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Cancer Vaccines A Primer About an Emerging Therapy
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Submitted By: Alfred Chang
Cancer Vaccines
A Primer About an Emerging Therapy
Alfred E. Chang, M.D.
Chief, Division of Surgical Oncology
University of Michigan Comprehensive Cancer Center
Ann Arbor, MI 48109
What is a vaccine?
A vaccine involves the administration of an agent to an individual which will
stimulate the immune system to react against the "foreign" components of the
vaccine. The vaccine can be administered into the skin, muscle, intraorally, or
intravenously. The foreign components of the vaccine are known as "antigens".
The end result of a vaccination procedure is to develop immunity in the individual
so that a subsequent exposure to the antigen(s) will evoke a response to eliminate
or destroy the antigen(s).
Vaccines have been highly effective in protecting people from infectious
organisms. The first successful vaccination procedure was described by Edward
Jenner in the 1790's. He observed that milkmaids appeared to be protected from
developing small pox. He theorized that their exposure to the cox pox virus made
them immune to infection by the small pox virus, which was very similar to the
cox pox virus. He went on to introduce the cox pox virus into humans and found
that they were protected against small pox. This demonstrated that the immune
system can be recruited to react to a particular infectious organism; and,
eventually eliminated small pox as a public health problem. Vaccinations for
bacterial and viral infectious agents are now routinely used for: influenza viruses,
measles, chicken pox, polio, pneumococcal bacteria, and hepatitis viruses. There
is a tremendous effort currently being conducted to identify an effective HIV
vaccine.
Because of the success in immunizing individuals against certain infectious
organisms, it has been the dream of clinicians and scientists to develop effective
vaccines against cancers. One of the earliest steps in that direction was pioneered
by William B. Coley in the 1890's. He was a general surgeon in New York City who
observed that occasional patients who developed an infection in the vicinity of
their cancer have reductions in the size of their tumors. He took the bold step of
taking live bacterial organisms and directly injecting them into growing soft tissue
tumors. To his amazement, some of these tumors shrank after developing a brisk
inflammatory response. It was theorized that the immune system was activated
by the inoculation of the bacteria and subsequently caused its destruction. This
was the first observation that the immune system could be activated to cause
tumor regression. Coley spent the rest of his career trying to isolate the toxins
produced by the bacteria which he felt were responsible for the antitumor effects.
What are the different types of cancer vaccines?
Coley initiated a series of studies attempting to activate the immune system
utilizing bacterial agents which included erysipelas streptococcus and Serratia
marcescens. Other bacterial agents which have been examined by other
investigators included bacillus Calmette-Guérin (BCG) and Corynebacterium
parvum (C. parvum). This form of therapy attempts to activate the immune
system in a non-specific fashion. Unfortunately, several clinical trials evaluating
these non-specific agents or their products proved ineffective. However, many of
these bacterial agents are now being combined with "tumor-associated" antigens
(TAAs) as a method to induce specific immunity to tumors. Tumor-associated
antigens are structures (ie., proteins, enzymes or carbohydrates) which are
present on tumor cells and relatively absent or diminished on normal cells. By
virtue of being fairly unique to the tumor cell, TAAs provide targets for the
immune system to recognize and cause their destruction.
The nature of tumor-associated antigens were unknown for a long time. Many of
the initial clinical studies of specific tumor vaccines involved utilizing the tumor
cell as a source of TAAs. These tumor cells were obtained from the patient and
rendered non-viable by irradiation or killing the tumor cells so that only the
membrane fragments remain for use as a vaccine. The tumor cell preparation was
then combined with an "adjuvant" prior to inoculation in the skin. An adjuvant is
an agent, such as BCG, which will augment the immune response to TAAs.
Many TAAs have now been identified and represent a diverse array of structures
associated with tumor cells. For example, some cancer cells manufacture and
secrete protein structures not normally produced by other cells. Examples
include: carcinoembryonic antigen (CEA) produced by colon cancers and other
adenocarcinomas (ie., breast, lung, gastric, and pancreas cancers); prostate
specific antigen (PSA) produced by prostate cancers; and alpha-fetoprotein (AFP)
produced by liver cancers (a.k.a. hepatomas). Clinical trials are underway to
vaccinate patients to these secreting proteins in an attempt to eradicate tumor.
Several TAAs expressed by tumors represent normal components of cells from
which the tumor originates. For example, PSA is made by prostate cancer cells
but also by normal prostate cells. Hence, immunity to PSA will hopefully impact
on prostate cancer cells but also may result in an "auto-immunity" to the prostate
gland. This is dramatically seen with the immune treatment of melanoma, a
malignant skin cancer. Melanoma tumors express TAAs which are also expressed
by normal melanosomes. Melanosomes are skin cells which make pigment and
give coloration to the skin. It has been reported that patches of "vitiligo" or
depigmentation can occur in individuals who undergo a tumor response of their
melanoma with immune treatments (either vaccination or other immune
therapies). This is an example of an autoimmune phenomenon which
demonstrates that an immune response can be mounted against normal "self"
antigens which also results in tumor regression.
Many of the gene therapies involving cancer represent a form of cancer vaccines.
The ability to introduce genes into cells is known as gene transfer. Investigators
have used these techniques to introduce genes into tumor cells to make them
more reactive to the patient's immune system. These genes contain the building
blocks for immune hormones (ie., interferon, interleukin-2 (IL-2),
granulocyte-macrophage colony-stimulating factor (GM-CSF), etc.) or other
stimulatory proteins which have been found to enhance the effectiveness of these
vaccines in animal studies.
Another area of active research in cancer vaccines has been with a unique cell
known as the dendritic cell (DC). Dendritic cells have been found to be necessary
to trigger the immune response to foreign antigens. DCs work by taking up
antigens and processing them into a form where other cells of the immune system
(ie., T cells) can respond to them. DCs can be removed from the blood stream,
grown in the laboratory, and then exposed (a.k.a. pulsing) to tumor antigen in
culture plates. When these "pulsed" DCs are injected back into the cancer-bearing
individual, an immune response is generated causing subsequent tumor
shrinkage. These latter findings have been observed in animal studies and are
now being tested in clinical trials.
Examples of different forms of tumor antigens and adjuvants
are listed in Table 1.
Tumor Antigens
|
Description
|
|
|
Autologous tumor cells |
Whole cells or portions (a.k.a. lysates) of cells
obtained from the patient being treated. |
Allogeneic tumor cells |
Whole cells or portions of cells obtained from different
patient(s). Common shared antigens exist among tumors of the same
histology. |
Gangliosides
(ie. GM2)
|
Carbohydrate structures present on melanoma and sarcoma
cancer cells. |
CEA
|
Oncofetal antigen present on colorectal cancers as
well as other gastrointestinal malignancies and breast cancer. |
PSA
|
Prostate specific antigen present on prostate cancer. |
MART-1 gp100 MAGE 1, 3
Tyrosinase
|
Melanoma associated antigens also present on normal
melanosomes. |
p53
|
Oncogene either overexpressed in tumor cells compared
to normal cells, or mutated in cancer cells. Present in many types of cancers. |
E6, E7
|
Viral antigens derived from papillomaviruses which
cause cervical cancer. |
Adjuvants
|
|
BCG
C.parvum
|
Bacterial organisms. |
Endotoxin Lipopolysaccharides
|
Products made by bacterial organisms. |
KLH
|
Keyhole limpet hemocyanin, an immunogeneic protein. |
IL-2
|
Cytokine which causes T cell activation and proliferation. |
GM-CSF
|
Cytokine which causes attraction of DCs and their
maturation. |
Cytoxan
|
Chemotherapeutic agent which is thought to reduce
tumor-induced suppression when given in low doses. |
Are any vaccines approved for clinical use?
There are no cancer vaccines which have been approved by the United States
Food and Drug Administration for routine use. Currently, cancer vaccines are
experimental and are being administered in the setting of clinical trials. Most of
these clinical trials involve patients with advanced cancers who have no other
standard treatments such as chemotherapy, surgery or radiation available to
them.
To date, melanoma is the tumor type where most of the clinical studies have been
performed with vaccines. There are more TAAs which have been identified for
melanoma tumors compared to any other cancer. There are several
multi-institutional trials evaluating tumor vaccines versus interferon-alpha in the
treatment of melanoma which has metastasized to local draining lymph nodes.
After surgical removal of the disease, standard therapy involves administration of
interferon-alpha for 1 year. These trials involve randomizing patients to receive
interferon-alpha or a cancer vaccine after surgery. Since vaccines are associated
with minimal toxicity, any results of these trials which demonstrate similar cure
rates in both groups will be beneficial for future patients since interferon-alpha
has a significant toxicity profile.
Other vaccine studies in melanoma involve patients with more advanced
melanoma (ie. Stage IV where melanoma has metastasized beyond the draining
lymph nodes). These vaccine studies generally involved a single institution where
a specific researcher is testing a vaccine he or she has developed. These vaccines
may involve tumor cells, tumor peptides, dendritic cells "pulsed" with TAAs, or
gene-modified tumor cells administered along with various adjuvants.
Studies are being conducted in advanced cancers such as breast cancer,
colorectal cancer, ovarian cancer, cervical cancer, and prostate cancer utilizing
tumor antigens identified in the above table. For the most part, these are phase I
or II studies to determine the toxicity profile of the vaccine, and to measure any
immunologic or tumor responses. Phase I studies are designed to test different
doses of the vaccine and determine what the toxicity may be with the different
doses. Phase II studies are designed to test a set dose of the vaccine and
determine what response rates are associated with that particular regimen.
How can I find out if I qualify for a vaccine?
If you have a history of a cancer which has been successfully removed and
treated with standard therapies, chances are you are not a candidate for a cancer
vaccine. If you have an advanced cancer which has failed standard treatments,
there may be research vaccine trials for which you are eligible. One source of
information is with the National Cancer Institute (NCI) Trials Database which is a
list and description of many clinical trials across the country. This is known as the
PDQ listing and can be accessed via the Internet (http://cancertrials.nci.nih.gov/)
or calling Cancer Information Service 1-800-4-CANCER. Another source of
information would be to contact your nearest NCI-designated cancer center (i.e.
University of Michigan Comprehensive Cancer Center). There are approximately 30
of these centers located across the country. These centers are reviewed and
certified by the NCI for the quality of their clinical research. Each NCI-designated
cancer center has an information line or website which will provide information
about their clinical studies.
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Additional Authors: |
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Works Cited: |
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Bibliography
Melanoma:
1. Hemmila MR, Chang AE: Clinical implications of the new biology in the
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