Biological therapy (sometimes called immunotherapy, biotherapy, or biological response modifier therapy) is a promising new addition to the family of cancer treatments that includes surgery, chemotherapy, and radiation therapy. Biological therapies use the body's immune system, either directly or indirectly, to fight cancer or to lessen side effects that may be caused by some cancer treatments.

The body has a natural ability to protect itself against diseases, including cancer. The immune system, a complex network of cells and organs that work together to defend the body against attacks by "foreign" or "non-self" invaders, is one of the body's main defenses against disease.

Researchers have found that the immune system may recognize the difference between healthy cells and cancer cells in the body and eliminate those that become cancerous. Cancer may develop when the immune system breaks down or is overwhelmed. Biological therapies are designed to repair, stimulate, or enhance the immune system's natural anticancer function.

Immune system cells and proteins called antibodies, which are part of the immune system, work against cancer and other diseases by creating an immune response against foreign invaders (antigens). This immune response is unique because antibodies are specifically programmed to recognize and defend against certain antigens. Antibodies respond to antigens by latching on to, or binding with, antigens, fitting together much the way a key fits a lock.

Immune system cells work against disease, including cancer, in a variety of ways. Immune cells include the following:

Lymphocytes, the main type of immune cell, are white blood cells found in the blood as well as in many other parts of the body. Lymphocytes include B cells, T cells, and NK cells.

B cells (B lymphocytes) mature into plasma cells that secrete antibodies (immunoglobulins), proteins that recognize and attach to antigens

T cells (T lymphocytes) directly attack targeted foreign invaders. T cells direct and regulate the immune response by signaling other immune system defenders. T cells produce proteins called lymphokines, which are one type of cytokine.  Cytokines are powerful chemical substances that control a number of cell activities, including the immune response.

NK cells (natural killer cells) destroy cancer cells by producing powerful chemical substances that bind to and kill any foreign invaders. Monocytes are white blood cells that travel into tissues and develop, when needed, into macrophages, or "big eaters," as part of the immune response. Monocytes and macrophages play a key role in phagocytosis, a process by which some cells "eat" other cells and foreign invaders.

Biological therapies used to treat cancer target some of these defenses, boosting, directing, or restoring the body's own cancer-fighting mechanisms.

Biological Response Modifiers

Substances used in biological therapies are often called biological response modifiers (BRMs). BRMs alter the interaction between the body's immune defenses and cancer, thus improving the body's ability to fight the disease. BRMs (such as cytokines and antibodies) are substances that occur naturally in the body.

Scientists can now make BRMs in the laboratory that imitate or influence natural immune response agents. BRMs can play many roles in cancer treatment, including directly inhibiting tumor cell growth and acting indirectly to help healthy cells, particularly immune cells, control cancer. BRMs may be used to:

• Enhance a cancer patient's immune system to fight cancer cell growth;
• Eliminate, regulate, or suppress body responses that permit cancer growth;
• Make cancer cells more susceptible to destruction by the immune response;
• Alter cancer cells' growth patterns to promote behavior like that of healthy cells;
• Block or reverse the process that changes a normal cell or a precancerous cell into a cancerous cell;
• Enhance a cancer patient's ability to repair normal cells damaged by other forms of cancer treatment, such as chemotherapy or radiation; and
• Prevent a cancer cell from spreading to other sites in the body.

Researchers are currently investigating a variety of BRMs, and many are being used in cancer treatment. These agents include interferons, interleukins, tumor necrosis factor, colony-stimulating factors, monoclonal antibodies, and cancer vaccines. These BRMs may prove to be most beneficial when used in combination with each other and/or with other treatments such as radiation and chemotherapy.

The Interferons (IFN)

Interferons are types of cytokines that occur naturally in the body. They were the first cytokines produced in the laboratory for use as BRMs. While there are three major families of interferons, including interferon alpha, interferon beta, and interferon gamma, interferon alpha currently is the most widely used in cancer treatment.

Researchers have found that interferons can improve a cancer patient's immune response against cancer cells. In addition, interferons may act directly on cancer cells by inhibiting their growth or promoting their development into cells with more normal behavior. Researchers believe that some interferons also may stimulate B cells and T cells, strengthening the immune system's anticancer function.

The Food and Drug Administration (FDA) has approved the use of a type of interferon alpha for the treatment of certain types of cancer including hairy cell leukemia, Kaposi's sarcoma (a rare cancer of cells lining blood vessels that often occurs in patients with AIDS), and chronic myelogenous leukemia, making it the first, but not only, BRM approved for cancer therapy. Studies have shown that interferon alpha may also be effective in treating other cancers such as renal cell carcinoma (a type of kidney cancer) and some non- Hodgkin's lymphomas (cancers that develop in the lymph system).

Using interferons combined with other BRMs or with chemotherapy, researchers are looking for improved treatments for these and other cancers in clinical trials (treatment studies). Investigators are exploring combinations of interferon alpha and chemotherapy to treat a number of cancers, including colorectal cancer, multiple myeloma, and melanoma.

Interleukins (IL)

Like interferons, interleukins are cytokines that occur naturally in the body and can be made in the laboratory. Although many interleukins (including IL-1 through IL-15) have been identified, interleukin-2 (IL-2) has been the most widely studied in cancer treatment.

IL-2 stimulates the growth and activities of many immune cells, such as lymphocytes, that can destroy cancer cells. Lymphocytes stimulated by IL-2, called lymphokine-activated killer (LAK) cells, have proven to be effective in destroying tumors. Lymphocytes can be removed from a cancer patient's blood, stimulated with IL-2 in the laboratory, and returned to the patient as LAK cells, with the goal of improving the patient's anticancer immune response.

Patients with advanced renal cell carcinoma or advanced melanoma have shown the best response to IL-2 therapy. In 1992, the FDA approved IL-2 for treating advanced metastatic renal cell carcinoma (kidney cancer that has spread). Researchers are investigating the benefits of IL-2, used alone or with other treatments, in other cancers such as colorectal cancer, ovarian cancer, and small cell lung cancer in ongoing clinical trials. Combinations of IL-2 with other treatment methods such as chemotherapy, surgery, or other BRMs are also under study. Some scientists believe that IL-2 therapy may help stop certain cancers from growing, which can improve the length and quality of life for some cancer patients. Other interleukins, including IL-3, IL-4, IL-6, and IL-12, are also being studied.

Tumor Necrosis Factor (TNF)

Tumor necrosis factor (TNF) is another type of cytokine under study. Like the interferons and interleukins, TNF stimulates the body's immune cells to fight cancer. TNF also directly affects tumor cells, damaging them and the blood vessels within the cancer. Without an adequate blood supply, a cancer cannot thrive. However, researchers are still uncertain exactly how TNF destroys tumors.

Although TNF has shown promising antitumor activity in laboratory studies, the dose needed for this level of activity is extremely toxic. Researchers have found that TNF therapy is most effective and least toxic when directed at a specific tumor site, rather than administered throughout the body. Clinical trials are under way to investigate the effectiveness of TNF therapy alone and in combination with other BRMs in treating a variety of cancers.

Colony-Stimulating Factors (CSFs)

Unlike TNF, colony-stimulating factors (CSFs) (sometimes called hematopoietic growth factors) usually do not directly affect tumor cells. Researchers have identified several CSFs (such as G-CSF and GM-CSF) that encourage bone marrow cells to divide and develop into various specialized white blood cells, platelets, and red blood cells. Bone marrow is important to the body's immune system because it is the source of all blood cells.

The CSFs' stimulation of the immune system may benefit patients undergoing cancer treatment. Studies have shown that CSFs have the potential to:

• Protect or restore bone marrow function when combined with chemotherapy or radiation, thus permitting the patient to tolerate higher doses of conventional anticancer therapy;
• Aid in separating cancer cells from bone marrow that scientists have removed from the patient's body;
• Stimulate immune system components, enhancing antitumor activity of other therapies; and
• Help treat infections and other problems that may occur in patients who have received chemotherapy or in those whose immune systems are impaired.

Researchers have found CSFs particularly beneficial when used in combination with high-dose chemotherapy. Because anticancer drugs can damage the body's ability to make white blood cells, which are responsible for fighting infection, patients have an increased risk of developing infections during chemotherapy. Doctors must carefully monitor white blood cell levels during chemotherapy. However, using CSFs, which stimulate white blood cell activity, doctors can give higher, perhaps more effective, chemotherapy doses with decreased risk of infection.

Because their immune system has been damaged, people who have had a bone marrow transplant are particularly susceptible to infections after the transplant. Doctors are evaluating the use of CSFs given to bone marrow transplant patients. Researchers have found that CSFs help blood cells in the immune system repair themselves more quickly after transplant, shortening the patient's recovery time and hospital stay.

Monoclonal Antibodies (MOABs)

Researchers are evaluating the effectiveness of certain antibodies made in the laboratory called monoclonal antibodies (MOABs). MOABs are specific for a particular antigen, and researchers are investigating ways to create MOABs specific to antigens found on cancer cells.

Researchers make MOABs by injecting human cancer cells into mice so that their immune systems will make antibodies against these cancer cells. Researchers remove the mouse cells that are producing these antibodies and fuse them with a laboratory-grown immortal cell to create a "hybrid" cell called a hybridoma. Hybridomas are like factories that can indefinitely produce large quantities of these pure antibodies or MOABs.

MOABs may be used in cancer treatment in a number of ways.

MOABs that react with specific types of cancer may enhance a patient's immune response to the cancer.
MOABs may be linked to anticancer drugs, radioactive substances
(radioisotopes), BRMs, or other toxins.  When the antibodies latch
 onto cancer cells, they deliver these poisons directly to the tumor,
 helping to destroy it.
Radioisotope-labeled MOABs may also prove useful in diagnosing certain cancers.
MOABs may help destroy any cancer cells in a patient's bone marrow before an autologous bone marrow transplant, in which bone marrow is  removed from a patient, stored, and later given back to the patient  after high-dose chemotherapy and/or radiation therapy.

MOABs are currently being tested in clinical trials in patients with lymphomas, colorectal cancer, lung cancer, leukemia, and a rare childhood cancer called neuroblastoma.

Because the MOABs originally produced from hybridomas were foreign (mouse) proteins, patients often developed an immune response to them, producing human antimouse antibodies (HAMA). Newer MOABs have been engineered to minimize this problem.

Tumor Vaccines

Tumor vaccines are another form of biological therapy currently under study. Vaccines for various diseases are effective because the immune system can develop acquired immunity to disease after initial exposure to it. This occurs because when T cells and B cells are activated, some of them become memory cells. The next time the same antigen enters the body, the immune system remembers how to destroy it.

Researchers are developing tumor vaccines that may encourage the immune system to recognize cancer cells in this way. Tumor vaccines may help the body reject tumors and also help prevent cancer from recurring. Researchers are also investigating ways that tumor vaccines can be used in combination with BRMs. Tumor vaccines are being studied in treating melanoma, renal cell cancer, colorectal cancer, breast cancer, prostate cancer, and lymphomas.

Side Effects

Like other forms of cancer treatment, biological therapies can cause various side effects, which can vary widely from patient to patient. Because BRMs are often administered by injection, rashes or swelling may develop at the site where the shots are given. Several BRMs, including interferons and interleukins, may cause flu-like symptoms including fever, chills, tiredness, and digestive tract problems. Blood pressure may also be affected. Side effects with IL-2 and TNF can often be severe, and patients need to be closely monitored during treatment. Side effects with antibody therapy vary, and allergic reactions may occur. Cancer vaccines may cause minor side effects including fever and muscle aches.

Clinical Trials

Details about clinical trials involving these and other biological therapies are available from PDQ, a National Cancer Institute (NCI) database of cancer information. Patients can ask their doctor to use PDQ, or they can call the NCI-supported Cancer Information Service (CIS) to request information about biological therapies and clinical trials.  

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