February 6, 2007
Cancer Vaccines and Cellular Immunotherapy for the Treatment of Cancer
Antoni Ribas, MD, Associate Professor of Medicine and Surgery, Divisions of Hematology/Oncology and Surgical/Oncology, David Geffen School of Medicine, UCLA, medical oncologist, and researcher Jonsson Comprehensive Cancer Center UCLA
This is a summary of a lecture that was presented on February 6, 2007.
The idea of a cancer vaccine is a compelling notion. Some of the thoughts that are conjured up include the eradication or the prevention of cancer from a vaccine. Certainly our history has illustrated that diseases can disappear with the development and vaccination of large populations. A vaccine is a substance that is created to stimulate the body’s inherent illness fighting mechanism, the immune system. Most approved vaccines are oriented toward preventing a disease, such as polio, small pox and flu vaccines.
When it comes to cancer, however, the issue is a bit different. The vaccines that are being researched are not about prevention, they are mechanisms to treat the cancer. The concept of cancer vaccines has been around for a long time and there have been many research protocols oriented toward developing vaccines to treat cancer. Cancer vaccines are, essentially, a form of immunotherapy. Immunotherapy is a means by which cancer is treated by turning on the immune system against cancer cells. The patient’s own body is used to fight the cancer. While many people believe that the immune system is a key element in treating cancer the research data does not support this widely held view point. Rather, there appears to be certain types of cancers that are more regulated by immune function and these types of cancers are expected to benefit from immunotherapy type approaches. There are a variety of promising approaches in clinical trials for cancer.
Dendritic Cell Vaccines
One form of immunotherapy that that is being studied is the dendritic cell vaccine. Dendritic cells are a special type of white blood cell. They have a key role in teaching the immune system what should and what should not be attacked. The dendritic cell in the lymph gland turns on the CD4 helper cells and the CD8 killer cells. The killer cells (lymphocytes) are then sent out into the body as fighter cells oriented to finding certain cells that have a particular antigen. The antigen is a short sequence of protein (peptide) that resides on the outside of the cancer cell. The dendritic cell vaccine is used to amp up the immune system to send out these killer cells which are programmed to find the specific protein and immobilize the cancer cell.
Dendritic cell based immunotherapy has been used here at UCLA in cancer research with melanoma and in other research. For some patients there has been a dramatic response. This dramatic response is what is called “proof of concept,” i.e., it means that the idea and implementation is possible and can lead to the desired outcome.
Research using dendritic cell vaccines has led to the following conclusions: dendritic cell vaccines are safe and, for the most part, do not have toxic side effects. Unfortunately, it is very costly to manufacture the dendritic cell vaccines ($5,000-$10,000 per vaccine). In the melanoma research each person received three vaccines. Also, the response rate is low, with only one in 10 having a positive response from an already highly selected population of people who are most likely to respond. When they work dendritic cell vaccines produce lasting results for many years but they are unlikely to be widely used for treating cancer because of the difficulty in making them, the expense and the low response rate.
Another form of immunotherapy research has been in the development of antibodies. Antibodies can block the many different types of chemical interactions that occur on the surface of the cell. Researchers have learned that there are chemicals that both promote the immune system functioning but also block it. For example, if the immune system was fully geared up all of the time and there were no “brakes” on the system, it might attack our own organs. Scientists are learning more about this and looking at means to “rev up” the system by stimulating it and/or by trying to remove some of the brakes. CTLA4 is a protein that resides on the T cells in the immune system that serves as a “natural brake on the system.” The theory behind anti-CTLA4 antibodies is that when given, they will block the braking action and release a strengthened assault on the cancer cells. At this time there are two of these CTLA4 antagonistic monoclonal antibodies in clinical development, ipilimumab and CP-675,206, originally named ticilimumab. (Note: the “mab” in the name stands for monoclonal antibody, the “u” refers to human, “im” refers to immune system and the first part refers to the specific compound.)
This approach is not yet FDA approved, but may be in the future. Most patients that receive anti-CTLA4 antibodies do not have side effects. About 1 in 10 patients have had serious side effects that may lead to surgery, specifically diarrhea and extensive skin rash. The good news is that when there is a positive patient response it lasts for years. This approach is being studied in melanoma, kidney, lung, breast, prostate cancer and lymphoma.
Combining Vaccines and Antibodies
Recently several researchers have combined the immunotherapy treatments of vaccines with antibodies. This has been tried in a phase I clinical trial combining a dendritic cell vaccine with CP-675,206, an anti-CTLA antibody. In the first group of patients, there was a durable response suggesting that these two approaches may have benefits. In addition to looking for treatment effects, researchers are also trying to understand more about how the mechanisms work in order to advance the research questions.
T Cell Adoptive Transfer Therapy
One the newest approaches in immunotherapy is called “T Cell Adoptive Transfer Therapy.” In this process the individual with cancer has his/her own white blood cells (lymphocytes) removed. In the laboratory these lymphocytes are then infected with a retrovirus which has the ability to infiltrate other cells. The retrovirus carries genes encoded with specific proteins, called T Cell Receptors (TCRs), into cells. When the gene is turned on the TCRs are produced, covering the outer surface of the lymphocytes. The TCRs recognize and bind to certain molecules found on the surface of the tumor cells and they activate the lymphocytes to mount an attack on the cancer cells. One study using this technology with melanoma patients had 2 of 18 patients show a significant response. While this is only a small number of patients, it does show a future direction for research. In addition, these methods also help scientists understand more about the process of immune regulation and gene therapeutic interventions
The scientific advances leading to a better understanding of how to efficiently turn on the immune system against cancer are leading to new treatment strategies and new discoveries. It has been illustrated that the immune system can be tricked into attacking cancer effectively in a small percentage of patients. The patients who have these responses do very well. Antibody-based treatments compared to personalized cancer vaccines are more likely to become widely used in the near future because they can be mass produced.
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