Reviewer: Ryan P. Smith, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: July 4, 2004
Author: Waldmann TA
Source: Nature Medicine, 9(3), 2003, pg. 269
Active immunotherapy has been successful against infectious agents that cause self-limiting diseases. Effective immunotherapy for chronic diseases and cancer, however, will require the optimization of many aspects of the immune system. This review highlights past approaches and describes more recent developments that suggest newer strategies for piquing our immune system for the treatment and prevention of cancer.
In 1796, Edward Jenner used cowpox vaccinations to induce immunity to smallpox. This virtually eradicated smallpox 180 years later. Using killed or attenuated pathogens, many other vaccines have been developed. Active immunotherapy against cancer is less effective, mainly because cancer cells have developed strategies to escape the normal immune response.
Recent immunologic insights have led to advances in the challenge of using vaccines against cancer. One insight is the identification of tumor antigens (small proteins recognized as "foreign" by the immune system) that stimulate the T-cells of the immune system. These tumor specific antigens are the result of mutations that cancer cells undergo, and in many cases that involve viral carcinogens, viral antigens. The latter example includes hepatitis B and C (for hepatoma or liver cancer), human papilloma virus (cervical cancer), and others. In certain lymphomas, the immunoglobulin antigen that the lymphoid cell is supposed to be producing becomes mutated, and hence a potential target for vaccines. In fact, this type of antigen was the target of the first monoclonal antibody therapy for a malignancy (B-cell lymphoma) in 1982. Rather than attempting to determine the exact antigen on the cancer cells themselves, an alternative approach has been to isolate and to study the immunogobulins that our bodies have produced in recognition of these foreign antigens. This may also provide oncologists with targets for vaccines against cancer cells.
The vaccine formulations targeting these antigens have caused a relatively weak immune response. However, extremely strong immune responses have been generated using a "boost" to the immune system, provided by viruses that encode antigens similar to the target. This is also a method of increasing the efficacy of cancer vaccines.
Recently, cells called antigen presenting cells (APCs) were discovered to play a pivotal role in the immune response. These cells, such as dendritic cells, process foreign antigens and then present them to T-cells, causing their intense activation. However, it is likely that only mature dendritic cells perform this function efficiently. In fact, immature dendritic cells can actually cause the suppression of responses to antigen. Interferon- g is a potential vaccine agent that could be used, as it generates mature dendritic cells. Hence, it would help create more T-cells that react to the antigen presented. Granulocyte macrophage colony stimulating factor (GM-CSF) is another chemical that stimulated the maturation of dendritic cells and which could be used to augment the immune response.
As noted above, a more vigorous dendritic cell presentation of antigens could trigger the immune response by T-cells. Another method is by administering co-stimulatory molecules with the vaccine. Co-stimulatory molecules are presenting along with the antigen by APCs to induce an aggressive response by the T-cells. This approach is based on the view that immune stimulation is primarily mediated by APCs rather than the tumor cells themselves.
Cytokines are somewhat like hormones, in that they can be generated at one site and travel through the bloodstream to stimulate an action at a distant site. These cytokines are used in the immune system for cell-to-cell communication. Hence, their augmentation is another target for immunotherapy. Many, such as interferon, are being used in limited settings already. Others, such as GM-CSF and interleukins (especially interleukin-2 and interleukin-15) are being actively studied. Other than directly administering the cytokines, another method involves introducing the gene that codes for the cytokine into a viral vector. This could elicit a longer lasting response.
There are a number of impediments to the effective immunotherapy of cancer that may limit the successful treatment of cancer by vaccines. Some of these are tumor associated, such as failing to induce co-stimulatory molecules or by producing factors (such as TGF- b) that inhibit effective immune responses. However, the major impediment may be a series of negative immunoregulatory mechanisms that are normally designed to prevent a too-vigorous immune response against self that lead to autoimmune diseases. There are at least four known pathways that inhibit this immunosurveillance, involving inhibitory cytokines such as cytotoxic T-lymphocyte antigen-4 (CTLA-4), interleukin-2, regulatory T-cells, and interleukin-13, which leads to the production of TGF- b.
Hence, the development of an effective cancer vaccine will require the identification of immunogenic tumor antigens, the optimization of APCs and their interaction with T-cells, and the blockade of inhibitory mechanisms to the immune system that impede immunotherapeutic efforts.
Passive immunotherapy involves the direct administration of antibodies to a patient to provide immunity against a disease or to fight off an infection. The most well known example of passive immunity is the diphtheria vaccine, which consists of antibodies to diphtheria toxin. Passive immunotherapy, in the form of monoclonal antibodies, is beginning to be used in the fight against cancer.
Monoclonal antibodies are usually partially derived from mice and serve as specific antibodies directed against one specific antigen (the type dependent upon the type of cancer), thought to be present on cancer cells. Difficulties in the past involved these mouse-derived antibodies' inability to induce an effective immune response and the fact that their survival in the blood stream is short-lived. Also, in most cases, the antibodies were not directed against an antigen essential for the cancer cell's survival. Strides in this area are being made as well. Rituximab (Rituxan), against the CD20 antigen found on B-cell lymphomas, was the first monoclonal antibody approved to treat malignancy. It is now the standard of care to administer rituximab in many types of non-Hodgkin's lymphoma. Trastuzumab (Herceptin), against the HER2/neu mutation has been approved to treat breast cancer. A monoclonal antibody has also shown exciting results in patients with HTLV-associated T-cell lymphoma.
As stated above, the major limitation in using monoclonal antibodies is that they do not effectively kill tumor cells themselves. Therefore, much effort is being placed into teaming the monoclonal antibody with a cytotoxic toxin or radionuclide to induce more effective cell killing. The first antibody teamed with a cytotoxin is gemtuzumab ozogamicin (Mylotarg), which is being used in the treatment of myelogenous leukemia. Radionuclides have been associated with rituximab, the monoclonal antibody against CD20 to induce more effective cell killing. The result, ibritumomab tiuxetan (Zevulin), is approved for the treatment of non-Hodgkin's lymphoma.
After many failures, with recent advances, cancer vaccines to induce active immunity against cancer cells, as well as passive immunity is proving to be efficacious. Many improvements still stand to be made, but with more effort and more discoveries, immunotherapy against cancer could become an effective tool in the fight against cancer.