Unlike chemotherapy and radiation therapy, which target the tumor itself, biologic therapies (biotherapy) focus on the body's biologic response to the tumor. Most of these therapies take advantage of the body's immune system, either directly or indirectly, to fight cancer or to lessen the side effects that may be caused by some cancer treatments. Since the 1980s, biotherapy has become an important modality for treating cancer. The agents used in this type of therapy are also known as biologic response modifiers.

The Immune System

In order for cancers to succeed, they must contend with the immune system, a complex network of cells and organs that work together to defend the body against hostile invaders. The most familiar intruders—bacteria, viruses, and other infectious organisms—originate from sources outside the body. Cancer cells—in many ways an even more dangerous foreign enemy—challenge the immune system from within.

The key cells involved in the immune system include the following:

Lymphocytes —This is a type of white blood cell primarily concentrated in areas of the body that commonly encounter hostile invaders. These include parts of the respiratory and gastrointestinal tracts, and the lymphatic system. The lymphatic system consists of an intricate series of so-called lymph channels and nodes that drain excess fluid from all the tissues of the body.

Types of lymphocytes include the following:

  • B cells—lead to the production of antibodies, which are proteins that recognize and attach to foreign substances (antigens), marking the antigens for destruction by other cells in the immune system
  • Cytotoxic T cells—directly attack infected or cancerous cells
  • Helper T cells—regulate the immune system's response by signaling other immune system cells
  • Natural Killer (NK) cells—produce powerful chemical substances that bind to and kill foreign invaders

Macrophages —This is a type of white blood cell known as a monocyte, which engulfs microscopic organisms and particles to destroy them. This process is known as phagocytosis (hence the name macrophage or “big eater”).

Cytokines —These are chemicals produced by both lymphocytes and monocytes. Cytokines include:

  • Interferons
  • Interleukins
  • Colony-stimulating factors

Cytokines and antibodies are important to biologic therapies.

How Do Biologic Therapies Work?

Biologic therapies repair, stimulate, or enhance the body’s response to cancer. According to the Leukemia and Lymphoma Society, the various biologic therapies do the following:

  • Eliminate, regulate, or suppress conditions that allow uncontrolled cell growth.
  • Enhance the immune system to fight the uncontrolled growth of cancer cells.
  • Make cancer cells more vulnerable to destruction by the immune system.
  • Change the growth patterns of cancer cells so that they are more like normal cells, and are less likely to metastasize (spread).
  • Block or reverse the process that changes a normal or precancerous cell into a cancerous cell.
  • Enhance the body's ability to repair normal cells that get damaged by other forms of treatment for cancer, such as chemotherapy and radiation .
  • Prevent a cancer cell from spreading to other parts of the body.

In general, the way biologic therapies modify the body's response to tumor cells can be divided into three broad classes:

  • Agents that augment, modulate, or restore the immune system
  • Agents that have direct anti-tumor activity
  • Agents that exert other biologic effects, such as interfering with the tumor's ability to metastasize or affecting its ability to differentiate or mature

Each biologic therapy has its own mechanism of action, as discussed in the section below.

What Are Biologic Therapies Used for?

Biologic therapies are most commonly used either to treat selected cancers that do not or have not responded to other forms of treatment, or to treat those few tumors (renal [kidney] cell and melanoma) that appear to occasionally respond to the body’s own immune defenses. Because the mechanism of actions differ among the biologic therapies, the types of cancers they are used for varies, as described below.

What Are the Major Types of Biologic Therapies?

The most common biologic therapies in use today include the following:

  • Interferons (IFN)
  • Interleukins (IL)
  • Colony-stimulating factors (CSF)—This is not a cancer therapy, but a treatment to offset the side effects of chemotherapy (eg, by raising the white cell counts).
  • Monoclonal antibodies (MOAB)

Interferons

Interferon (IFN) occurs naturally in the body. First characterized in 1957, researchers discovered that IFN is produced by virally infected cells and is capable of protecting other cells from infection. IFNs were the first cytokines produced in a laboratory for use as a biologic therapy. There are three major types:

  • Interferon alpha—This is the type of interferon most often used in cancer treatment. Interferon alpha is used in melanoma with very little benefit. After 12 months of use, a 12-month survival rate is seen. This treatment has not been used successfully with other malignancies.
  • Interferon beta—used for multiple sclerosis
  • Interferon gamma—used for chronic granulomatous disease

Interferons have a wide range of biologic effects, including antiviral, antiproliferative, and immunomodulatory. The exact mechanism with which these proteins exert their anti-tumor effects is unknown and is probably through a combination of actions. But, researchers have determined that interferons enhance your immune system’s ability to fight cancer cells and act directly on these cells by slowing growth and encouraging normal behavior.

Interferon alpha (Roferon-A, Intron A, Wellferon) is FDA-approved for the treatment of hairy cell leukemia , melanoma , chronic myeloid leukemia , and AIDS-related Kaposi's sarcoma .

Interleukins

Like interferons, interleukins (IL) occur naturally in the body and can be synthesized in a laboratory. Interleukins are named numerically: IL-1, IL-2, IL-3, up to IL-18. IL-2 has been the most widely studied in cancer treatment.

IL-2 stimulates the growth and activity of many cancer-killing immune cells, including NK cells and cytotoxic T cells. In addition, IL-2 enhances antibody responses. Both animal and human studies have shown that IL-2 can reverse immune deficiencies. Interestingly, studies have shown no differences in the biologic activity between naturally occurring IL-2 and IL-2 created in the lab.

IL-2 (Proleukin) is FDA-approved for the treatment of metastatic kidney cancer and metastatic melanoma. IL-1-alpha, IL-1-beta, IL-4, IL-6, and IL-12 are currently in clinical trials.

Colony-stimulating Factors

Colony-stimulating factors (CSFs), also known as hematopoietic growth factors, do not affect cancer cells directly. Instead, CSFs help stimulate the production of new red blood cells, white blood cells, and platelets. This is important because many cancer treatments, like chemotherapy and radiation, can decrease the levels of blood cells, putting you at risk for infection, anemia, and bleeding problems. Stimulating blood cell production can help stimulate your immune system.

Some examples of CSFs include the following:

  • G-CSF (Neupogen) and GM-CSF (Leukine, Prokine)—increase the number of white blood cells, which reduces the risk of infection; also used to stimulate the production of stem cells in preparation for stem cell or bone marrow transplants
  • Erythropoietin (Epogen, Procrit)—increase the number of red blood cells and reduce the need for red blood cell transfusion
  • Oprelvekin (Neumega)—increase the number of platelets and reduce the need for platelet transfusions

Monoclonal Antibodies

Monoclonal antibodies (MOABs) are laboratory-produced substances that are highly specific for a single target antigen. The process begins by injecting a mouse with cells from a specific human cancer. After the mouse has mounted an immune response (which includes producing antibodies to fight the cancer cells), its spleen is removed to obtain the antibodies. These antibodies are fused with laboratory-grown cells to create "hybrid" cells called hybridomas. These new cells can grow indefinitely and produce antibodies—MOABs—that have a predetermined specificity for the antigens associated with that cancer.

MOABs can be used in cancer treatment in a number of ways, for example:

  • React with certain types of cancer, which may enhance your immune response to the cancer.
  • Be programmed to act against specific cell growth factors, thereby interfering with the growth of cancer cells.
  • Be linked to anticancer drugs, radioactive substances, other biologic therapies, or other toxins. When the MOABs attach to a cancer cell, they deliver these poisons to the cancer cell and kill it directly.
  • Possibly help destroy cancer cells living in bone marrow that has been removed from a person in preparation for a bone marrow transplant .

The MOAB rituximab (Rituxan) has been FDA-approved for the treatment of B-cell non-Hodgkin's lymphoma that has relapsed or not responded to chemotherapy. The MOAB trastuzumab (Herceptin) has been FDA-approved for the treatment of metastatic breast cancer when the tumor expresses excess amounts of a protein called HER-2.

What Adverse Effects Can Occur With Biologic Therapies?

Adverse effects are specific to the type of biologic therapy used.

Interferons

Side effects are similar for all classes of IFN; variations are based on dosage, schedule, and type. But, the toxicity has been well established. Almost all people receiving IFN therapy report fatigue. The treatment is generally given as long-term therapy, so side effects are divided into acute (occurring early) and late or chronic (occurring as therapy progresses).

Acute Side Effects of Interferons

At the beginning of therapy, you will most likely experience flu-like symptoms—almost all patients do. The symptoms may be severe in the beginning, but in most cases your body will adjust. Symptoms include chills 2 to 4 hours after injection of IFN followed by fever spikes. In addition, you may experience headaches, muscle pain, joint pain, and malaise.

Chronic Side Effects of Interferons

Chronic side effects tend to increase in intensity after you have been on IFN therapy for several weeks. Loss of appetite with weight loss and fatigue can be severe enough to limit the dose you are given. Other side effects include lack of energy (lethargy), lack of concentration, decreased blood counts, protein in your urine, and low blood pressure. Other less common side effects include nausea, vomiting, diarrhea , altered taste, depression , mood swings, decreased sex drive, and memory problems. In some cases, the effects on mood can be significant, even leading to severe depression. For this reason, most oncologists will not give interferon to someone with a history of depression.

Interleukins

Severe toxicities are associated with high doses of IL-2. The range and severity of the effects is related to dose, schedule, and the simultaneous use of other cancer therapies.

The more common side effects include the following:

  • Flu-like symptoms—chills, followed by fever, fatigue, headache, muscle pain, joint pain, and malaise
  • Gastrointestinal effects—nausea, vomiting, diarrhea, decreased appetite

Other side effects include the following:

  • Integumentary (skin) system—redness, rash, dry skin, itchiness
  • Cardiovascular system—low blood pressure, rapid heart rate, arrhythmia , edema (fluid retention), weight gain
  • Central nervous system—confusion, disorientation, drowsiness, lethargy, anxiety , depression, irritability
  • Decreased blood counts—anemia, thrombocytopenia, eosinophilia, lymphopenia
  • Compromised kidney function
  • Hypothyroidism —decrease in function of the thyroid gland

There are many medications used to help manage the toxicities of IL-2. If you are experiencing any side effects, talk with your doctor about what therapies would work for you.

Colony-stimulating Factors

CSF therapy is generally well tolerated and side effects are minimal. Bone pain is the only side effect commonly reported. This can usually be controlled with non-narcotic pain relievers. You may experience skin redness (erythema) at the site of the injection.

Monoclonal Antibodies

With MOABs, allergic reaction to mouse protein is a major concern. This acute reaction can result in anaphylaxis , which begins with flushing and hives , but if left untreated can progress to respiratory distress and even death. However, this is rare.

More common side effects that can occur in the first 24 hours to 1 week after the therapy include: fever, chills, profuse sweating, malaise, nausea, vomiting, itchiness, difficulty breathing, and low blood pressure.

A delayed toxicity that can occur two to four weeks after therapy is serum sickness. This results from circulating immune complexes (large, heavy antigen-antibody particles) being deposited into tissues. Symptoms include hives, itchiness, joint pain, swollen glands, and flu-like symptoms.

Which Cancers Are Biologic Therapies Used to Treat?

For details on the use of biologic therapies for specific cancers, see the following articles: