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Understanding Cancer Series
How immune cells are activated to attack foreign invaders
Key Points
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- What is a cancer vaccine?
Cancer vaccines are intended either to treat existing cancers (therapeutic vaccines)
or to prevent the development of cancer (prophylactic vaccines). Both types
of vaccines have the potential to reduce the burden of cancer. Treatment or
therapeutic vaccines are administered to cancer patients and are designed to
strengthen the body’s natural defenses against cancers that have already developed.
These types of vaccines may prevent the further growth of existing cancers,
prevent the recurrence of treated cancers, or eliminate cancer cells not killed
by prior treatments. Prevention or prophylactic vaccines, on the other hand,
are administered to healthy individuals and are designed to target cancer-causing
viruses and prevent viral infection. - Is any cancer vaccine currently available in the United States?
Yes. The single cancer vaccine licensed by the Food and Drug Administration
is a prophylactic vaccine against hepatitis B virus, an infectious agent associated
with liver cancer. There are no licensed therapeutic vaccines to date. However,
several treatment vaccines are in large-scale testing in humans. If clinical
trial results are favorable, additional cancer vaccines may be approved for
use in the United States within the next few years. - How are therapeutic vaccines designed to treat cancer?
Vaccines used to treat cancers take advantage of the fact
that certain molecules on the surface of cancer cells are either unique or more
abundant than those found on normal or non-cancerous cells. These molecules,
either proteins or carbohydrates, act as antigens, meaning that they can stimulate
the immune system to make a specific immune response. Researchers hope that
when a vaccine containing cancer-specific antigens is injected into a patient,
these antigens will stimulate the immune system to attack cancer cells without
harming normal cells. - Why does the immune system need a vaccine to help fight cancer?
The immune system generally doesn’t “see” tumors as dangerous or foreign, and
doesn’t mount a strong attack against them. One reason tumor molecules do not
stimulate an effective immune response may be that tumor cells are derived from
normal cells. So, even though there are many molecular differences between
normal cells and tumor cells, cancer antigens are not truly foreign to the body,
but are normal molecules, either altered in subtle ways or more abundant.Another reason tumors may not stimulate an immune response is that cancer cells
have developed ways to escape from the immune system. Scientists now understand
some of these tricks, which include shedding tumor antigens, and reducing the
number of molecules and receptors that the body normally relies on to activate
T cells (specific immune cells) and other immune responses. Reducing these
molecules makes the immune system less responsive to the cancer cells; the tumor
become less “visible” to the immune cells. Hopefully, this knowledge can be
used by researchers to design more effective vaccines. - What strategies are used to design effective cancer treatment vaccines?
Researchers have developed several strategies to stimulate an immune response
against tumors. One is to identify unusual or unique cancer cell antigens that
are rarely present on normal cells.Other techniques involve making the tumor-associated antigen more immunogenic,
such as (a) altering its amino acid structure slightly, (b) placing the gene
for the tumor antigen into a viral vector (a harmless virus that can be used
as a vehicle to deliver genetic material to a targeted cell), and (c) adding
genes for one or more immuno-stimulatory molecules into vectors along with the
genes for the tumor antigen.Another technique is to attach something that is definitely foreign, known as
an adjuvant, to tumor molecules (see Question 8). By using the adjuvant as a
decoy, the immune system may be tricked into attacking both the antigen/adjuvant
complex (the vaccine) and the patient’s tumor. - What types of treatment vaccines are currently under investigation?
The types of vaccines listed below represent various methods investigators have
devised for presenting cancer antigens to the body’s immune system. This list
is not meant to be comprehensive.Antigen/adjuvant vaccines
Antigen vaccines were some of the first cancer vaccines investigated. Antigen
vaccines commonly use specific protein fragments or peptides to stimulate the
immune system to fight tumor cells. One or more cancer cell antigens are combined
with a substance that causes an immune response, known as an adjuvant. A cancer
patient is vaccinated with this mixture. It is expected that the immune system,
in responding to the antigen-carrying adjuvant, will also respond to tumor cells
that express that antigen.Whole cell tumor vaccines
Taken either from the patient’s own tumor (autologous) or tumor cells from one
or more other patients (allogeneic), these whole cell vaccine preparations contain
cancer antigens that are used to stimulate an immune response.Dendritic cell (DC) vaccines
Specialized white blood cells known as dendritic cells (DCs) are taken from
a patient’s blood through a process called
leukapheresis.
In the laboratory, the DCs are stimulated with the patient’s own cancer antigens,
grown in petri dishes, and re-injected into the patient. Once injected, DC
vaccines activate the immune system’s T cells. Activation by DCs is expected
to cause T cells to multiply and attack tumor cells expressing that antigen.Viral vectors and DNA vaccines
Viral vectors and DNA vaccines use the nucleic acid sequence of the tumor antigen to produce the cancer
antigen proteins. The DNA containing the gene for a specific cancer antigen is manipulated in the
laboratory so that it will be taken up and processed by immune cells called antigen-presenting cells (APCs).
The APC cells then display part of the antigen together with another molecule
on the cell surface. The hope is that when these antigen-expressing APC cells
are injected into a person, the immune system will respond by attacking not
only the APC cells, but also tumor cells containing the same antigen. Vector-based and
DNA vaccines are attractive because they are easier to manufacture than some other vaccines.Idiotype vaccines
Since antibodies are molecules containing protein and carbohydrate, they can
themselves act as antigens and induce an antibody response. Antibodies produced
by certain cancer cells (i.e., B-cell lymphomas and myelomas), called idiotype
antibodies, are unique to each patient and can be used to trigger an immune
response in a manner similar to antigen vaccines. - Which antigens are commonly found in cancer vaccines?
Cancer cell antigens may be unique to individual tumors, shared by several tumor
types, or expressed by the normal tissue from which a tumor grows. In 1991,
the first human cancer antigen was discovered in the cells of a patient with
metastatic melanoma, a potentially lethal form of skin cancer. The discovery
led to a flurry of research to identify antigens for other cancers.Treatment Vaccines
Patient-specific vaccines
Patient-specific vaccines use a patient’s own tumor cells to generate a vaccine
intended to stimulate a strong immune response against an individual patient’s
malignant cells. Each therapy is tumor-specific so, in theory, cells other
than tumor cells should not be affected. There are several kinds of patient-specific
vaccines that use antigens from a patient’s own tumor cells but deliver the
antigen differently.Prostate Specific Antigen (PSA) is a prostate-specific protein
antigen that can be found circulating in the blood as well as on prostate cancer
cells. PSA is present in small amounts in men who do not have cancer, but the
quantity of PSA generally rises when prostate cancer develops. Patients
have been shown to mount T-cell responses to PSA.Sialyl Tn (STn) is a small, synthetic carbohydrate that mimics the mucin molecules (the
primary molecule present in mucus) found on certain cancer cells.Heat Shock Proteins (HSPs) (e.g., gp96) are produced
in cells in response to heat, low sugar levels and other stress signals. Besides
protecting against stress, these molecules are also involved in the proper processing,
folding, and assembling of proteins within cells. In laboratory experiments,
HSPs from mouse tumors, in combination with small peptides, protected mice from
developing cancer. The human vaccine consists of heat shock protein and associated
peptide complexes isolated from a patient’s tumor. HSPs are under investigation
for treatment of several cancers including liver, skin, colon, lung, lymphoma
and prostate cancers.Ganglioside molecules (e.g., GM2, GD2, and GD3) are complex molecules
containing carbohydrates and fats. When ganglioside molecules are incorporated
into the outside membrane of a cell, they make the cell more easily recognized
by antibodies. GM2 is a molecule expressed on the cell surface of a number
of human cancers. GD2 and GD3 contain carbohydrate antigens expressed by human
cancer cells.Carcinoembryonic antigen (CEA) is found in high levels in people with colorectal, lung, breast
and pancreatic cancer as compared with normal tissue. CEA
is thought to be released into the bloodstream by tumors. Patients
have been shown to mount T-cell responses to CEA.MART-1 (also known as Melan-A) is an antigen expressed
by melanocytes — cells that produce melanin, the molecule responsible for the
coloring in skin and hair. It is a specific melanoma cancer marker that is
recognized by T cells and more abundant on melanomas than normal cells.Tyrosinase is a key enzyme involved in the initial stages of
melanin production. Studies have shown that tyrosinase is a specific marker
for melanoma and more abundant on melanomas than normal cells.Prevention Vaccines
Viral proteins on the outside coat of the cancer-causing viruses are
commonly used as antigens to stimulate the immune system for prevention vaccines. - What are adjuvants? Which adjuvants are commonly used in treatment vaccines?
To heighten the immune response to cancer antigens, researchers
usually attach a decoy substance, or adjuvant, that the body will recognize
as foreign. Adjuvants are weakened proteins or bacteria which “trick”
the immune system into mounting an attack on both the decoy and the tumor cells.
Several adjuvants are described below:Keyhole limpet hemocyanin (KLH) is a
protein made by a shelled sea creature found along the coast of California and
Mexico known as a keyhole limpet. KLH is a large protein that both causes an
immune response and acts as a carrier for cancer cell antigens. Cancer antigens
often are relatively small proteins that may be invisible to the immune system.
KLH provides additional recognition sites for immune cells known as T-helper-cells
and may increase activation of other immune cells known as cytotoxic T-lymphocytes
(CTLs).Bacillus Calmette Guerin (BCG) is an inactivated form of the
tuberculosis bacterium routinely used for decades to vaccinate against TB.
BCG is added to some cancer vaccines with the hope that it will boost the immune
response to the vaccine antigen. It is not well understood why BCG may be especially
effective for eliciting immune response. However, BCG has been used for years
with other vaccines, including the vaccine for tuberculosis.Interleukin – 2 (IL-2) is a protein made by the body’s immune
system that may boost the cancer-killing abilities of certain specialized immune
system cells called natural killer cells. Although it can activate the immune
system, many researchers believe IL-2 alone will not be enough to prevent cancer
relapse. Several cancer vaccines use IL-2 to boost immune response to specific
cancer antigens.Granulocyte Monocyte-Colony Stimulating Factor (GM-CSF) is a protein that stimulates the proliferation of antigen-presenting cells.
QS21 is a plant extract that, when added to some vaccines, may improve the immune response.
Montanide ISA-51 is an oil-based liquid intended to boost an immune response.
- Why are some vaccines used to treat specific kinds of cancer?
Many cancer vaccines treat only specific types of cancers
because they target antigens found on specific cancers. For example, a vaccine
against prostate cancer may be able to attack cancer cells within the prostate
itself or cells that have spread to other parts of the body, but would not affect
cancers originating in other tissues.Vaccines that target antigens found on several different
kinds of cancer cells are used to treat multiple cancers. The effectiveness
of the vaccine would be expected to differ according to the amount of antigen
on different kinds of cancer cells. Researchers also are investigating a possible
“universal” cancer vaccine that might cause an immune response against cancer
cells that originate from any tissue. - Are there vaccines under development to prevent cancer?
Yes, some vaccines currently under investigation have the potential to reduce
the risk of cancer. These vaccines target infectious agents that cause
cancer and are similar to traditional prophylactic vaccines, which target other
disease-causing infectious agents such as those that cause polio or measles.
Non-infectious components of cancer-causing viruses, commonly the viral coat
proteins (proteins on the outside of the virus), serve as antigens for these
vaccines. It is hoped that these antigens will stimulate the immune system
in the future to attack cancer-causing viruses, which should, in turn, reduce
the risk of the associated cancer.For example, the human papilloma virus (HPV) causes nearly all cases of cervical
cancer. Preventing infection by HPV is expected to dramatically reduce the
risk of cervical cancer. One promising vaccine against HPV is expected to enter
large-scale human trials in the near future. Another promising prevention vaccine
targets the hepatitis C virus, linked to the development of liver cancer. - Which vaccines have reached Phase III testing?
The results from ongoing Phase III trials, listed in the table below, will determine
whether vaccines will play a role in the treatment and prevention of different
cancers. The information is derived from government
databases including the National Cancer Institute’s clinical trials database,
www.cancer.gov/search/clinical_trials,
and the National Institute’s of Health clinical trials Web site,
http://clinicaltrials.gov.
Information on each trial can also be obtained by clicking the link in the far
right column of the table below.Click to view Phase III Vaccine Trials
Further information about cancer vaccines can be found at:
http://www.nci.nih.gov/clinicaltrials/understanding/treating-cancer-with-vaccine-therapy.