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THE POTENTIAL OF IMMUNOTHERAPY FACILITATED BY GENE
THERAPY FOR TREATMENT OF PROSTATE CANCER
Sagar Kumar, [email protected], Budny 10:00, Katie Banbury, [email protected], Budny 10:00
Abstract—Since the late 1800’s, gene therapy, the
transplantation of normal genes into cells in place of missing
or defective genes to correct genetic disorders, has promised
innovation in many areas, ranging from agriculture to
medicine. Current and future applications of gene therapy are
extensive, but this paper will specifically focus on the
combination of gene therapy with immunotherapy the
prevention or treatment of disease by stimulating the immune
system and the potential of these combined therapies to treat
cancer. The recent discovery of this groundbreaking
combination makes it possible to strengthen the immune
system and program it to destroy cancerous cells.
We will discuss in detail the history of gene therapy, how
gene therapy methods are altered in immunotherapy, and why
this approach shows such great potential in cancer treatment,
specifically the treatment of prostate cancer. Recently, the first
successful immunotherapy vaccine, Sipuleucel-T, was
approved by the United States Food and Drug Administration
(FDA). That prostate cancer is the most common and the
second most deadly cancer in men makes this breakthrough
even more significant. We will delve into possible future
directions of immunotherapy for cancer treatment,
investigating the use and sustainability of the Sipuleucel-T
vaccine in conjunction with conventional cancer treatments,
such as chemotherapy and radiation, through the analysis of
current and concluded clinical trials.
Key Words—Gene Therapy, Immunotherapy, Prostate
Cancer, Sipuleucel-T, Conventional Cancer Therapy,
Immunotherapy, Immune System
HISTORY AND DEVELOPMENT OF
CANCER VACCINES
Cancer vaccines, also known as biological response
modifiers, work by stimulating or restoring the immune
system’s ability to fight infectious cancer cells. The immune
system is a complex network of cells, tissues, organs, and the
substances they make that allow the body to fight infections
and other diseases. The immune system defends the body from
disease-causing microbes and can protect the body against
threats posed by certain damaged, diseased, or abnormal cells,
University of Pittsburgh Swanson School of Engineering 1
Submission Date 2017-02-10
including metastatic cancer cells. White blood cells,
leukocytes, play the main role in immune responses. They
protect the body against diseases that causes microbes and
abnormal cells. Other types of leukocytes, known as
lymphocytes, provide targeted protection against specific
threats. The major groups of lymphocytes responsible for
carrying out immune responses against threats are B cells and
T cells. B cells make antibodies, which are large proteins that
bind to foreign invaders and abnormal cells to destroy them.
On the other hand, T cells can either prompt infected and
abnormal cells to self-destruct, inducing a process called
apoptosis, or they can kill infected and abnormal cells by
releasing toxic chemicals. Contrary to typical abnormal cells,
cancer cells carry antigens, a toxin or other foreign substance
that induces an immune response in the body, which mark
healthy cells with an immune trigger. In response, the immune
system mounts an attack on the healthy cell because of the
presence of an infectious foreign substance, leaving the
original cancer cell unharmed. Several factors make it difficult
for the immune system to target growing cancers, including the
difficulty of the immune system to recognize the cancer cells
due to the very slight alteration in the cell surface proteins from
a healthy cell. For this reason, cancer vaccines were created
[1].
There are two broad types of cancer vaccines: preventive
and treatment. Preventive vaccines are intended to prevent
cancer from developing in healthy people, where treatment
vaccines are meant to treat an existing cancer by strengthening
the body’s natural immune response. Human papillomavirus
and hepatitis B virus vaccines are examples of treatment
vaccines. Cancer treatment vaccines are still being developed
and researched, however, there is currently one approved
cancer treatment vaccine, Sipuleucel-T, for the treatment of
metastatic prostate cancer. Cancer vaccines, regardless of their
type, employ modified antigens to help the immune system
recognize and fight infectious cells. These vaccines work by
stimulating the production of antibodies that bind to specific
targeted tumor cells and block their ability to cause infection.
All cancer preventive vaccines approved by the FDA have
been made using antigens from microbes, which are bacteria
that cause or contribute to the development of cancer.
Throughout this paper, the sustainability of SipuleucelT will be discussed in detail. For this discussion, sustainability
Sagar Kumar
Katie Banbury
will be defined as both increasing the “quality of life” and the
extent to which Sipeuleucel-T will be significant in the future.
Cancer treatment vaccines are also being developed using
weakened or dead cancer cells that carry cancer associated
antigen(s) or immune cells that are modified to present such
antigens on their surfaces. These cells can come from the
patient themselves, resulting in an autologous vaccine, or the
cells can come from another patient, resulting in an allogeneic
vaccine. Regardless of the various development methods,
cancer vaccines delay the growth of cancer cells and, in some
cases, eliminate it completely [1].
First Gene Therapy
Adenosine Deaminase (ADA) deficiency, a condition that
leaves patients substantially more susceptible to contracting
infections and diseases, was incurable until September of 1990
when Dr. W. French Anderson conducted the very first gene
therapy trial on a four–year old girl at the NIH Clinical Center.
The therapy consisted of Dr. Anderson inserting genes that
boosted the production of ADA into his patient’s previously
extracted white blood cells. After the white blood cells were
injected with ADA boosting genes, the white blood cells were
then inserted back into the four-year old girl. This process,
however, was not designed on a whim. The development of
this treatment began in 1985, when doctors Kenneth Culver,
W. French Anderson, and Michael Blaese found that cells from
patients with ADA deficiency could be corrected in tissue
culture, meaning that the cells were grown in a lab. The doctors
used a retrovirus, an RNA group which hosts tumor specific
enzymes, to deliver the corrected ADA genes into the ADA
deficient cells, thereby boosting the production of ADA. In
1986, the team of doctors studied the transfer of corrected
genes into the bone marrow of animals. From this study, they
discovered that there was an insufficient number of cells
receiving the corrected gene. Through extensive research, in
1988 the group of doctors found that transferring the genes into
white blood cells instead of the bone marrow greatly increased
the number of cells that accepted the corrected gene. The
success and phenomenal results of this new delivery system
prompted the group of doctors to consider the administration
of the treatment in humans. Finally, in 1990 the team worked
with Dr. Steven Rosenberg to test the safety and effectiveness
of the gene therapy on humans. After the gene therapy was
studied and approved, the team of doctors decided to conduct
the gene therapy on a four-year old girl who had ADA
deficiency. The development of this gene therapy has led
researchers around the world to develop different gene
therapies by stimulating the immune system to treat various
diseases. Figure 1 below summarizes the process of gene
therapy [2].
Figure 1- Description of the step-by-step process of gene
therapy
First Immunotherapy
Immunotherapy, the prevention or treatment of disease with
substances that stimulate immune system response, is a branch
of gene therapy used in the treatment of cancer. The use of
immunotherapy began in 1796 when doctor Edward Jenner
designed a vaccine with cowpox to counteract the effects of
smallpox. Using the design of this vaccine, doctor Steven
Rosenburg developed a vaccine which would be useful in the
treatment of metastatic cancers, such as prostate cancer. In
1987, cytotoxic T-lymphocyte antigen 4 (CTLA-4) was
discovered, which researchers then studied to find that CTLA4 prevents T cells, cells deployed by the immune system when
foreign invaders are recognized, from attacking tumor cells.
This discovery led researchers to question whether blocking
CTLA-4 would allow the immune system’s T cells to
successfully attack foreign tumor cells. Through extensive
research, researchers found that by using antibodies to block
CTLA-4’s interaction with T cells, the addition of antibodies
would allow the immune system’s T cells to attack and
eradicate the tumor cells in mice. As more research was
conducted, Bristol-Myers Squibb, a pharmaceutical company
which was a part of a biotechnology firm called Medarex,
acquired the rights to the antibody that successfully blocked
the CTLA-4. Bristol-Myers Squibb then used the antibody on
patients who had been suffering from metastatic melanoma
and found that the patients who used the antibody lived an
average of 10 months longer than the patients who had refused
the antibody treatment. This immunotherapy treatment was the
first treatment that had extended life in an advanced melanoma
trial.
Moreover, a biologist in the early 1990’s discovered a
molecule that was expressed in dying T cells, which he named
programmed death 1 (PD-1), which was revealed to best
another T cell disabler. After this observation, an antibody was
designed that would target and destroy PD-1. This antibody
produced remission in multiple patients regardless of their
cancer type. After this antibody was used as treatment,
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clinicians reported that across 300 cancer patients, tumors
shrunk in 31% of melanoma patients, 29% of kidney cancer
patients, and 17% of lung cancer patients, making this
antibody extremely successful and revolutionary for its time.
Although both anti CTLA-4 and anti PD-1 antibodies were
very successful, some patients experienced tumor growth
which was then followed by complete remission months later,
showing that neither antibody produced immediate results.
Anti CTLA-4 antibody and anti PD-1 antibody are currently
the most effective forms of cellular immunotherapy. Both
antibodies restrict the immune system from attacking the cells,
T cells. The results of the first successful immunotherapy have
led scientists to further study immunotherapy and design
various cellular immunotherapies for various diseases and
cancers [3].
Oncolytic Virus Therapies
Oncolytic virus therapy works differently than the other
therapies in that this therapy uses a modified virus that causes
tumor cells to self-destruct, which generates a stronger
immune response against the cancer. An example of oncolytic
virus therapy is ProsAtak, which uses a disabled virus as a
vector to deliver a gene directly to tumor cells, and is followed
by an anti-herpes drug called Valtrex, which kills the cancer
cells containing the gene that was originally delivered by the
disabled virus [4]. ProsAtak will be described later to show its
effectiveness in the treatment of metastatic prostate cancer.
Checkpoint Inhibitors
Another promising approach to the treatment of cancer
using immunotherapy is through the use of checkpoint
inhibitors. This type of treatment works by targeting molecules
that serve as checks and balances in the regulation of immune
responses. Checkpoint inhibition therapy works in two ways,
either by blocking inhibitory molecules or by activating
stimulatory molecules, which both are very effective in getting
the immune system to fight against the cancer cells, which are
often not recognized by the immune system since the cancer
cells contain antibodies that the immune system views as
healthy. These treatments are designed to enhance anticancer
immune responses that already exist in the patient’s body, and
if the anticancer immune response is not present in the
patient’s immune system, these treatments create the
anticancer immune response [4]. This treatment however, is
very new and not much research has been conducted.
However, based on the current experimental results, this
branch of immunotherapy shows great potential in increasing
the immune response in metastatic cancer patients, which
could potentially eradicate cancer cells from a patient’s body.
IMMUNOTHERAPY: THE SEVEN
BRANCHES
Immunotherapy is used in the treatment of diseases, more
common in the treatment of cancer, using substances that
stimulate the immune response within the patient. Since
immunotherapy is a relatively new type of cancer therapy, the
potential of such treatment is large. Currently, there are seven
broad categories of immunotherapy: therapeutic vaccines,
oncolytic virus therapies, checkpoint inhibitors, adoptive cell
therapies, adjuvant immunotherapies, cytokines, and
monoclonal antibodies. All of these categories hold great
potential in the treatment of metastatic cancers even though
they all work differently [4]. In terms of sustainability, all
seven branches of immunotherapy play a role in improving the
“quality of life” in cancer patients who opt to use the therapies.
All branches improve the conditions of cancer patients and
help them deal with upcoming debilitating conditions, which
further supports the claim that immunotherapy improves the
patient’s quality of life.
Adoptive Cell Therapies
Therapeutic Vaccines
Adoptive cell therapy is a unique branch of
immunotherapy in that the treatment is ex vivo, meaning the
treatment does not actually take place within the body of the
patient. In this therapy, immune cells are extracted from the
patient and then genetically modified and treated with
chemicals to enhance their activity and response strength in the
patient’s body. Once the immune cells have been genetically
modified, the cells are then injected back into the patient to
improve the immune system’s anti-cancer response [4].
Therapeutic vaccines are designed to provoke an immune
response against antigens that are specific to the tumor as well
as antigens that are in general association with the tumor.
These vaccines work by telling the immune system to attack
the cancer cells that have these antigens on their outer
membrane. Provenge, a therapeutic vaccine for prostate
cancer, has been approved by the FDA after a phase III trial
indicated that the vaccines increased the rate of survival in
metastatic prostate cancer patients by more than four months
[4]. Although Provenge will be further explained later, it
should be noted that this therapeutic cancer vaccine has very
few side effects and the effectiveness is unmatched when
compared to other courses of treatment.
Monoclonal Antibodies
An often-underestimated immunotherapy treatment using
monoclonal antibodies is a very successful and effective
course of treatment in metastatic cancers. Monoclonal
antibodies are molecules that are generated in a lab, and the job
of these antibodies is to target specific antigens on tumors.
Unlike polyclonal antibodies which require the secretion a
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network of multiple B cells to target a single antigen,
monoclonal antibodies are more efficient because they only
require the secretion of one B cell [4]. This treatment, like all
immunotherapy treatments, is designed to generate an immune
response that provokes the immune system to target tumor
associated antigens which in result could potentially eradicate
any cancer cells present in the patient’s body.
Although most prostate cancer patients have adenocarcinomas,
there are other types of prostate cancer: sarcomas, small cell
carcinomas, neuroendocrine tumors, and transitional cell
carcinomas. All of these types of prostate cancer have been
shown to be treated through the application of the different
branches of immunotherapy mentioned above. Figure 2,
above, shows where the immunotherapy is applied [4].
Regarding sustainability, defined here as “quality of life”, the
application of immunotherapy in prostate cancer patients has
clear implications to human quality of life. Because
immunotherapy enables doctors to manipulate the cancer
patient’s immune response, this therapy enhances the ability of
investigators to find the underlying cause of the weak immune
response which can be fixed and strengthened with the use of
immunotherapy. This therapy has great potential to increase
the quality of life by expediting the search for treatments and
cures for prostate cancer.
Adjuvant Immunotherapies and Cytokines
Cytokines and adjuvant immunotherapies are not
individual treatments on their own; they are two branches of
immunotherapy that are used in combination with the other
branches of immunotherapy. Cytokines are messenger
molecules that help control the growth and activity of immune
system cells [4]. Using cytokines alongside the other
immunotherapies is beneficial because each immunotherapy is
dependent on the activity of immune cells. Adjuvant
immunotherapy utilizes adjuvants, which are substances that
boost the immune response. Based on the descriptions of the
other branches of immunotherapy, adjuvants can be used in
every immunotherapy so that the immune response in
increased which in result would cause the other therapies to
work more efficiently and increase their potential in
eradicating the body of metastatic cancer cells. Although all
seven branches of immunotherapy are broad, their potential in
curing cancer is phenomenal and crucial if positive long term
results are desired at the risk of a few mild side effects.
Therapeutic Vaccines
In a phase III trial of PROSTVAC conducted by Bavarian
Nordic Inc., a therapeutic cancer vaccine consisting of virus’s
vaccinia and fowlpox to deliver prostate-specific antigens
(PSA) directly to prostate cancer cells, the immunotherapy
showed tremendous results. The vector was shown to stimulate
an immune response against PSA, which led the immune
system to attack the cancer cells in the prostate of the patient.
The results of this trial were promising and on average led to
an 8.5-month increase in the life expectancy of metastatic
prostate cancer patients [5]. The results of therapeutic cancer
vaccine trials show that it is the most effective form of
immunotherapy in the treatment of prostate cancer.
APPLICATIONS OF THE SEVEN BRANCHES OF
IMMUNOTHERAPY
Figure
2-
Shows
location
of
tumor
in
prostate
Oncolytic Virus Therapies
Oncolytic virus therapy has also shown promise in the
treatment of prostate cancer. ProsAtak, an effective oncolytic
virus therapy, uses a disabled virus as a vector to deliver a gene
directly to the tumor cells in the prostate. After the vector has
delivered the gene, the patient is given an oral anti-herpes drug,
Valtrex, to kill the cancer cells containing the gene. This
therapy is currently being used in combination with radiation
therapy. A phase II/III trial conducted by Advantagene Inc.
showed that the use of oncolytic virus therapy, ProsAtak, with
radiation therapy greatly reduces the side effects of the
radiation, which also strengthens the significance of the
therapy in terms of sustainability, therapy and increases the
rate at which cancer cells are killed. The results also showed
that the rate of recurrent cancer cells decreased significantly,
making oncolytic virus therapy very effective in the treatment
of metastatic prostate cancer [6].
As mentioned earlier, the potential of immunotherapy is
enormous. More specifically, prostate cancer is an example of
a cancer that has the potential of being completely resolved
using immunotherapy. In prostate cancer, cells in the prostate
gland begin to grow uncontrollably. The majority of prostate
cancers are adenocarcinomas that root from the gland cells,
which make the prostate fluid that is added to the semen.
Checkpoint Inhibitors
Nivolumab, a checkpoint inhibitor used in a phase II trial
conducted by Sidney Kimmel Comprehensive Cancer Center,
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shows results that checkpoint inhibition therapy is successful
in the treatment of prostate cancer. The results of the study
showed that Nivolumab blocked the biomarkers on proteins
that help tumor cells escape the surveillance of the immune
system, and in response to the blocking off biomarkers, the
immune system was able to target and destroy the tumor cells
in the patient’s prostate [7]. Therapeutic application
checkpoint inhibitors are currently still being studied, but
based on the published results, these inhibitors can often
prompt the remission of prostate cancer. The potential of
checkpoint inhibitors will increase as more research and
experiments are conducted.
Adjuvant Immunotherapies and Cytokines
Adjuvant immunotherapy and the use of cytokines are
complementary treatments. Basically, the two treatments are
utilized to enhance the effectiveness of other immunotherapy
treatments. Both treatments are used to boost the effectiveness
of Sipuleucel-T, a therapeutic cancer vaccine developed to
treat metastatic prostate cancer. Using adjuvant
immunotherapy along with Sipuleucel-T in a phase II study
conducted by the Masonic Cancer Center at the University of
Minnesota, researchers found that the speed at which the
Sipuleucel-T vaccine stimulated the patient’s immune
response had nearly doubled as opposed to when patients were
treated with just Sipuleucel-T [10]. These results had indicated
that the application of adjuvant immunotherapy was
significant in the effectiveness of the therapeutic cancer
vaccine. Cytokines work by controlling the growth and activity
of immune system cells, similar to adjuvant immunotherapy.
A phase II trial using CYT107, a cytokine used to stimulate the
immune system, conducted by Fred Hutchinson Cancer
Research Center showed that the application of cytokines, after
the application of Sipuleucel-T, greatly reduced the ability of
the tumor cells to spread to other areas of the prostate once the
tumor cells had started reacting to the immune system attack
(VII). This study proved that the application of cytokines does
indeed boost the effectiveness of other immunotherapy
treatments such as the therapeutic cancer vaccine SipuleucelT.
Adoptive Cell Therapies
Another successful application of immunotherapy has
been through the branch of adoptive cell therapy, where
immune cells are removed from a patient, genetically modified
to enhance immune response, and then re-introduced into the
patient to improve the immune system’s anticancer response.
A phase II trial, conducted by Jonsson Comprehensive Cancer
Center, used genetically modified T cells to target cancerspecific antigen NY-ESO-1, a protein present on tumor cells.
The adoptive cell therapy successfully targets and kills the
cancerous antigen and allows the immune system to kill the
cancer cells [8]. The application of adoptive cell therapy has
the potential to rid a patient of the metastatic cancer cells
present in his prostate.
Monoclonal Antibodies
SIPULEUCEL-T, A THERAPEUTIC
IMMUNOTHERAPY VACCINE
The application of monoclonal antibodies in the treatment
of prostate cancer has been just like the application of
therapeutic cancer vaccines. Monoclonal antibodies are
generated in a lab and used to stimulate an immune response
in cancer patients. Results from a phase I/II trial of Tisotumab
Vedotin, an engineered monoclonal antibody, conducted by
Genmab indicated that monoclonal antibodies truly play a big
part in the remission of prostate cancer. The engineered
antibody targets a protein involved in tumor signaling, and
prompts the immune system to respond to the protein as a
foreign substance. After the immune system, has identified the
infectious protein, an immune response is triggered and the
immune system is directed to kill the protein [9]. Since tumor
cells cannot function without the presence of its proteins, this
therapy causes the tumor cells to die overtime which in
response eliminates the tumor cells from the patient’s prostate.
Because monoclonal antibody treatment is a relatively new
therapy, there are multiple research studies and experiments
being conducted to find the extent of how effective the therapy
really is. As of now, the results found by Genmab show that
the use of monoclonal antibodies have the potential to
eradicate metastatic cancer cells.
Sipuleucel-T, also known as PROVENGE, is an autologous
cellular immunotherapy vaccine designed to stimulate a
patient’s immune system against cancer. Sipuleucel-T is
currently the only therapeutic cancer vaccine that has been
approved by the FDA and is now being used to treat metastatic
prostate cancer. Figure 3 below clearly shows the step-by-step
process of the vaccine [11] [13].
There are several steps in the administration of SipuleucelT. First, the patient’s blood is run through a machine in a
process called leukapheresis. During this process, the patient’s
immune cells are collected. Then, these immune cells are
exposed to a protein which is intended to stimulate and direct
them against prostate cancer. After the immune cells, have
been exposed to the protein, the activated cells are then
returned to the patient to treat the prostate cancer. SipuleucelT is administered through IV in a cycle of three doses, over
two week intervals [11].
This cancer vaccine is composed of autologous presenting
cells (APCs), also known as” accessory cells”, which display
antigens on their surface. The APCs are activated by the
recombinant human protein, PAP-GM-CSF, consisting of
prostatic acid phosphatase (PAP), which is an antigen
expressed in prostate cancer tissue, linked to granulocyte-
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Katie Banbury
macrophage colony-stimulating factor (GM-CSF), an immune
cell activator [11]. In addition to APCs, Sipuleucel-T contains
numerous T cells and B cells which aid in the remission of
metastatic prostate cancer cells. The application of SipuleucelT has on average increased the life expectancy of metastatic
prostate cancer patients by three years, proving that it is a
crucial therapy in the treatment of prostate cancer.
With respective to sustainability, the application of the
cancer vaccine Sipuleucel-T to metastatic prostate cancer
patients has the potential to drastically improve the quality of
life of individuals with this debilitating disease and to prevent
future persons from developing this disease. In addition, gene
therapy with Sipuleucel-T may be applied to many other
metastatic cancers and improve the quality of life of
individuals with these diseases by treatment and increase
overall quality of life by preventing more individuals from
developing these diseases. Not only does this vaccine improve
the quality of life, it also shows how significant this treatment
will be in the future. The contents of this vaccine have the
ability to be passed down to offspring which in response would
cause an improved immune response which could help people
fight diseases without the use of various therapies. This effect
supports the claim that in terms of sustainability, Sipuleucel-T
has great significance towards the treatment of cancer in the
future and in general has great significance towards the
enhancement of the quality of life.
chemotherapy, the foundation of treatment of metastatic
disease, damages healthy cells, causing fatigue, pain, nerve
damage
and
other
debilitating
symptoms.
There has been extensive research and success in animal
models with the combination of immunotherapy -- which
boosts the body’s natural defenses to fight the cancer -- and
these conventional therapies in animal models, setting the
stage for clinical trials using this treatment strategy.
Immunotherapy presents the possibility of cancer treatment
with far fewer detrimental effects [12]. Using immunotherapy
towards the treatment of cancer, as mentioned above, holds
great value when talking about sustainability. Not only does
the application of immunotherapy hold great significance in
the treatment of cancer in the future, but in the short term,
immunotherapy has shown to increase the quality of life in
cancer patients.
Preliminary evidence from preclinical and early phase
clinical trials indicates promising results when conventional
anticancer therapies are used in combination with
immunotherapy. Recently, phase III clinical trials of multiple
vaccines provided evidence that immunotherapies can prolong
survival in patients with metastatic cancer, providing a therapy
that harnesses the immune system to provide robust and
adaptable cancer treatment rather than a rigid and destructive
one. However, therapeutic cancer vaccine treatment alone is
not sufficient; it is necessary to combine these cancer vaccines
with conventional cancer treatment for optimal results [14].
Practical Application of Immunotherapy with
Conventional Cancer Treatment
Despite the emergence of new and improved therapies over
the past few years, the goals of reducing the risk of disease and
improving the quality of life are not always reached. Although
the conventional treatments are life extending, they are rarely
curative. However, the addition of immunotherapy to standard
treatments, through the use of therapeutic cancer vaccines, has
proven to complement traditional cancer therapies by inducing
a therapeutic antitumor immune response [14] [15]. Figure 4
briefly shows the mechanisms involved in the application of
conventional cancer treatments.
Figure 3 - Shows how the vaccine works in a few steps
IMMUNOTHERAPY FOR CANCER
TREATMENT
For many years, the conventional cancer treatments have
been chemotherapy and radiation. Although they are
somewhat successful, these treatments are harsh on the
patient's body and have myriad side effects. For example,
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Sagar Kumar
Katie Banbury
immunomodulatory effects of radiation and radiation’s effect
on tissues. A great deal of preclinical research into combining
radiation therapy with active therapeutic cancer vaccines has
been shown in clinical studies using this combination as a
multimodal therapy for cancer [14] [15].
FUTURE DIRECTIONS
The immune system is flawed in that it normally does not
recognize and kill cancer cells because it deems their surface
proteins as “normal.” As a result, to be able to gain control of
the immune system, therapeutic cancer vaccines are extremely
promising treatments. So far, the clinical impact of vaccination
alone has been limited. However, suppressed immunogenic
cells that are a result of the vaccine could potentially be cleared
or inhibited with the combination of vaccine therapy and
conventional cancer treatment such as chemotherapy and
radiation therapy. This potential is large because cancer cells
treated conventionally become more vulnerable to T cells,
which can increase the effectiveness of the vaccination when
combined with standard cancer treatments. Since each of the
different treatments has unique features that can enhance the
success of cancer vaccines, a multimodal approach, including
several therapy platforms in combination with the vaccines,
could possibly result in even greater collaborative antitumor
effects. Immunotherapy itself is a very broad type of treatment.
It has several branches: therapeutic cancer vaccines, oncolytic
virus therapy, checkpoint inhibitors, adoptive cell therapy,
monoclonal
antibodies,
cytokines,
and
adjuvant
immunotherapy - which all play a crucial role in the treatment
of cancer. Evidence from past and ongoing clinical trials have
proven that each branch of immunotherapy is effective, but its
effectiveness can be enhanced with the combination of
conventional cancer treatments. In particular, immunotherapy
in conjunction with conventional cancer treatments has shown
extraordinary results in the treatment of prostate cancer. With
Sipuleucel-T
being
the
only
FDA
approved
immunotherapeutic cancer vaccine, researchers have found
that its application leads to results suggesting that metastatic
prostate cancer is no longer incurable. Immunotherapeutic
approaches facilitated by gene therapy show great promise in
treating multiple cancers; currently, we know that this
approach has the potential to cure metastatic prostate cancer.
With the definition of sustainability in mind, the
information found clearly shows that the application of this
therapy does in fact improve the quality of life and also holds
great significance for future cancer treatment approaches.
Figure 4 - Depicts the mechanisms of different conventional
cancer treatments
Combining Chemotherapy and Immunotherapy
Until recently, it was unheard of to combine chemotherapy
with immunotherapy because of the compromised immune
system that results from chemotherapy treatment. Generally, it
was believed that chemotherapy, when used in combination
with a cancer vaccine, would have a negative effect on the
patient. However, lately, a number of findings suggest that
combining immuno- and chemotherapy results in better
clinical responses in advanced cancer patients. Recent
evidence also suggests that specific chemotherapeutic
regimens can reduce the tumor growth rate in cancer patients
when combined with specific cancer vaccines. The reason for
this phenomenon may be that, as a result of the cell death
caused by chemotherapy, the presentation of antigens furthers
the activation of the immunotherapy induced T cell response,
which ultimately leads to increased killing of cancer cells [14]
[15].
Although there has been a surge of interest in the potential
therapeutic benefits of regimens combining cancer vaccines
with standard-of-care chemotherapy there are several
important considerations. For example, the fact that employing
a vaccine in combination with chemotherapy earlier rather than
later in the disease treatment process shows significantly
different results.
Combining Radiation Therapy and Immunotherapy
Although local control of the primary tumor is necessary for
radiation therapy and can usually prevent metastasis, radiation
generally fails to control pre-existing systemic disease, which
may manifest as undetectable micro metastases. However,
since radiation therapy and therefore irradiation ultimately
leads to immunogenic death, this leaves cancer cells more
vulnerable to killing by T cells from the therapeutic cancer
vaccine, causing a more efficient response to even the
surviving irradiated cancer cells. Interest in combining
radiation and immune-based therapies for the treatment of
cancer is growing in proportion to our understanding of the
SOURCES
[1] "Cancer Vaccines." National Cancer Institute. 12.18.15.
https://www.cancer.gov/about-cancer/causesprevention/vaccines-fact-sheet Accessed 2.26.17
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Katie Banbury
[2] “Gene Therapy.” National Institutes of Health.
https://history.nih.gov/exhibits/genetics/sect4.htm Accessed
2.26.17
[3]
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ACKNOWLEDGMENTS
We would like to thank Barbara Edelman for helping us
revise our work. Without her, the quality of this work would
not have been professional. We would also like to thank
various peers who helped us by giving insight on our topic
area. We are also very grateful for Josh Zeleznick for taking
time out of his day to help give instructions on how to
approach this paper. And finally, we would like to thank
Jacob Meadows for acting as a friend and advisor throughout
the process of this paper. The completion and quality of this
paper would’ve been compromised if it weren’t for all the
people mentioned above.
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