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 specific molecules 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 specific antigens 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), and trastuzumab 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 radioactive molecule. 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 effects of 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 and dendritic 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 several hematologic 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) and granulocyte 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.