Immunotherapy is a treatment that uses elements of the immune system to fight a disease. Although this approach has been a theoretical one for decades, immune treatments using antibodies directed against leukemia or lymphoma cells have been approved for use by the U.S. Food and Drug Administration (FDA), and treatments using immune cells and vaccines are being tested in clinical trials.

The immune system is normally responsible for protecting the individual from an invasion by foreign agents, especially bacteria and viruses. The immune system is designed to rid the body of invading germs and cells infected by germs. The immune system is composed of cells that originate in the marrow and the thymus (a lymphoid organ in the chest that is critical to immune cell development in infancy and childhood). The immune system cells are called lymphocytes. Three main types of cells are B lymphocytes, T lymphocytes, and natural killer lymphocytes. These are often called B cells, T cells and NK cells for short. An important cooperating cell is derived from blood cell development. This cell, which is related to a monocyte, is an antigen-presenting cell.

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Immune System Components
The immune system can be thought of as having two principal parts: One contains the B cells, which can also develop into plasma cells, and the second contains the T cells and closely related NK cells.

The B cells and plasma cells normally make antibodies against foreign antigens. Examples of foreign antigens are the proteins on the surface of invading bacteria or viruses. The immune system reacts to foreign substances or antigens by developing antibodies to try to neutralize or inactivate the antigen. The antibodies bind to the specific antigen on the cell surface. Cancer cells have antigens on their surface. Immunotherapy is an attempt to use immune cells or antibodies to recognize those antigens and attack them to kill the cancer cell.

The T cells develop after passing from the marrow to the thymus where they mature, and later, accumulate in the lymph nodes, spleen, and other lymphatic structures. The name T cell results from the role of the thymus in their development. T cells have a variety of functions. They assist B cells to recognize an antigen so the B cell can make antibodies efficiently. They also make and secrete hormones that act on other cells to support several normal body responses.

NK cells were named natural killers because they spontaneously attack cells infected by viruses or other microorganisms. NK cells, under some circumstances, can kill cancer cells by attaching to the outer surface of the cancer cell and releasing a substance that destroys the cancer cell.

Another cell type, the antigen-presenting cell (APC), which is not a lymphocyte, is an important cooperating cell in the function of the immune system. It prepares the antigen on the cell surface and presents it to the T cell and NK cell. Without the processing of the antigen by the cooperating cell the other cells cannot work effectively.

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Natural Immunity
The role of natural immunity in cancer has been studied for several years. It was initially thought that the immune system had only a small role in battling cancer. When cancers begin they are only a few cells in size. The immune system might not attack the cancer when it is small, perhaps because it does not recognize the cancer cells as invaders. Therefore, scientists thought it unlikely that an immune attack could be used successfully when the cancer is larger. Recently, researchers determined that the immune system could be used to fight some cancers. It appears that certain types of blood cancer are susceptible to an immunotherapy approach.

One reason for reexamining immune therapy for cancer arose from an observation during the study of marrow transplantation. It was observed that the T cells of a stem cell donor played a role that has come to be known as the graft versus leukemia effect. In this treatment a patient with leukemia treated with a marrow transplant receives donor T cells. Minor differences in tissue type, even between siblings, permits the donor T cells to recognize and attack the leukemia cells of the patient. This effect, which is most notable in chronic myelogenous leukemia, has also been observed among patients with myeloma who are treated with allogeneic transplantation. The effect may occur in other lymphoid malignancies as well.

The graft versus leukemia effect suggested that donor lymphocytes might be useful for some patients treated with transplantation for a blood-related cancer. Technological advances, the ability to harvest specific lymphocytes and new knowledge of genetics and immunology have made it possible to develop immunology treatments for blood-related cancers.

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Immunotherapy Treatment Approaches
Researchers are studying immunotherapy with three general approaches. First, the immune cells from the patient or a transplant donor are used to attack residual leukemia, lymphoma or myeloma cells that remain after chemotherapy. Second, using samples of tumors, antibodies can be made in laboratories that are able to attach to antigens on the malignant cell. Third, vaccines are being developed that may suppress malignant cells left in the body after therapy and thereby prolong remission. Immunotherapy can be used alone or in combination with other existing treatment for leukemia, lymphoma and myeloma.

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Immune Cell Treatment
Clinical investigators are treating relapsed marrow transplant patients, especially those with chronic myelogenous leukemia (CML), with infusions of donor white blood cells that suppress the growth of leukemia cells. The patient receives an infusion of donor lymphocytes that are able to recognize the leukemia cells and attack or suppress them. This method has been helpful in treating relapsed CML after allogeneic bone marrow transplantation. The method may also be a helpful treatment for patients with relapsed myeloma after allogeneic stem cell transplantation.

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Treatment with Antibodies
The immune system responds to the introduction of an antigen on the cell surface by making antibodies against that antigen. Antibodies are proteins released by plasma cells, also called immunoglobulins, which recognize and bind to specific foreign substances called antigens on the cell surface.

Natural antibodies inactivate or mark for destruction any foreign particles like bacteria, viruses or foreign chemicals (like harmful toxins). The antibody binds specifically to its antigen on the cell surface. These proteins fit together like a matched pair.

Antibodies can also be made in the laboratory. When antibodies used in treatment are made in the laboratory rather than in the patient's body the therapy is sometimes called passive immunotherapy. The laboratory development is complex but a simple explanation may suffice here. If material from one species is injected into another, the latter will recognize it as foreign and make antibodies against it. Human cells injected into rabbits, for example, stimulate rabbit antibodies to be formed against the human antigens on the cells.

The laboratory technique can be used to generate a specific antibody called a monoclonal antibody. Injection of cancer cells into a certain strain of mice makes their immune systems produce antibodies against the cancer cells. The cells making these monoclonal antibodies are then removed from the mice and fused, or joined, with a laboratory grown "immortalized" human cell to create a hybrid cell. A hybrid cell is one that results as the offspring from two different species. Immortal cells can be reproduced continuously. The laboratory fusion process for a hybrid cell can produce large quantities of monoclonal antibodies designed to target the original cancer cell. The term monoclonal means that each molecule of the antibody is exactly alike.

Some monoclonal antibodies can be used to treat leukemia and lymphoma because they recognize and attach to specific cell targets (antigens). The monoclonal antibody can destroy the cancer cell when it attaches to the critical antigen on the cancer cell.

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Examples of Monoclonal Antibody Treatment
In 1997 the FDA approved the first monoclonal antibody called rituximab (Rituxan) for the treatment of B-cell lymphoma. The antibody is directed at the target CD20 antigen on lymphoma cells. There are several B-cell antigens; CD20 is one of them. Cell surface antigens have been given a cluster designation (CD) followed by a number, thus rituximab is referred to as an anti-CD20 antibody. Rituximab has become an important agent to treat lymphocytic malignancies that are considered to be CD20 positive.

An antibody linked to a chemical toxin called calicheamycin, with the trade name Mylotarg, is used for treatment of older patients with acute myelogenous leukemia who do not respond to initial treatment or who relapse after successful initial treatment. Mylotarg has proven useful in producing or restoring remission in some patients with acute myelogenous leukemia.

Some monoclonal antibodies can be used to treat leukemia and lymphoma because they recognize and attach to specific cells. The monoclonal antibody can destroy the cancer cell when it attaches to the critical antigen on the cancer cell.

Monoclonal antibodies can also be linked to a radioactive isotope to target and kill specific cancer cells. These antibodies are injected into the patient in the hope that the antibodies will latch on to the antigen on the cancer cells and destroy the cells. These are called conjugated monoclonal antibodies. They deliver the toxic substance directly to the cancer cells. Examples of this treatment are the new drugs (Zevalin®, approved by the FDA for non-Hodgkin lymphoma in March 2002 and Bexxar®, approved by the FDA for non-Hodgkin lymphoma in June 2003) that carry radioactive substances to the antigen on the cancer cell.

One advantage in the development of drugs or treatments targeted to the leukemia or lymphoma cell is the possible decrease in side effects in normal tissues. Targeted treatments affect the cancer cells and some closely related cells but do not affect a wide array of normal cells. This is uniquely different from the effects of chemotherapy that may effect normal cells as well as the cancer cells. Targeted treatment may also increase the frequency of and prolong remissions. Sometimes the targeted therapy is used alone but more often in combination with chemotherapy.

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Vaccines
Vaccines designed to treat cancer do not prevent the disease, as in classical vaccine therapy for viruses or bacteria such as the polio vaccine. The vaccines being developed in cancer research are designed to treat a cancer and reduce its potential to grow. Researchers are working on vaccines that could prevent cancer from recurring. Many of the cancer vaccines being developed are intended to start a specific reaction to an antigen and focus the body response toward the tumor. This means that the vaccine starts the immune response against the specific cancer cells present in the patient. The effect is achieved by a stimulus to the T cells that search for and destroy the tumor cells.

Cancer vaccines are of different types. Some vaccines contain antigens or parts of antigens purified from cancer cells obtained from the patient or from the cancer cells of another patient. Scientists have discovered the genetic codes of some of the antigens making possible the creation of more effective vaccines. DNA vaccines are being tested that contain the DNA (material in the cell nucleus with the genetic code) for the specific antigen. In some approaches cells are isolated in the laboratory and start making antibodies after insertion of the cancer antigen. In each case, the basis for the vaccine is to expose the patient's immune system to large amounts of antigens found on the cancer cells. The exposure should then act as a stimulus to the patient's immune system to fight the disease. The hope is that the immune system of the patient will inhibit the growth of cancer cells. Lymphomas are among the cancers being targeted by vaccines.

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Other Non-specific Adjuvant Therapy
Other treatments used to stimulate the immune system in a general way and used in combination with the monoclonal antibodies, vaccines or chemotherapy are substances referred to as cytokines. Cytokines are hormones produced by the body that help the immune system to function. These substances were identifed in the laboratory several years ago and are now produced as drugs used as an adjunct therapy to boost the immune system. Examples of these treatments are granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2) and interferon.

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Immunotherapy Clinical Trials
Patients interested in immunotherapy should discuss this treatment with their physician to learn if they are candidates for such treatment. If the treatment is not available, the physician may refer the patient to a clinical trial studying a form of immunotherapy. The National Cancer Institute maintains a list of clinical trials on their Web site.

Everyone has the right to apply to a clinical trial, but must meet eligibility criteria. Clinical trials are designed to answer specific research questions. The eligibility criteria ensure that the questions will be answered and that trial results are reliable. These criteria also help protect patients; there must be at least a good chance that a patient will be helped by the treatment being tested in the clinical trial. To participate in clinical trials, patients must meet the eligibility criteria and agree to follow study guidelines.

See The Leukemia & Lymphoma Society Clinical Trial Service pages in this Web site for further information about how clinical trials work.

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References
Biological Therapies: Using the Immune System to Treat Cancer, Cancer Facts, National Cancer Institute, April 2000.

Immunotherapy for Cancer, Scientific American, Old, LJ, September 1996.

A New Era of Cancer Immunotherapy (CA-A cancer journal for clinicians), March-April 1999. American Cancer Society

Treating Cancer with Vaccine Therapy Web site, National Cancer Institute, 2000.

Understanding the Immune System, Science Behind the News Web site. National Cancer Institute, 2001.

The Leukemia & Lymphoma Society provides information for educational purposes only. We encourage you to review this educational material with your healthcare professional. The Society does not provide medical or other healthcare opinions or services. The inclusion of another organization's resources or referral to another organization does not represent an endorsement of a particular individual, group, company or product.