Posted on February 5th, 2009 by
By Mary L. Disis, M.D. Associate Professor, Division of Oncology, University of Washington, Seattle, WA
Vaccines contain cells or antigens which, when injected into the body, cause an immune response with the production of antibodies and immune lymphocytes (T-cells) that specifically attack the injected cell or antigen. These antibodies and immune lymphocytes normally attack and kill invaders such as bacteria, viruses and parasites. Vaccines have been widely used to control and even eradicate infectious diseases such as polio and smallpox.
For many years there have been attempts to use the principles of vaccination developed in infectious diseases to get the body to attack and kill cancer cells. This type of treatment is included in the broad category of cancer therapy know as immunotherapy. One problem limiting success of cancer vaccines is that the body, in general, does not recognize cancer cells as being foreign to the body which is a requirement for initiating an immune response.
The application of immunotherapeutic principles to the treatment and prevention of breast cancer is a relatively new undertaking. Although cancer vaccines have been extensively studied in other cancers such as melanoma, the therapeutic efficacy of these approaches is not well explored in breast cancer. However, like melanoma, under certain circumstances breast cancer cells can elicit an immune response. Recently, several breast cancer antigens which can induce an immune response in patients have been identified. This has led to enthusiasm for testing vaccines for the treatment of breast cancer.
One advance in the theoretical application of cancer vaccines is a better understanding of the stage of cancer in patients most likely to benefit from immunization. When we are vaccinated to prevent an infectious disease, we receive immunization before we are exposed to the germ to prevent us from getting infected. Similarly, cancer vaccines will probably not be effective for patients with bulky, metastatic disease; rather, vaccines will be most useful for patients whose cancer is in remission, but who are at high risk of relapse from minimal residual disease. Therefore, the use of vaccines is an attractive strategy for the prevention of breast cancer relapse in patients without measurable cancer but who have a high chance of recurrence. Other advantages of vaccines include the killing of breast cancer cells that are resistant to chemotherapy and, in general, vaccines are not toxic as are most other treatment modalities for breast cancer.
There are two types of vaccine strategies currently being tested in patients with breast cancer: (1) cell-based vaccines, and, (2) breast cancer antigen specific vaccines.
Prior to the identification of specific cancer antigens, whole cancer cells were the main component of cancer vaccines. Vaccines utilizing an intact cancer cell or cancer cell lysates, i.e. broken down cancer cells, have the theoretical advantage of exposing multiple cancer specific antigens to the immune system of the patient. Both autologous cancer cells (breast cancer cells from the patient’s own tumor) and allogeneic tumor cells (breast cancer cells from another person) have been used in the vaccination of breast cancer patients. Autologous breast cancer vaccines are weakly immunogenic, that is, they don’t stimulate strong immune responses in patients. Furthermore, not every breast cancer patient will have enough cancer cells to develop a vaccine.
There are many strategies under investigation for trying to make breast cancer cells more recognizable by the immune system, such as engineering them to secrete immune stimulation factors called cytokines. Unfortunately, many strategies which would improve the immune stimulatory properties of whole cancer cell vaccines, require that the breast cancer cells be grown outside the body so that they may be altered in culture systems. Unlike other cancers such as melanoma, which can be grown very well in laboratory cultures, breast cancer cells are difficult to expand once removed from the patient. Thus, autologous cellular vaccines have limited clinical applicability.
Allogeneic breast cancer vaccine cells do not require removal of tissue from the patient and are less expensive to prepare as they have already been established in culture. Some breast cancer cell lines grow well in culture and are widely available. Furthermore, allogeneic cells appear to be more immunogenic as they are foreign and may induce a strong T-cell response against common cross-reacting breast cancer antigens. Despite these benefits, clinical studies of allogeneic breast cancer cellular vaccines indicate that the vaccines are still not capable of generating very robust tumor specific immune responses.
Breast cancer antigen specific vaccines offer several advantages to the whole cancer cell approach. First, antigen specific vaccines are easy to formulate. The vaccines, which target a specific immunogenic breast cancer related protein, are similar to infectious disease vaccines in that they can be used to immunize any patient whose tumor bears the antigen. The goal would be the generation of an immune response that would kill cancer cells bearing that antigen. In addition, targeting a specific protein in breast cancer would allow very specific measurement of the generation of an immune response. Thus, antigen specific breast cancer vaccines are a good starting point for developing effective immunization strategies for breast cancer therapy.
Our group has been studying the HER-2/neu oncogenic protein as an immune target in breast cancer. HER-2/neu is a growth factor receptor protein that is found in abundance in about 30% of breast cancers and is most likely directly related to uncontrolled cancer growth. We have been conducting clinical trials of vaccines directed against the HER-2/neu protein using a variety of different strategies. These initial clinical trials are designed to determine the toxicities associated with vaccine administration and to measure the immune responses generated by the vaccines. Patients who do not generate a measurable immune response are unlikely to have a benefit from vaccination.
In one clinical trial of the first 22 patients to complete 6 vaccinations with a vaccine composed of fragments of the HER-2/neu protein called peptides, 16 (73%) developed T cell immunity to the HER-2/neu protein. There has been essentially no toxicity, except local irritation, from the administration of these vaccines. It is too early to estimate whether or not there is a benefit from this vaccine.
Several strategies for improving the effectiveness of cellular vaccines as well as immunization regimens targeting specific breast cancer antigens are currently being tested in patients with breast cancer. Once a vaccine has shown the ability to robustly immunize breast cancer patients the most important question can be asked- does immunity to breast cancer prevent cancer from recurring? This question can only be answered in the context of carefully designed clinical trials enrolling large numbers of patients with similar disease characteristics. It is our hope the role of cancer vaccines in the fight against the breast cancer will be defined over the next few years. In the meantime patients with breast cancer are encouraged to enroll in clinical trials attempting to improve vaccine therapy.
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