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Immunotherapy Cancer Treatment
John W. Park, MD
Christopher C. Benz, MD

Reprinted with Permission from Supportive Cancer Careby E.H. Rosenbaum, MD and I.R. Rosenbaum, Sourcebooks, Naperville, IL, 2001

Interferons and Other Cytokines
Monoclonal Antibodies
Cancer Vaccines

The concept of immunotherapy is based on the body's natural defense system, which protects us against a variety of diseases. Although we are less aware of it, the immune system also works to aid our recovery from many illnesses.

For many years, physicians believed that the immune system was effective only in combating infectious diseases caused by such invading agents as bacteria and viruses. More recently, we have learned that the immune system may play a central role in protecting the body against cancer and in combating cancer that has already developed. This latter role is not well understood, but there is evidence that in many cancer patients the immune system slows down the growth and spread of tumors. The body's ability to develop an immune reaction to tumors may help determine which patients are cured of cancer using conventional therapies, including surgery, radiation and drugs.

One immediate goal of research in cancer immunology is the development of methods to harness and enhance the body's natural tendency to defend itself against malignant tumors. Immunotherapy represents a new and powerful weapon in the arsenal of anticancer treatments.

Immunotherapy seems to offer great promise as a new dimension in cancer treatment, but it is still very much in its infancy. Immunotherapies involving certain cytokines and antibodies have now become part of standard cancer treatment. Other examples of immunotherapy remain experimental. Although many clinical trials of new forms of immunotherapy are in progress, an enormous amount of research remains to be done before the findings can be widely applied.

Immunotherapy of cancer began about one hundred years ago when Dr. William Coley, at the Sloan-Kettering Institute, showed that he could control the growth of come cancers and cure a few advanced cancers with injections of a mixed vaccine of streptococcal and staphylococcal bacteria known as Coley's toxin. The tuberculosis vaccine, Bacillus Calmette-Guerin (BCG), developed in 1922, is known to stimulate the immune system and is now used to treat bladder cancers.

Many years of research have finally produced the first successful examples of immunotherapies for cancer. Sometimes referred to as biological response modifiers or as biological therapies, these new treatments-such as interferons and other cytokines, monoclonal antibodies, and vaccine therapies-have generated renewed interest and research activity in immunology.

Interferons and Other Cytokines
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Interferons belong to a group of proteins known as cytokines. They are produced naturally by white blood cells in the body (or in the laboratory) in response to infection, inflammation, or stimulation. They have been used as a treatment for certain viral diseases, including hepatitis B.

Interferon-alpha was one of the first cytokines to show an antitumor effect, and it is able to slow tumor growth directly, as well as help to activate the immune system. Interferon-alpha has been approved by the FDA and is now commonly used for the treatment of a number of cancers, including multiple myeloma, chronic myelogenous leukemia, hairy cell leukemia, and malignant melanoma. Interferon-beta and interferon-gamma are other types of interferons that have been investigated.

Other cytokines with antitumor activity include the interleukins (e.g., IL-2) and tumor necrosis factor. IL-2 is frequently used to treat kindey cancer and melanoma.

Some of the problems with these cytokines, including many of the interferons and interleukins, are their side effects, which include malaise and flu-like syndromes. When given at a high dose, the side effets can be greatly magnified.

Monoclonal Antibodies
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Another important biological therapy involves antibodies against cancer cells or cancer-associated targets. Monoclonal antibodies are artificial antibodies against a particular target (the "antigen") and are produced in the laboratory. The original method involved hybridoma cells (a fusion of two different types of cells) that acted as factories of antibody production. A major advance in this field was the ability to convert these antibodies, which originally were made from mouse hybridomas, to "humanized" antibodies tha more closely resemble our natural antibodies. Even newer techniques can be used to generate human antibodies from genetically engineered mice or bacteria containing human antibody genes. Monoclonal antibodies have been widely used in scientific studies of cancer, as well as in cancer diagnosis.

As therapy for cancer, monoclonal antibodies can be injected into patients to seek out the cancer cells, potentially leading to disruption of cancer cell activities or to enhancement of the immune response againast the cancer. This strategy has been of great interest since the original invention of monoclonal antibodies in the 1970s. After many years of clinical testing, researchers have proven that improved monoclonal antibodies can be used effectively to help treat certain cancers. An antibody called rituximab (Rituxan) can be useful in the treatment of non-Hodgkin's lymphoma, while trastuzumab (Herceptin) is useful against certain breast cancers. Other new monoclonal antibodies are undergoing active testing.

Researchers also are studying ways of linking cytotoxic drugs, toxins, or radioisotopes to monoclonal antibodies to enhance their effectiveness against cancer cells. In this case, the antibodies would function as a targeted delivery mechanism; the result would be like a "guided missile, " capable of seeking out a specific target-a cancer cell.

Cancer Vaccines
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As described above, biological therapy or immunotherapy is now considered a fourth modality of cancer treatment, and examples such as interferon and monoclonal antibodies have become part of standard cancer treatment. Many types of immunotherapy, such as cancer vaccines, remain experimental. Experimental therapies in general are also discussed in the next section.

Vaccines have revolutionized public health by preventing the development of many important infectious diseases, including polio, small pox, and diphtheria. It has been much more difficult to develop effective vaccines to prevent cancer, or to treat patients who already have cancer. Attempts to develop such cancer vaccines, despite many decades of experimental work, have yet to yield proven results. In spite of this, a notable increase in interest has been generated by recent advances in the areas of immunology and cancer biology, which have led to more sophisticated and promising vaccine strategies than those previously available. Cancer vaccines typically consist of a source of cancer-associated material (antigen), along with other components, to further stimulate the immune response against the antigen. The challenge has been to find better antigens, as well as to package the antigen in such a way as to enhance the patient's immune system to fight cancer cells that have the antigen.

Increasingly, cancer vaccines have been shown to be capable of improving the immune response against particular antigens. The result of this immunologic effect is not always sufficient to reverse the progression of cancer. However, cancer vaccines have been generally well tolerated, and they may provide useful anticancer effects in some situations. For example, in malignant lymphoma, a number of laboratory studies have indicated that vaccination using lymphoma-associated proteins called idiotype can stimulate the immune systems of mice sufficiently to help them resist the development of lymphomas.

In clinical trials, idiotype vaccines continue to be tested and have been associated with indications of clinical benefit in some lymphoma patients. In malignant melanoma, a wide variety of vaccine strategies have been introduced into clinical trials, and some have been found to stimulate the immune response against the cancer.

Cancer vaccines continue to be evaluated in these diseases as well as most other cancer types. The many new strategies for vaccine construction and immune stimulation may lead to the emergence of clinically useful cancer vaccines. An example of one exciting new approach being tested in melanoma and other cancers is the use of dendritic cell vaccines. Dendritic cells help to turn on the immune response.

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