Biological Therapies for Cancer
- What is biological
therapy?
Biological therapy involves the use of living organisms, substances derived
from living organisms, or laboratory-produced versions of such substances to
treat disease. Some biological therapies for cancer use vaccines or bacteria to stimulate the body’s immune system to act against cancer cells. These types of biological therapy, which are sometimes referred to
collectively as “immunotherapy” or “biological response modifier therapy,” do
not target cancer cells directly. Other biological therapies, such as antibodies or segments of genetic material (RNA or DNA), do target cancer cells directly. Biological therapies that interfere
with specificmolecules involved in tumor growth
and progression are also referred to as targeted therapies. (For more information, see Targeted Cancer Therapies.)
For patients with cancer, biological therapies may be used to treat the
cancer itself or the side effects of other cancer treatments. Although many forms of biological therapy
have been approved by the U.S. Food and Drug Administration (FDA), others
remain experimental and are available to cancer patients principally through
participation in clinical trials (research studies involving people).
- What is the immune system
and what role does it have in biological therapy for cancer?
The immune system is a complex network of organs, tissues, and specialized cells. It recognizes and destroys foreign invaders, such
as bacteria or viruses, as well as some damaged, diseased, or abnormal cells in
the body, including cancer cells. An immune response is triggered when the immune system encounters a substance, called
an antigen, it recognizes as “foreign.”
White blood cells are the primary players in immune system responses. Some white blood
cells, including macrophages and natural killer cells, patrol the body, seeking out foreign invaders and diseased, damaged, or
dead cells. These white blood cells provide a general—or nonspecific—level of
immune protection.
Other white blood cells, including cytotoxic T cells and B cells, act against specific targets. Cytotoxic T cells release chemicals that
can directly destroy microbes or abnormal cells. B cells make antibodies that
latch onto foreign intruders or abnormal cells and tag them for destruction by
another component of the immune system. Still other white blood cells,
including dendritic cells, play supporting roles to ensure that cytotoxic T cells and B cells do
their jobs effectively.
It is generally believed that the immune system’s natural capacity to
detect and destroy abnormal cells prevents the development of many cancers.
Nevertheless, some cancer cells are able to evade detection by using one or more
strategies. For example, cancer cells can undergo genetic changes that lead to
the loss of cancer-associated antigens, making them less “visible” to the
immune system. They may also use several different mechanisms to suppress
immune responses or to avoid being killed by cytotoxic T cells (1).
The goal of immunotherapy for cancer is to overcome these barriers to an
effective anticancer immune response. These biological therapies restore or
increase the activities of specific immune-system components or
counteract immunosuppressive signals produced by cancer cells.
- What are monoclonal
antibodies, and how are they used in cancer treatment?
Monoclonal antibodies, or MAbs, are laboratory-produced antibodies that
bind to specificantigens expressed by cancer cells, such as a protein that is present on the surface of cancer cells but is absent from (or
expressed at lower levels by) normal cells.
To create MAbs, researchers inject mice with an antigen from human cancer
cells. They then harvest the antibody-producing cells from the mice and
individually fuse them with a myeloma cell (cancerous B cell) to produce a
fusion cell known as a hybridoma. Each hybridoma then divides to produce
identical daughter cells or clones—hence the term “monoclonal”—and antibodies
secreted by different clones are tested to identify the antibodies that bind
most strongly to the antigen. Large quantities of antibodies can be produced by
these immortal hybridoma cells. Because mouse antibodies can themselves elicit
an immune response in humans, which would reduce their effectiveness, mouse antibodies
are often “humanized” by replacing as much of the mouse portion of the antibody
as possible with human portions. This is done through genetic engineering.
Some MAbs stimulate an immune response that destroys cancer cells. Similar
to the antibodies produced naturally by B cells, these MAbs “coat” the cancer
cell surface, triggering its destruction by the immune system. FDA-approved
MAbs of this type include rituximab, which targets the CD20 antigen found on non-Hodgkin lymphoma cells, and alemtuzumab,
which targets the CD52 antigen found on B-cell chronic lymphocytic leukemia (CLL) cells. Rituximab may also trigger cell death (apoptosis) directly.
Another group of MAbs stimulates an anticancer immune response by binding
to receptors on the surface of immune cells and inhibiting signals that prevent immune
cells from attacking the body’s own tissues, including cancer cells. One such
MAb, ipilimumab,
has been approved by the FDA for treatment of metastatic melanoma, and others are being investigated in clinical studies(2).
Other MAbs interfere with the action of proteins that are necessary for
tumor growth. For example, bevacizumab targets vascular endothelial growth factor
(VEGF), a protein secreted by tumor cells and other cells
in the tumor’s microenvironment that promotes the development of tumor blood vessels. When bound to bevacizumab, VEGF cannot interact with its cellular
receptor, preventing the signaling that leads to the growth of new blood
vessels.
Similarly, cetuximab and panitumumab target
the epidermal growth factor receptor (EGFR), andtrastuzumab targets the human epidermal growth factor
receptor 2 (HER-2). MAbs that bind to cell surface growth factor receptors prevent the targeted receptors from sending their normal
growth-promoting signals. They may also trigger apoptosis and activate the
immune system to destroy tumor cells.
Another group of cancer therapeutic MAbs are the immunoconjugates. These
MAbs, which are sometimes called immunotoxins or
antibody-drug conjugates, consist of an antibody attached to a cell-killing
substance, such as a plant or bacterial toxin, a chemotherapy drug, or a radioactivemolecule.
The antibody latches onto its specific antigen on the surface of a cancer cell,
and the cell-killing substance is taken up by the cell. FDA-approved conjugated
MAbs that work this way include 90Y-ibritumomab tiuxetan, which targets the CD20 antigen to deliver radioactive yttrium-90 to B-cell non-Hodgkin lymphoma cells; 131I-tositumomab, which targets the CD20 antigen to deliver radioactive iodine-131 to
non-Hodgkin lymphoma cells; and ado-trastuzumab emtansine, which targets the HER-2 molecule to deliver the drug DM1, which inhibits
cell proliferation, to HER-2 expressing metastatic breast cancer cells.
- What are cytokines, and
how are they used in cancer treatment?
Cytokines are signaling proteins that are produced by white blood cells. They help mediate and regulate immune responses, inflammation, and hematopoiesis (new blood cell formation). Two types of cytokines are
used to treat patients with cancer: interferons (INFs)
and interleukins (ILs). A third type, called hematopoietic growth factors, is used to counteract some of the side effectsof certain chemotherapy regimens.
Researchers have found that one type of INF, INF-alfa, can enhance a
patient’s immune response to cancer cells by activating certain white blood
cells, such as natural killer cells anddendritic cells (3). INF-alfa may also inhibit the growth of cancer
cells or promote their death (4,5). INF-alfa has been approved for the
treatment of melanoma, Kaposi sarcoma, and severalhematologic cancers.
Like INFs, ILs play important roles in the body’s normal immune response
and in the immune system’s ability to respond to cancer. Researchers have
identified more than a dozen distinct ILs, including IL-2, which is also called T-cell growth factor. IL-2 is naturally produced by activated T cells. It
increases the proliferation of white blood cells, including cytotoxic T cells
and natural killer cells, leading to an enhanced anticancer immune response (6). IL-2 also facilitates the production of antibodies by B cells to further target cancer cells. Aldesleukin, IL-2 that is made in a
laboratory, has been approved for the treatment of metastatic kidney cancer and
metastatic melanoma. Researchers are currently investigating whether combining
aldesleukin treatment with other types of biological therapies may enhance its
anticancer effects.
Hematopoietic growth factors are a special class of naturally occurring
cytokines. All blood cells arise from hematopoietic stem cells in the bone marrow. Because chemotherapy drugs target proliferating cells, including normal
blood stem cells, chemotherapy depletes these stem cells and the blood cells
that they produce. Loss of red blood cells, which transport oxygen and nutrients throughout the body, can cause anemia.
A decrease in platelets, which are responsible for blood clotting, often leads to abnormal bleeding. Finally, lower white blood cell counts
leave chemotherapy patients vulnerable to infections.
Several growth factors that promote the growth of these various blood cell
populations have been approved for clinical use. Erythropoietin stimulates red blood cell formation, and IL-11 increases platelet
production. Granulocyte-macrophage
colony-stimulating factor (GM-CSF) andgranulocyte colony-stimulating
factor (G-CSF) both increase the number of white
blood cells, reducing the risk of infections. Treatment with these factors
allows patients to continue chemotherapy regimens that might otherwise be
stopped temporarily or modified to reduce the drug doses because of low blood cell numbers.
G-CSF and GM-CSF can also enhance the immune system’s specific anticancer
responses by increasing the number of cancer-fighting T cells. Thus, GM-CSF and
G-CSF are used in combination with other biological therapies to strengthen
anticancer immune responses.
- What are cancer treatment
vaccines?
Cancer treatment vaccines are designed to treat cancers that have already developed rather than
to prevent them in the first place. Cancer treatment vaccines contain
cancer-associatedantigens to enhance the immune system’s response to a patient’s tumor cells.
The cancer-associated antigens can be proteins or another type of molecule found on the surface of or inside cancer
cells that can stimulate B cells or killer T cells to attack them.
Some vaccines that are under development target antigens that are found on
or in many types of cancer cells. These types of cancer vaccines are being
tested in clinical trials in patients with a variety of cancers, including
prostate, colorectal, lung, breast, and thyroid cancers. Other cancer vaccines
target antigens that are unique to a specific cancer type (7-14). Still other vaccines are designed against an
antigen specific to one patient’s tumor and need to be customized for each
patient. The one cancer treatment vaccine that has received FDA approval, sipuleucel-T,
is this type of vaccine.
Because of the limited toxicity seen with cancer vaccines, they are also being tested in clinical
trials in combination with other forms of therapy, such as hormonal therapy, chemotherapy,radiation therapy, and targeted therapies. (For more information see Cancer Vaccines.)
- What is bacillus
Calmette-Guérin therapy?
Bacillus Calmette-Guérin (BCG) was the first biological therapy to be
approved by the FDA. It is a weakened form of a live tuberculosis bacterium that does not cause disease in humans. It was first used medically as
a vaccine against tuberculosis. When inserted directly into the bladder with
a catheter, BCG stimulates a general immune response that is directed not only against the foreign bacterium itself but
also against bladder cancer cells. How and why BCG exerts this anticancer
effect is not well understood, but the efficacy of the treatment is well
documented. Approximately 70 percent of patients with early-stage bladder cancer experience a remissionafter
BCG therapy (15).
- What is oncolytic virus
therapy?
Oncolytic virus therapy is an experimental form of biological therapy that involves the
direct destruction of cancer cells. Oncolytic viruses infect both cancer and
normal cells, but they have little effect on normal cells. In contrast, they
readily replicate, or reproduce, inside cancer cells and ultimately cause the cancer cells
to die. Some viruses, such as reovirus, Newcastle disease virus, and mumps
virus, are naturally oncolytic, whereas others, including measles virus,
adenovirus, and vaccinia virus, can be adapted or modified to replicate
efficiently only in cancer cells. In addition, oncolytic viruses can be
genetically engineered to preferentially infect and replicate in cancer cells
that produce a specific cancer-associated antigen, such as EGFR or HER-2 (19).
One of the challenges in using oncolytic viruses is that they may
themselves be destroyed by the patient’s immune system before they have a
chance to attack the cancer. Researchers have developed several strategies to
overcome this challenge, such as administering a combination of
immune-suppressing chemotherapy drugs like cyclophosphamide along with the virus or “cloaking” the virus within a protective
envelope. But an immune reaction in the patient may actually have benefits:
although it may hamper oncolytic virus therapy at the time of viral delivery,
it may enhance cancer cell destruction after the virus has infected the tumor
cells (20-23).
No oncolytic virus has been approved for use in the United States, although
H101, a modified form of adenovirus, was approved in China in 2006 for the
treatment of patients with head and neck cancer. Several oncolytic viruses are
currently being tested in clinical trials. Researchers are also investigating
whether oncolytic viruses can be combined with other types of cancer therapies
or can be used to sensitize patients’ tumors to additional therapy.
- What is gene therapy?
Still an experimental form of treatment, gene therapy attempts to introduce
genetic material (DNAor RNA) into living cells. Gene therapy is being studied in clinical trials for
many types of cancer.
In general, genetic material cannot be inserted directly into a person's
cells. Instead, it is delivered to the cells using a carrier, or “vector.” The
vectors most commonly used in gene therapy are viruses, because they have the
unique ability to recognize certain cells and insert genetic material into
them. Scientists alter these viruses to make them more safe for humans (e.g.,
by inactivating genes that enable them to reproduce or cause disease) and/or to improve
their ability to recognize and enter the target cell. A variety of liposomes
(fatty particles) andnanoparticles are also being used as gene therapy vectors, and scientists are
investigating methods of targeting these vectors to specific cell types.
Researchers are studying several methods for treating cancer with gene therapy.
Some approaches target cancer cells, to destroy them or prevent their growth.
Others target healthy cells to enhance their ability to fight cancer. In some
cases, researchers remove cells from the patient, treat the cells with the
vector in the laboratory, and return the cells to the patient. In others, the
vector is given directly to the patient. Some gene therapy approaches being
studied are described below.
o
Replacing an altered tumor suppressor
gene that produces a nonfunctional protein (or no protein) with a normal version of the gene. Because tumor
suppressor genes (e.g., TP53) play a role in preventing cancer,
restoring the normal function of these genes may inhibit cancer growth or
promote cancer regression.
o
Introducing genetic material to block the
expression of an oncogene whose product promotes tumor growth. Short RNA or DNA molecules with
sequences complementary to the gene’s messenger RNA (mRNA) can be packaged into vectors or given to cells directly. These
short molecules, called oligonucleotides, can bind to the target mRNA,
preventing itstranslation into protein or even causing its degradation.
o
Improving a patient's immune response to cancer. In one approach, gene therapy is used to introduce cytokine-producing genes into cancer cells to stimulate the immune response to the
tumor.
o
Inserting genes into cancer cells to make them more
sensitive to chemotherapy, radiation therapy, or other treatments
o
Inserting genes into healthy blood-forming stem
cells to make them more resistant to theside effects of cancer treatments, such as high doses of anticancer drugs
o
Introducing “suicide genes” into a patient's cancer
cells. A suicide gene is a gene whose product is able to activate a “pro-drug”
(an inactive form of a toxic drug), causing the toxic drug to be produced only in cancer cells in
patients given the pro-drug. Normal cells, which do not express the suicide
genes, are not affected by the pro-drug.
Proposed gene therapy clinical trials, or protocols, must be approved by at least two review boards at the researchers’
institution before they can be conducted. Gene therapy protocols must also be
approved by the FDA, which regulates all gene therapy products. In addition,
gene therapy trials that are funded by the National Institutes of Health must be registered with the NIH Recombinant DNA Advisory Committee.
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