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Cancer Vaccines: A novel
approach to cancer
Amber Harper
March 1st, 2007
PAS 645
Dr. Hadley
2
Abstract
Cancer still remains a major cause of death worldwide despite many therapies and
treatment modalities available. The major forms of cancer treatment are chemotherapy,
radiation, and surgery. These are treatments that the majority of us are familiar with. A
form of treatment that may not be as well known is Immunotherapy. Immunotherapy is
considered by many to be the “fourth modality” for the treatment of cancer.
Immunotherapy is based on utilizing the patient’s immune system to fight the cancer.
Along with other types, cancer vaccines fall under this category of Immunotherapy.
Cancer vaccines do not work in the same manner as prophylactic vaccines, such as
vaccines given in childhood to prevent an illness. The majority of cancer vaccines are
used for the treatment of cancer, not for prevention. The main types of cancer vaccines
are tumor cell vaccines, dendritic cell vaccines, antigen vaccines, anti-idiotype vaccines,
and DNA vaccines. These vaccines are being studied in many different types of cancers.
At this time, cancer vaccines do not play a big role in the treatment of cancer and are only
available in clinical trials. Researchers have made progress and with more advancement
could make cancer vaccines a treatment of the future. Several cancer vaccines may not
be too far from our reach. Excitingly, within the last two years, several cancer vaccines
received fast-track status from the FDA.
These are Sipuleucel-T (Provenge) by
Dendreon Corporation, a prostate cancer vaccine and OncoVAX by Intracel, a colon
cancer vaccine.
Cancer vaccines may provide patients with a new option for the
treatment of cancer. Clinically, cancer vaccines are important because they could offer
cancer patients new hope for survival and a better quality of life.
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Introduction
Despite numerous types of therapies and preventative strategies against cancer,
cancer still takes numerous lives worldwide each year (Berzofsky, 2004). In 2006, it was
predicted that 565,000 Americans would die of cancer and approximately 1.4 million
would be diagnosed (ACS, 2006). The knowledge gained about the immune system has
become a major influence on the idea of immunotherapy against cancer, including cancer
vaccines (Berzofsky, 2004).
Major forms of cancer treatment include chemotherapy,
radiation, or surgery. Immunotherapy treatments are considered to be relatively new.
Immunotherapy is also considered by many to be the “fourth modality” for the treatment
of cancer. There are several types of immunotherapy that are being studied in the use
against cancer. Other than cancer vaccines, some of these include monoclonal antibodies
and nonspecific immunotherapies and adjuvants. Adjuvant means along with another
type of therapy. In general, Immunotherapy is most commonly used as an adjunct to
other types of therapies but may used alone. Immunotherapy may play a bigger role in
the treatment of localized or smaller cancers instead of more advanced cancer.
Melanoma seems to be a prime target for Immunotherapy. Progress has been made
through research and researchers do believe that advancements can be made that will
improve the lives of people with cancer (ACS, 2006).
Currently, cancer vaccines are only being studied in clinical trials. To this date,
the Federal Drug Administration (FDA) has not approved any cancer vaccines for the
treatment of cancer in the United States (ACS, 2006). It seems that some vaccines are
not far from reaching this status. In 2005, a prostate cancer vaccine called Provenge
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received fast- track status by the FDA (Tabi, 2006b).
In 2006, a colon cancer vaccine
named OncoVAX also received fast-track status by the FDA (Intracel, 2006).
Presently, the Human Papilloma Virus (HPV) vaccine is probably the most well
known vaccine associated with prevention of cancer. The Federal Drug Administration
(FDA) recently approved its use. The HPV vaccine is labeled a cancer vaccine for
cervical cancer, but it is actually an anti-viral vaccine. The HPV vaccine is used to
prevent infection by HPV, which is known to cause cervical cancer (Tabi, 2006b).
When the majority of us hear the word vaccine, prevention of some type of
disease comes to mind. In fact most vaccines are used in the prevention of some type of
disease such as chicken pox or measles. Cancer vaccines are different in that the majority
of them are for treatment not prevention. There are several other differences between
prophylactic vaccines and cancer vaccines. The majority of prophylactic vaccines are
administered during childhood to provide the child with lasting immunity against a
particular disease. Generally, patients that receive prophylactic vaccines are not already
affected with the disease.
Most patients receiving cancer vaccines already have
established disease, which is some type of cancer. Most conventional vaccines involve
induction of an immune response producing antibodies against the disease. The majority
of cancer vaccines involve the induction of a T-cell response.
Also conventional
vaccines have been studied in large cohorts while cancer vaccines have been studied in
small cohorts (Tabi, 2006b).
Cancer vaccines can play a vital role in the prevention and treatment of cancer,
which could save many lives. It is possible that we may use these vaccines in our
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practice sometime in the future. Cancer vaccines may become a new therapy option for
individuals with cancer or at high risk for cancer.
Background
Lymphocytes are a type of white blood cell and are derived from resident stem
cells by a process known as hematopoiesis in the bone marrow. After hematopoiesis,
they leave the bone marrow and circulate in the blood and lymphatic systems.
Lymphocytes may then take up residence in lymphoid organs. Lymphocytes have many
characteristics that allow them to elicit an effective immune response. Lymphocytes
produce and display antigen-binding cell-surface receptors and display characteristics of
specificity, memory, and diversity.
Another vitally important characteristic of
lymphocytes is that they establish self/non-self recognition. The two major types of
lymphocytes are T-lymphocytes (T-cells) and B-lymphocytes (B-cells) (Goldsby, 2003).
T-cells and antigen presenting cells are key players in the immune response.
After maturation in the thyroid gland, T-cells express a unique antigen-binding molecule
on its membrane, the T-cell receptor (TCR). These T-cell receptors recognize cellmembrane proteins called major histocompatability complex (MHC) molecules
associated with a foreign peptide (a protein fragment from a foreign entity such as a
bacterium). Class I MHC molecules are found on almost all nucleated cells. Class II
MHC molecules are expressed on antigen-presenting cells only. An immature T-cell
proliferates and differentiates into memory T-cells and other effector T-cells, when it
encounters an antigen bound to an MHC molecule on the cell it has not encountered
before (Goldsby, 2003).
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Antigen presentation plays a vital role in immunization strategies including cancer
vaccines. Manipulation of the process of antigen presentation can allow for a more
effective response against tumor antigen (Goldsby, 2003).
Antigen presenting cells
(APCs) phagocytose or endocytose the antigen. A portion of the antigen will be bound
by a specific class II MHC molecule and “presented” to CD4+ T-helper cells, a subset of
T-cells. Once CD4+ T-helper cells are activated, they can activate B-lymphocytes,
mediate specific classes of antibody production, and differentiate into memory T-helper
cells. APCs include macrophages, B-lymphocytes and dendritic cells. These cells have
two characteristics that distinguish them from other cells. As mentioned earlier, they
express MHC II molecules on their membranes. They can also activate T-helper cells by
delivery of co-stimulatory signals.
B-lymphocytes mature in the bone marrow and are
unique from other cells in that they differentiate into plasma cells, which secrete
antibodies (Goldsby, 2003).
The immune system does display highly developed responses against cancer.
Though, effective immunity against the cancer frequently fails to develop. The immune
system is then described as being blinded to the tumor (Armstrong, 2001a). Growing
tumors provide “danger” signals. These “danger” signals are a consequence of the
disruption of the surrounding microenvironment and of the genotoxic stress of cell
transformation. These signals elicit a response from the cells of the innate immune
system. Ideally, inflammation would be induced and innate effector cells with antitumor
activity would be activated. Antigen presenting cells (APC’s), especially dendritic cells
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would also be stimulated, which would engulf tumor-derived antigens. These APC’s
would then migrate to lymph nodes to trigger T and indirectly B lymphocytes (Blattman,
2004).
The existence of the tumor cell is evidence that the cancer managed to elude or
overcome the immune response (Blattman, 2004). There are several mechanisms in
which this can occur. Accumulation of the cells of the immune system can be prevented
by physical means. There can also be deficient expression of costimulatory proteins,
major histocompatability complex (MHC), and interference of the recognition of natural
killer (NK) and natural killer T (NKT) cells. Some tumors actually release proteins such
as vascular endothelial growth factor (VEGF) and (IL)-10 to prevent the elicitation of an
inflammatory response. These proteins can hinder the differentiation and activation of
dendritic cell activation. These proteins can also increase expression of a protein called
STAT3, which will disrupt the production of pro-inflammatory molecules. Tumor cells
are still capable of eluding eradication even when the immune response does occur. This
can be achieved by decreasing expression of antigens, rendering tumor-specific T-cells
inactive, provoking regulatory T-cells and by removing tumor-specific T-cells in a
specific manner. (Blattman, 2004). Regulatory T-cells release mediators to control the
immune response (Goldsby, 2003).
Cancer vaccines utilize the action of mounting an immune response to fight
cancer that is already present in the body.
Cancer vaccines are considered active
immunotherapy because it is normal for your body to mount an immune response when
injected with immunogenic substances. Cancer vaccines are supposed to be specific for
cancer cells and not bring about a generalized immune response (ACS, 2006)
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There are different types of cancer vaccines that are now under study. These
vaccines are created to work using different mechanisms. The five main types are tumor
cell vaccines, dendritic cell vaccines, antigen vaccines, anti-idiotype vaccines, and DNA
vaccines (ACS, 2006).
The induction of a cell-mediated response by tumor antigens forms the basis of
cancer vaccines. The source of the tumor antigens could be an established cell lines or
the individual patient. Theoretically, antigens derived from the individual patient would
elicit a specific response only to the tumor antigens rather than potentially allotypic
determinants (Goldsby, 2003).
Characteristics that would be considered ideal for a
tumor antigen to possess would include immunogenecity and expression on tumor cells.
Most tumor antigens are not considered to be specific to tumors because of their
expression on normal tissues. For this reason, these tumor antigens are labeled “tumor
associated” instead of tumor specific (Armstrong, 2001b).
Adjuvants are substances that can enhance the immune response in a non-specific
manner when administered with the antigen. Adjuvants may use a variety of mechanisms
to create their effect. There are only a few that are licensed for human use. These
include Alum (aluminum salts) and MF59 (oil/surfactant emulsion). Adjuvants may
utilize Toll-like receptors to trigger a pro-inflammatory response. They also enhance
uptake by antigen presenting cells (APC’s) and maintain a high concentration of antigen
after injection (Tabi, 2006a)
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Tumor Cell Vaccines
Tumor cell vaccines were one of the earliest forms of cellular therapy. These
vaccines utilize whole tumor cells, which are rendered safe by irradiation (Armstrong,
2001a). The irradiation process prevents cell division of the tumor cells (Goldsby, 2003).
The irradiated cells are then mixed with an adjuvant. Tumor cell vaccines have the
benefit that tumor antigens do not have to be identified before treatment. These vaccines
also allow all relevant antigens to be included in the vaccine (Armstrong, 2001a). In
these vaccines, many epitopes are recognized by the immune system. An epitope is a
specific site on the antigen that is recognized by the cells of the immune system
(Goldsby, 2003).
Erythematous reactions at the site of injection are the main side effects of these
vaccines (Armstrong, 2001a). In many tumor cell vaccines, tumor cells may be modified
by adding new chemicals or new peptides. A specific immune response is initiated when
the tumor cells are injected into the body. The body’s immune system will then attack
the similar cancer cells that are remaining in the body (ACS, 2006).
There are two basic types of tumor cell vaccines. These are autologous and
allogenic. In autologous vaccines, the tumor cells are removed from the individual
during surgery, killed, and then reinjected into that same individual. Reinjection can be
performed shortly after surgery or later. The tumor cells can be preserved by freezing.
This allows reinjection to be performed at a later time. There are several disadvantages
to these vaccines. Creating an autologous tumor cell vaccine for each individual patient
can be expensive.
Also, the mutation of cancer cells over time can create difficulty if
reinjected at a later time. It may also be difficult to retrieve enough usable cells during
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surgery to create the vaccine. These obstacles may be overcome if researchers create
new ideas for vaccines that can be used in any patient with a certain type of cancer (ACS,
2006).
In allogenic vaccines, tumor cells are used that were previously obtained from a
different individual other than the individual that is to receive the vaccine. Allogenic
tumor vaccines can contain a mixture of cells that were obtained from several individuals
instead of a single individual. These vaccines usually contain one or more adjuvants
(ACS, 2006).
Currently, tumor cell vaccines are only available through clinical trials. To this
date, the FDA has not approved the general use of tumor cell vaccines. Cancers that
these vaccines are being studied in include: melanoma, colorectal cancer, kidney cancer,
ovarian cancer, breast cancer, lung cancer and leukemia (ACS, 2006).
Dendritic Cell Vaccines
The cell that is primarily responsible for the efficacy of cancer vaccines is the
dendritic cell. The dendritic cell has a remarkable ability to capture and process antigen
(Armstrong, 2001a). Dendritic cells are classified as professional antigen processing
cells along with macrophages and B-lymphocytes. Dendritic cells are considered to be
the most efficient antigen presenting cells. Dendritic cells contain high proportions of
class II MHC molecules and exhibit a great amount of co-stimulatory activity (Goldsby,
2003).
Dendritic cells can now be generated outside of the body from an individual’s
peripheral blood monocytes or CD34+ hemopoietic stem cells. These characteristics
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have made dendritic cell vaccines an appealing idea. Whole antigens, peptide fragments,
or tumor cell lysates can be attached to dendritic cells. Dendritic cell vaccines can be
combined with gene therapy. The use of recombinant viral vectors is one of these
techniques. These viral vectors do not have the ability to replicate. A lasting expression
of antigen is achieved by introduction of the genetic material into the dendritic cells.
Dendritic cells can actually be destroyed causing a problem with this technique. Using
retroviruses may avoid this problem by preventing viral genes from being produced.
(Armstrong, 2001a).
Dendritic cell vaccines must be individually tailored for each patient, making this
an expensive process. These dendritic cells are made capable of recognizing cancer
antigen. Exposing the dendritic cells to the antigen and gene therapy are techniques used
to accomplish this task. The dendritic cells are then injected into the individual, which
then stimulates the immune response.
These vaccines are only obtainable through
clinical trials at this time. Some cancers that these vaccines are being studied in include:
prostate cancer, melanoma, breast cancer, lung cancer, colorectal cancer, kidney cancer,
leukemia, non-Hodgkin lymphoma (ACS, 2006).
Antigen Vaccines
Antigen vaccines include peptide vaccines. In peptide vaccines only one specific
epitope is injected rather than many epitopes as in whole tumor cell vaccines. These
individual epitopes are combined with an adjuvant before administration. Only class I
MHC restricted peptide has been used in peptide vaccines. These vaccines do not have to
be tailored to each individual patient. The genetic code of many of these antigens has
been identified. There are several advantages to these vaccines. Many of these antigens
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can be obtained by the use of man-made chemicals and vast amounts of antigens obtained
in laboratories. Antigens can be changed so that the immune system can identify them
more easily (ACS, 2006). A disadvantage to these vaccines is that the MHC haplotype,
or type of conserved MHC, of each individual must be identified. Also the portion of the
tumor cell that the MHC I binds must be identified for each patient. Tumors with slight
genetic variation that do not contain the peptide epitope any longer may also be targeted
by the immune system. This is a cause of concern (Armstrong, 2001b). Some antigens
are specific for a certain type of cancer; others may induce an immune response in
several cancers. Numerous antigens may be combined in a particular vaccine in order to
stimulate the immune system to respond to several antigens that could possibly be present
on the tumor cells (ACS, 2006).
Some cancers that antigen vaccines are being studied in include: kidney cancer,
pancreatic cancer, melanoma, ovarian cancer, breast cancer, prostate cancer, and
colorectal cancer (ACS, 2006).
Anti-Idiotype Vaccines
Anti-idiotype vaccines are based on the idea that antibodies can also act as
antigens. These antibodies that are acting as antigens can trigger an immune response.
As mentioned earlier, plasma cells, which are derived from B-cells produce one type of
antibody. The idiotype of an antibody is unique to that group of antibodies. The immune
system not only produces antibodies that bind to antigens but also antibodies that treat
other antibodies like antigens. For example, antibody A will “act” as an antigen to
antibody B. Antibody A actually resembles the original antigen that stimulated the
production of antibody B initially. In these types of cancer vaccines, these original
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antigens are cancer cells. This idea would be used to create a vaccine in which the
antibodies (which resemble the cancer cells) would be injected into the cancer patient.
This would trigger an immune response against the cancer. An advantage to these
vaccines is that they would not have to be individually tailored to each patient. The
primary target for these vaccines is lymphoma (ACS, 2006).
DNA Vaccines
Interest in DNA vaccines was brought about when an immune response was
induced from the injection of DNA intramuscularly (Armstrong, 2001b). The basis of
DNA vaccines is introduction of the tumor antigen genes instead of the tumor antigen
itself. An advantage to DNA vaccines is that viral vectors are not needed. These antigen
genes can be introduced into dendritic cells for endogenous processing or into other cells
to allow for cross-presentation by dendritic cells. Disadvantages of DNA vaccines is that
the antigen DNA sequence must be known in detail and that high doses of the plasmid
DNA is required in order to elicit an immune response (Berzofsky, 2004). The idea of
these vaccines is that the body would be provided with a constant supply of antigens to
allow the immune response to continue against the cancer. Cells in the body take up the
injected DNA. Specific antigens would then be made. These antigens would be made on
a continuous basis. Cells could possibly be removed from the body, treated with the
altered DNA and reinjected into the patient’s body. DNA vaccines are now being studied
in these cancers in clinical trials: prostate cancer, leukemia, melanoma, and head and
neck cancer (ACS, 2006).
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Selected Cancer Vaccines
Currently, there are many different types of cancer vaccines that are being
studied. Several cancer vaccines were chosen to be discussed. Excitingly, in November
of 2005, Sipuleucel-T (Provenge), a prostate cancer vaccine, by Dendreon Corporation
received fast-track review status from the FDA.
This vaccine is indicated for the
treatment of asymptomatic, metastatic, androgen-independent prostate cancer (AIPC) in
men. The FDA determined that Provenge met criteria including improving survival in
these patients. The awarded fast track status Provenge received allows for expedited
regulatory review and is now allowed to submit a U.S. biologics license application
(BLA) on a rolling basis. This also allows the BLA to be reviewed by the FDA before
the complete application is actually submitted (Dendreon, 2006).
Provenge could be the first in this group of active immunotherapy and may have
low toxic effects on the patients (Dendreon, 2006). Provenge is an example of a dendritic
cell vaccine (Brand, 2006). The antigen target for Provenge is prostatic acid phosphatase
(PAP). PAP is found in about 95% of prostate cancers. Provenge is currently being
studied in men with AIPC in a Phase III trial that compares the product to placebo.
Patients are being recruited from the United States and Canada. (Dendreon, 2006)
Medical need is great for this vaccine. In the U.S. prostate cancer causes 30,000 deaths a
year and is the most common noncutaneous cancer in men (Tarassoff, 2006). More than
one million men in the U.S. are affected by prostate cancer. A double-blind placebocontrolled study of Provenge in 98 men with AIPC showed a 3.3 month or 21 percent
improvement in median survival in patients who received Provenge compared to placebo.
A final three-year follow-up showed that 32 percent of the men that received Provenge
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were alive compared to 21 percent of men in the placebo group. This is a 52 percent
improvement of survival rate.
Another active immunotherapy product created by
Dendreon is Lapuleucel-T. The target of Lapuleucel-T is Her2/neu positive cancers.
These cancers would include lung, colon, breast, and ovarian (Dendreon, 2006).
Lung cancer is the number one cause of cancer death of both men and women
(ACS, 2006). A non-small cell carcinoma vaccine is being studied at the University of
Kentucky. Non-small cell lung cancer (NSCLC) is a main cause of death in both men
and women in the world. Conventional therapies do not effectively treat lung cancer in
many cases (Department of Microbiology, Immunology, and Molecular Genetics Faculty
Listing, 2004).
This vaccine is an autologous vaccine that involves the pulsing of
dendritic cells with apoptotic bodies.
These apoptotic bodies are derived from an
allogenic NSCLC cancer line. Patients with Stage IA to IIIB NSCLC were treated with
the vaccine. These patients had been treated with prior surgery, chemoradiation, or
multimodality therapy. A clear immunologic response was not observed in five of the 16
patients. Five of 16 patients showed an antigen-independent response. The response
may have been tumor specific in the other six patients (Hirschowitz, 2004). A response
to the vaccine has been shown in various stages of NSCLC (Department of Microbiology,
Immunology, and Molecular Genetics Faculty Listing, 2004).
OncoVAX, a colon cancer vaccine by Intracel also received fast-track status from
the FDA in 2006 (Intracel, 2006). In the United States colon cancer is the second most
common cause of cancer death in both men and women (ACS, 2006).
This vaccine is
intended for the treatment of Stage II colon cancer. This vaccine is administered after
surgery to reduce the recurrence of colon cancer. Sixty-five percent of patients with
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colon cancer are cured with surgery alone. OncoVAX can be used as an adjuvant to
improve 5-yr survival and recurrence-free survival of patients that are not cured with
surgery alone. OncoVAX is an example of an autologous vaccine. As described earlier,
the tumor cells are removed from the individual during surgery, killed with irradiation,
and injected back into that same individual to elicit an immune response. After removal
of the tumor cells during surgery, the tumor cells are made into a vaccine within 48
hours. This is frozen and split into four doses, which will be four vaccines. The vaccine
is not used immediately. Patients must wait a few weeks to receive the vaccines, so that
the immune system can gain recovery and boost a strong response. The main side effect
of OncoVAX is an erythematous skin reaction at the injection site that may develop into
an ulcer but will heal in two to three months. Some patients may develop mild flu like
symptoms or a slight fever. These should only last a few days. OncoVAX may not result
in unpleasant symptoms that may be caused by some other cancer therapies (Intracel,
2006).
A multi-center randomized phase III controlled clinical trial of Stage II and Stage
III colon cancer patients has been completed for OncoVAX. After surgical removal of the
primary tumor, patients received either OncoVAX therapy or no therapy. It was found
that using OncoVAX in an adjuvant setting significantly improves recurrence-free
interval (57.1 percent relative risk reduction). Five-year overall survival and recurrencefree survival were also significantly improved. These statistics were for patients with
Stage II colon cancer. No statistically relevant benefits were shown in the patients with
Stage III colon cancer (Groot, 2005). A new randomized Phase III trial is planned for
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this year. Some European companies have already made OncoVAX available for use
(Intracel, 2006).
Discussion/Conclusion
It is now clear that the immune system does exhibit a highly developed response
against tumor cells. The problem is that an effective immune response against the cancer
frequently fails to develop. Tumors cells have sophisticated mechanisms in which they
can evade the immune response. Cancer vaccines may offer a method that can enhance
the immune response enabling the body to more efficiently fight the cancer. In essence,
these vaccines may prevent the tumor cells from overcoming or evading the immune
response. Presently, it seems that cancer vaccines may be more effective in the treatment
of cancer that is not advanced. Even with this limitation, it seems that great progress has
been made in this new methodology.
With the recent approval of the HPV vaccine, it seems that interest has been
stimulated in our approach to cancer. This new interest may aid in the acceptance and
trust of vaccines used in the treatment of cancer. It is important to understand that there
is a defining difference between the HPV vaccine and cancer vaccines as discussed here.
The HPV vaccine provides immunity against a virus that causes cervical cancer. The
majority of cancer vaccines are for the treatment of cancer. These vaccines do not create
immunity to any type of virus.
Clinically, cancer vaccines are not yet at our fingertips. Much research and
interest has been shown in these areas. Even though there are many advantages and
benefits to cancer vaccines, there are several problems with the development of cancer
vaccines. In general, one problem is not harming normal cells while still effectively and
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specifically seeking out cancer cells. Another issue is eliciting an immune response that
is great enough to effectively eradicate the tumor. Overcoming the body’s mechanisms
that allow the tumor to evade the immune response also poses a challenge (Berzofsky,
2004).
As mentioned earlier, cancer vaccines and immunotherapy in itself is considered
relatively new but many consider immunotherapy the “fourth modality” of cancer
treatment. Much research is still needed in order to make these vaccines a big player in
our treatment of cancer. There are definite hurdles to overcome for the development and
success of cancer vaccines. It seems that researchers are actively trying to overcome these
issues. Clinically, these vaccines could make a huge impact on our approach to treating
cancer. Most importantly, these vaccines could mean better quality of life and longer
survival for our patients with cancer.
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