Biological therapies

Also known as: Biological agents, biological response modifiers, biotherapy, immunotherapy

Anatomy or system affected: Blood, cells, immune system, lymphatic system

Definition: Treatments that use natural substances from the immune system to fight disease or infections or to overcome side effects from other treatments.

Indications and Procedures

Biological therapies are treatments designed to improve or restore the ability of the immune system to fight disease and infection and to help protect the body from side effects of other treatments. The immune system consists of a number of different organs and structures, including the spleen, lymph nodes, bone marrow, tonsils, and white blood cells, the latter of which play an especially important role in fighting disease. There are a number of different types of white blood cells, including B and T lymphocytes and natural killer (NK) lymphocytes. B lymphocytes, also called B cells, produce antibodies that attack other cells, and T lymphocytes, or T cells, directly attack diseased cells and signal other immune system cells to defend the body. The NK cells make chemicals that bind to and kill foreign invaders in the body.

In addition to the various lymphocytes, the immune system contains other white blood cells called monocytes, which engulf and digest foreign invaders. Dendritic cells of the immune system are used to transport and deliver foreign cells to other immune system cells. Lymphocytes and monocytes are produced in the bone marrow and are later distributed into the bloodstream to be available to every part of the body.

The immune system secretes two types of substances to fight disease: antibodies and cytokines. Antibodies respond to foreign invaders that they recognize, called antigens. An antibody is found to match or recognize a specific antigen and attach itself to the antigen to give an immune response. Cytokines are proteins produced by the immune system to directly attack cells. They are considered messenger cells, as they communicate with other cells to form a response. Biological therapies, therefore, are designed in part to boost the immune response, both directly and indirectly, in order to make the immune system respond to diseased or cancerous cells.

There are four goals of biological therapies. The first is to make the immune system better able to recognize diseased or cancer cells in order to destroy them, prevent them from spreading, or make them more like healthy cells. The second is to stop the process that converts normal cells to cancer cells. The third is to improve the body’s ability to repair or replace damaged cells. The fourth is to stop side effects caused by other forms of cancer treatments, such as chemotherapy and radiation therapy.

Uses and Complications

There are different types of biological therapies. The method of treatment used will vary depending on what type of cancer or other disease is involved, how far the disease has spread, and what other treatments have been or are being used. The types of biological therapies that are utilized today are predominantly for treating cancer patients. These therapies include monoclonal antibodies, cancer vaccines, growth factors, cancer growth inhibitors, angiogenesis inhibitors, interferons and interleukins, and gene therapy.

Monoclonal antibodies are specific antibodies developed in a laboratory that recognize only a single type of antigen or foreign invader in the body. Antigens are typically found on the surface of various cancer cells, so by producing specific antibodies for these antigens, one can selectively attack cancer cells of interest. A monoclonal antibody can also be programmed to act against cell growth factors, thereby interfering with the growth of cancer cells. Monoclonal antibodies can be developed to react with anticancer drugs or other toxins by attaching to the cancer cell and aiding in the destruction of that cell. They can also be established to carry radioisotopes that, when attached to a cancer cell, will identify that cell and can then be used to identify the specific cancer type. Examples of monoclonal antibodies approved by the Food and Drug Administration (FDA) include rituximab (Rituxan) and trastuzumab (Herceptin). Rituxan is used for the treatment of non-Hodgkin lymphomas, and Herceptin is used to treat breast cancer that involves an overproduction of the ERBB2 protein.

Vaccines are another type of biological therapy that is widely used to prevent diseases, including influenza, mumps, measles, and other infectious diseases. Vaccines work by introducing an inactive (typically weakened or killed) disease-causing agent to the immune system so that it will later be able to recognize any active forms of the agent and produce the necessary antibodies to destroy them. Cancer vaccines are an emerging area of research and have been developed for only a few cancer types or cancer-associated viruses, such as human papillomavirus (HPV), which has been linked to cervical cancer. The first HPV vaccine was made available to the public in 2006. The Bacillus Calmette-Guérin (BCG) is primarily used to prevent tuberculosis but is increasingly being used to treat superficial bladder cancer as well. The advantage of a vaccine is that it has the ability to trigger an immune response in the body. White blood cells in the body can make antibodies that will recognize the proteins in the vaccine, whether the vaccine is from a virus, bacterium, or cancer cell. The antibodies will then be available to fight those antigens and prevent or decrease the impact of disease.

Growth factors are considered biological therapies because they are natural substances in the body that are used to stimulate the bone marrow to produce blood cells. Growth factors are used in conjunction with other types of cancer treatments, since chemotherapy devastates both the normal and the diseased population of blood cells in a cancer patient, thus depleting the blood cells needed for health. After chemotherapy is completed, growth factors can be given to a patient to boost blood counts and help fight infection and further disease. Examples of growth factors include filgrastim (Neupogen) and pegylated G-CSF (Neulsta).

Cancer growth inhibitors or blockers are natural substances that can block a growth factor that will otherwise trigger a cancer cell to divide and grow. Growth factors that reside on the surface of cancer cells include epidermal growth factor (EGF) and fibroblast growth factor (FGF), which control cell growth, and platelet-derived growth factor (PDGF), which controls blood vessel development and cell growth. Each of these growth factors has a specific receptormolecule on the cell surface of the cancer cell, such as epidermal growth factor receptor (EGFR). Most cancer cell inhibitors currently used, such as tyrosine kinase inhibitors and proteosome inhibitors, will block the signaling pathway of receptors. Examples of tyrosine kinase inhibitors include iminitab (Gleevac), used to treat chronic myeloid leukemia (CML), and bortezomib (Velcade), used to treat melanoma.

Angiogenesis inhibitors are substances that block cancer blood-vessel growth. Angiogenesis is the process of growing new blood vessels. Angiogenesis inhibitors are used to stop tumors from growing their own blood vessels. Since cancer cells need a blood supply to continue their growth and division process, blocking blood-vessel growth will eventually kill the cancer cell. Angiogenesis inhibitors can block the growth factor from reaching the cell, block the signaling within a cell, or affect the signal between cells. One example of an anti-angiogenic drug is thalidomide, which affects the chemicals that cells use to signal one another. This drug has proven helpful in treating melanoma and other cancers.

Interferons and interleukins are substances that are part of the body’s immune response, called cytokines. These cytokines work by interfering with the growth and cell division of cancer cells, by stimulating an immune response and enhancing the ability of killer T cells and other cells to attack and kill cancer cells, and by encouraging the cancer cell to produce chemicals that attract the immune system to them. Interferons and interleukin-2 are used to treat cancers such as melanoma, multiple myeloma, and some types of leukemia.

Gene therapies are currently experimental, but they have potential to treat cancers and other diseases. Genes are made up of strands of deoxyribonucleic acid (DNA), which are coded messages for various functions in the body. Normal cells have a set of genes that are needed for normal growth, development, and maintenance of the body’s systems and functions. Cancer cells differ from normal cells in that a genetic mutation has occurred that gives rise to uncontrolled cell growth and division. The advantage of gene therapy is that it targets specific cancer cells, thereby not affecting normal cells that would otherwise be destroyed by conventional therapies.

Side effects are associated with each type of biological therapy. They vary depending on the individual’s medical history, diagnosis, and type of therapy. Each person may react differently to specific treatments. Biological therapies often cause flulike symptoms, such as chills, fever, muscle aches, nausea, vomiting and diarrhea, bone pain, loss of appetite, and fatigue. Other side effects may include rashes, bleeding or bruising easily, and low levels of blood cells. Swelling at the injection site is also common. Side effects may be severe, mild, or absent. If they are severe, then patients may need to stay in the hospital during treatment. Side effects do not often last long, and they usually go away after treatment is completed. Allergic reactions may have additional symptoms.

Certain treatments can be given to control side effects, such as Neupogen or G-CSF to increase white blood cell counts and help prevent infection in patients who use chemotherapy; Procrit, Epogen, or erythropoietin to increase red blood cell counts in patients who develop anemia; and IL-11, interleukin-11, Oprelvekin, or Neumega to increase platelet counts. Paracetamol or antihistamine may be given before the first treatment to prevent an allergic reaction.

Challenges

A primary challenge of Biological Therapies are the complexities cancer can pose. In particular are what are essentially counter-defenses employed by cancers to defeat the body's immune system. Many cancers employ stealth-like characteristics to mask their presence from detection so that the body's natural defenses cannot be activated against them. Secondly, cancers are continuously mutating to become better at defeating the immune system. Cancers also attract other cells in helping them create formations such as tumors. In essence, each cancer patient is struggling with their own personalized form of cancer. Biological therapies, nonetheless, offer the prospect of using the inherent characteristics of cancer against the disease itself. For example, in the process of growing tumors, cancers can emit substances such as neo-antigens. Neo-antigens are proteins that are formed following cancer mutations. Because these are not natural to a body's immune system, new forms of immunotherapies are being formed for their detection and vaccines to destroy them.

Perspective and Prospects

Biological therapies have been investigated for many years as an important advance in the treatment of cancer and other diseases. It could be said that biological therapies have been in use for more than two hundred years with the discovery of immunization by Edward Jenner to treat a disease called vaccinia, or cowpox. Around the beginning of the twentieth century, William B. Coley began treating cancer patients with bacteria to build an immune response. This approach, which became known as Coley toxins, was used for decades with great success. In 1908, Paul Ehrlich received the Nobel Prize in Physiology or Medicine for his work on biotherapies by discovering receptor molecules (antigens) that reside on cell surfaces that can attach to antibodies, triggering the release of antitoxins to fight disease. Work on biological therapies continued in the 1980s when interferon came to be used for the treatment of a blood disorder called hairy-cell leukemia. This treatment became FDA approved for this and other cancer disorders such as chronic myeloid leukemia, AIDS-related Kaposi sarcoma, and genital warts. Further work on cytokines gave rise to interleukin treatment for kidney cancer, metastatic cancer, and AIDS.

Further developments have led to many treatments for cancer, viral diseases, and autoimmune disorders. With current technologies in genetics, more information about the genetic basis of cancer has led to advances in biological therapies for more than two hundred types of cancer. Most therapies to date are not targeted to a specific genetic makeup. However, new therapies are arising that can target specific genetic mutations that have become known. For example, Herceptin can treat HER2-positive metastatic breast cancer, and MabThera can be used for particular genetic mutations in non-Hodgkin lymphoma. This individualized type of therapy will not only improve the management of different diseases but also decrease the toxicity of treatment that results from an individual’s genetic makeup. Most of what is used today for biological therapies is just the beginning, with the future holding tremendous promise for continued success with these treatments.

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