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.

How Does the Immune System Work?

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:
    • 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.
  • 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.

Macrophage

Macrophage
©2009 Nucleus Medical Media, Inc.

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.

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 (eg, kidney cell, 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.

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:

The way that these proteins exert their anti-tumor effects is unknown. It is probably through a combination of actions. Researchers have determined that interferons enhance the immune system’s ability to fight cancer cells, and act directly on these cells by slowing growth and encouraging normal cellular behavior.

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.

Aldesleukin (Proleukin) is an IL-2 that is used to treat metastatic kidney cancer and metastatic melanoma.

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 the 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

There are a number of MOABs available. Examples include:

  • Rituximab (Rituxan)—used to treat non-Hodgkin's lymphoma
  • Trastuzumab (Herceptin)—used to treat metastatic breast cancer when the tumor expresses excess amounts of a protein called HER-2
  • Cetuximab (Erbitux)—used to treat cancers of the colon and rectum, as well as head and neck cancer
  • Panitumumab (Vectibix)—used to treat metastatic colorectal cancer
  • Bevacizumab (Avastin)—used to treat a certain type of brain tumor, kidney cancer, colon cancer, rectum cancer, lung cancer, and breast cancer
  • Alemtuzumab (Campath)—used to treat chronic lymphocytic leukemia

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. The symptoms may be severe in the beginning. But, in most cases, your body will adjust. Symptoms include chills 2-4 hours after injection of IFN followed by fever spikes. In addition, you may experience headaches, muscle pain, joint pain, and discomfort.

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
  • Lack of concentration
  • Decreased blood counts
  • Protein in your urine
  • Low blood pressure
  • Less common side effects:
    • Nausea and vomiting
    • Diarrhea
    • Altered taste
    • Depression—In some cases, the effects on mood can be significant, even leading to severe depression. For this reason, most doctors will not give interferon to someone with a history of depression.
    • Mood swings
    • Decreased sex drive
    • Memory problems

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:

  • Flu-like symptoms (eg, chills, fever, fatigue, headache, muscle pain, joint pain)
  • Gastrointestinal effects (eg, nausea, vomiting, diarrhea, decreased appetite)

Other side effects include:

  • Skin—redness, rash, dry skin, itchiness
  • Heart and lungs—low blood pressure, rapid heart rate, arrhythmia , edema (fluid retention), weight gain
  • Nervous system—confusion, disorientation, drowsiness, lethargy, anxiety, depression, irritability
  • Decreased blood counts—anemia, thrombocytopenia, eosinophilia, lymphopenia
  • Problems with kidney function
  • Hypothyroidism

There are many medicines 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 pain relievers. You may experience skin redness 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, a severe, sometimes life-threatening, allergic reaction. This is rare, though.

More common side effects that can occur in the first 24 hours to 1 week after the therapy include:

  • Fever
  • Chills
  • profuse sweating
  • Discomfort
  • Nausea and vomiting
  • Itchiness
  • Difficulty breathing
  • Low blood pressure

A delayed toxicity that can occur 2-4 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
  • 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:

Bladder cancer
Brain tumors
Breast cancer
Cervical cancer
Colorectal cancer
Kidney cancer
Leukemia
Melanoma
Multiple myeloma
Non-Hodgkin's lymphoma