore
displaying MHC markers is detrimental to a pathogen or mutated cell. This means it
would be selectively advantageous for pathogens to have a mutation that limits MHC
complex presentation, allowing for the evasion of the immune response.

A logical question now is, what would happen if this occurred with mutated
self-cells? The answer is, we would get cancer. Some cancer cells have developed
mechanisms making it harder to be detected by the immune system. These
mechanisms include minimizing TAA expression on the cell surface and expressing
surface proteins that can result in immune cell inactivation or suppression. The
differences between normal self-cells and cancerous self-cells are subtle and hard to
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distinguish but nevertheless exist. Cancer cell species possess structural differences
that mark them as foreign to induce an immune response. An example of this is the
Ras oncoproteins that have become cancerous by substitutions in the 12, 13, or 61
residues (Weinberg, 2014). Additionally, the p53 transcription factor commonly
mutated in cancer can display altered structure with substituted amino acids as well.
These altered oncoproteins display their changed structure and amino acids sequence
in a manner observable to scientists.

Chromosomal translocations can also identify cancer-specific proteins. When
previously unlinked genes are fused together the fusion region would have a new
amino acid sequence and can be recognized as foreign (Weinberg, 2014). Genomic
instability can also result in mutated structures due to the increased chance of error
associated with a larger number of cell cycles. These mutated structures can
frequently be found in alleles unrelated to tumor progression and just be a product of
a more volatile cell cycle. Any of these changes are difficult to distinguish, and if only
found in low concentrations then such aberrations are essentially invisible to the
immune system. Developing ways to better identify these small changes and stimulate
the corresponding immune response is a current challenge faced in immunotherapy.

Monoclonal Antibody Treatments

Many viable approaches for treatment have been established but further work
needs to be done to fully eradicate immune system evasion. Present efforts in specific
immunotherapy can be divided into three main classifications: monoclonal antibodies,
immune checkpoint inhibitors, and cancer vaccines. To review, the immune system
can attack foreign agents by producing antibodies that attach to a specific antigen
indicating the cell to be destroyed. Monoclonal antibodies (mAbs) can be designed by
researchers in a laboratory to specifically target an antigen. To date, we have only
been able to identify particular antigenic markers on a few types of cancer cells for
mAbs to target. One type of mAb treatment is called antibody-drug conjugates
(ADCs). ADCs are created by linking mAbs to a toxic substance (NCI, 2015); the
antibody acts like a locating device and circulates the body to find its target antigen,
at which point the toxic substance, commonly a chemotherapy drug, is released to kill
the cell. Kadcyla®, Adcetris®, and Zevalin® are three examples of FDA approved
ADCs. Kadcyla® targets and destroys the overactive HER2 protein in breast cancer
with the chemotherapy drug DM1. Adcetris® targets the CD30 antigen on
lymphocytes and uses the MMAE chemotherapy drug to eradicate it (Rosenberg,
2014). The drug Zevalin® is slightly different. The mAb targets the CD20 antigen but
instead of a chemotherapy drug, it is attached to a small radioactive particle that
delivers its radioactivity directly into cells to destroy them (Rosenberg, 2014).

One benefit of using monoclonal antibodies is that it lessens the destruction
felt by healthy cells in alternative cancer treatments. Being able to pick which cells
are to be destroyed minimizes the resulting stress on the body. Typical side effects of
the aforementioned drugs include weakness, nausea, fever, or chills. These and
numerous other side side effects typically depend on what substance the mAbs are
attached to. For cancers with known and visible antigens monoclonal antibody
immunotherapies are a viable option (Neves and Hang Fai, 2015).
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Related to monoclonal antibodies is adoptive cell transfer (ACT). The ACT
immunotherapy approach involves using a patient’s own immune cells and
engineering them to distinguish and attack tumors by taking advantage of the body’s
naturally produced tumor-infiltrating T lymphocytes (TILs). TILs are able to
recognize and attack tumors by distinguishing MHC antigens in specific cancer types
but generally are found in insufficient amounts to make a difference. The first step is
extracting and amplifying these TILs typically by the T-cell growth factor interleukin-
2. Next, it is imperative to deplete the remaining lymphocytes in a patient because
some lymphocytes, like regulatory T cells, can suppress the immune response.
Additionally, without competition from other lymphocytes the TILs can exclusively
receive cytokine cell’s growth-promoting abilities (Rosenberg, 2008). Limitations of
this treatment are that not all cancers will give rise to TILs or have easily recognizable
antigens. ACTs are commonly used in the treatment of melanoma cancers, which are
distinct by having more mutations in comparison to other types of cancer and are
therefore easier to be recognized by the immune system (Rosenberg, 2014). If more
proteins on cancer cell’s surfaces are isolated, both mAbs and ACTs can be further
advanced to treat a wider range of cancers. The monoclonal antibody technique is the
most promising avenue for immunotherapy. It offers a treatment method that can be
uniquely tailored to an individual’s cancer diagnoses with relatively minimal side
effects.

Immune-Mediated Checkpoints

The immune system has a unique organization of checkpoints, with specific
molecules needing to be altered in order to start an immune response. Some cancers
evade the immune response by tricking these checkpoints to essentially remain
hidden. One such mechanism is the PD1/PD-L1 checkpoint. PD1 is a cell surface
receptor which when bound to PD-L1 acts like an off switch to prevent normal cells
from being attacked by T cells. PD1/PD-L1 has been found to be upregulated in many
cancers, making the cells invisible to the immune system. Some drugs containing
mAbs that are designed to target PD1 and PD-L1 receptors yield incredible promise
for cancer treatment. Opdivo® is one example of a PD1 inhibitor (Dolan, 2014).

Combination therapy with other immune checkpoint inhibitors can increase
overall immune responses, but this also increases the risk of dangerous immune-
mediated side effects. Some researchers have begun searching for biomarkers that
indicate if a patient will respond to immune checkpoint blockade treatments. The
obvious answer is increased expression of the treatment targets, such as PD-L1.
Indeed, tumors without PD-L1 overexpression have a very low response rate to the
drug Nivolumab. However, response rates in tumors overexpressing the protein vary
from 36-100% (Goodman and Razelle, 2017). There must be another, yet to be
discovered, factor that determines immune checkpoint evasion, suggesting this
treatment method needs to be further expanded to impact the most patients.

Cancer Vaccines

Cancer is not viral in origin but some viruses have been linked to different
types of cancer. For example, human papilloma virus (HPV) and hepatitis B virus
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(HBV) have been linked to cervical, throat, and liver cancers. If vaccination against
these viruses can lessen one’s risk of developing certain cancers, is there hope we
could develop vaccines that directly target cancer cells? Some researchers are trying
to do just that. The only FDA approved cancer vaccine in the United States is
Sipuleucel-T, otherwise known as Provenge®, for the treatment of advanced prostate
cancer (Kim, 2016). The method behind this vaccine involves removing one’s
immune system blood cells and transforming them into dendritic cells by exposure to
chemicals in a laboratory. These dendritic cells are then incubated with prostatic acid
phosphatase (PAP), a common prostate cancer antigen, and granulocyte-macrophage
colony stimulating factor, a glycoprotein necessary for the dendritic cells to mature.
The resulting dendritic cells are then returned to the patient's body, where they
activate T-cells to attack cells that express PAP (Gomella et al, 2014). Although this
does not provide a cure it does help extend the patient’s life. Side effects are
considered to be mild but much more research needs to be completed before cancer
vaccines can become mainstream.

Conclusion

Cancer immunotherapy has seen recent promising advances yet there is still a
vast amount of research that needs to be completed before we can conquer cancer.
This paper reviewed three main types of cancer treatment emphasizing likelihood of
patient benefit. Currently, immunotherapy has only been effective in treating a few
cancer subtypes and scientists have yet to identify the biomarkers that indicate
whether a specific tumor will respond to immunotherapy or not. Similarly, there are
many untested combination therapies that may lead to increased favorable responses
in cancer types that had been thought to be resistant to immunotherapy. Finally, most
immunotherapy methods don’t last long within the body, which is perhaps the largest
inhibitor on their efficacy. The monoclonal antibody technique is likely to be the
future of immunotherapy. If further developed, this technique offers a more
specialized treatment style to avoid the “blunt force approach” employed by current
therapies. With further research this promising topic could be employed on a wider
range of cancers.

Acknowledgements

I would like to thank my Revision Club Partners, Eric Dahl and Eric Jacques,
classmate Shivani Gohel, and Professor Akbari for all their guidance with this article.

References

Chaplin, David D. “Overview of the Immune Response.” The Journal of allergy and
clinical immunology 125.2 Suppl 2 (2010): S3–23. PMC. Web. 06 June 2017.

Dolan, D.E. and Gupta, S. (2014). PD-1 pathway inhibitors: Changing the landscape
of cancer immunotherapy. Cancer Control. 21(3), 231-7
7

Dunn, Gavin P., Bruce, Allen T., Ikeda, Hiroaki, Old, Lloyd J., and Schreiber, Robert
D., “Cancer Immunoediting: From Immunosurveillance to Tumor Escape” Nature
Immunology, (2002) 3.11: 991-98. Web.

Fenner, Frank, "Frank Macfarlane Burnet 1899–1985," Historical Records of
Australian Science (1987) 7, no.1: 39–77

Gomella, Leonard G., Francisco Gelpi-Hammerschmidt, and Chandan Kundavram.
“Practical Guide to Immunotherapy in Castration Resistant Prostate Cancer: The Use
of Sipuleucel-T Immunotherapy.” The Canadian Journal of Urology 21.2 Supp 1
(2014): 48–56. Print.

Goodman, Aaron, Sandip P. Patel, and Razelle Kurzrock. “PD-1-PD-L1 Immune-
Checkpoint Blockade in B-Cell Lymphomas.” Nature Reviews. Clinical Oncology
14.4 (2017): 203–220. PubMed. Web.

Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in
Health and Disease. 5th edition. New York: Garland Science; 2001. The major
histocompatibility complex and its functions. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK27156/

Kim, Jung Hoon et al. “Current Status and Perspective of Immunotherapy in
Gastrointestinal Cancers.” Journal of Cancer 7.12 (2016): 1599–1604. PMC. Web.
04. June. 2017.

Mackat, Ian R. “The Assembly of Antibody Explanations.” Science 284.5412 (1999):
269-270 Science Magazine. DOI: 10.1126/science.284.5412.269

(NCI) "Immunotherapy: Using the Immune System to Treat Cancer." National
Cancer Institute. N.p., n.d. Web. 07. June. 2017.

Neves, Henrique, and Hang Fai Kwok. “Recent Advances in the Field of Anti-Cancer
Immunotherapy.” BBA Clinical 3 (2015): 280–288. PubMed Central. Web.

Parish, Christopher R, “Cancer Immunotherapy: The Past, the Present, and the
Future,” Immunology & Cell Biology, (2003) 81, 106-113; doi: 10.1046/j.0818-
9641.2003.01151.x

Rosenberg, Steven. “Adoptive Cell Transfer: A Clinical Path to Effective Cancer
Immunotherapy.” Nature reviews. Cancer 8. 4 (2008): 299–308. PMC. Web. 07.
June. 2017.

Rosenberg, Steven. "CCR Connections Skip to Main Content." CCR Connections: In
the Clinic - Adopting Bodily Defenses to Cure Cancer. N.p., 2014. Web. 07. June.
2017.

Weinberg, Robert A. The Biology of Cancer. 2nd ed. New York: Garland Science,
2014. Print.
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Wu, J., and L. L. Lanier. "Natural Killer Cells and Cancer." Advances in Cancer
Research. U.S. National Library of Medicine, 2003. Web. 04. June. 2017.