S. Jack Wei, MD & Lara Bonner Millar, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 11, 2010
The immune system is an intricate network of organs, highly specialized cells, and chemical signals that work to protect our bodies from foreign invaders, particularly infections. The immune system is able to differentiate between normal host cells and foreign cells because different types of cells frequently display different antigens. Antigens are proteins that are found on the surface of cells and often differ from one type of cell to the next. While normal, host cells also present antigens, the immune system is able to differentiate between antigens found naturally within the body (self-antigens) and antigens from foreign invaders.
When the immune system encounters a foreign antigen, a cascade of events occurs which is intended to clear the foreign substance from the body. Initially, foreign cells are encountered by antigen-presenting cells (APCs, the most important of which is the dendritic cell), which engulf them and break up the foreign antigen into small protein pieces known as epitopes. The APC presents these epitopes to lymphocytes, a type of white blood cell. There are two main types of lymphocytes: T-cell lymphocytes and B-cell lymphocytes. The APC can present the epitope to either a CD8 (cytotoxic) T-cell which go on to directly kill the foreign cells, or to a CD4 (helper) T-cell which release chemical signals that work to both help cytotoxic T-cells kill foreign cells and to induce B-cell lymphocytes to produce antibodies.
The presentation of antigens to T-cells is not enough to produce a vigorous immune reaction. Co-stimulation through a variety of chemical signals must also occur in order for the immune response to adequately respond. Without these co-stimulatory signals, the response of T-cells is weak and often inadequate at destroying the foreign cells. In the presence of co-stimulation, the reaction of T-cells and B-cells is brisk and additional cells, such as natural killer cells, are recruited to help destroy the foreign invaders. This complex system works together to form the immune response.
Most of us have received vaccination for infectious diseases, such as measles and mumps. These vaccines use weakened or killed viruses, bacteria, or other germs to start an immune response in the body. Cancer vaccines are designed to work in a similar manner by teaching the immune system to attack and destroy cancer cells. Normally, when foreign cells enter the body (for example, when an infection occurs), the immune system responds to the invasion and clears the body of the foreign cells. Unlike infectious cells, cancer cells are not recognized as foreign by the body. Instead, the immune system thinks the cancer cells are part of the normal body and do not mount an immune response against the cancer. Cancer vaccines allow the immune system to recognize cancer cells as foreign and, therefore, get the immune system to attack the cancer cells.
Most commonly, vaccines are used to prevent infections. By introducing inactivated or killed forms of a virus or bacteria to the immune system before an infection actually occurs, the immune system is "primed" to recognize potential infections. Antibodies that are specific for the vaccine are increased in the body and allow for a very rapid response to potential infections by the viruses or bacteria associated with that vaccine. In this way, actual infections can be quickly recognized by the immune system and eliminated before a significant infection can take hold.
A true cancer vaccine contains cancer cells, parts of cells, or pure antigens. The vaccine increases the immune response against cancer cells that are already present in the body, in contrast to vaccines for diseases that are designed to prevent infection. Cancer vaccines spur the immune system into recognizing tumor cells as foreign invaders so that they may be destroyed by the host immune system. Tumor cells often express distinct antigens known as tumor-associated antigens (TAAs). One of the greatest problems with developing cancer vaccines has been that most TAAs are also present in normal cells. Because the immune system sees these antigens as self-antigens, no immune response is mounted. If the immune system can be taught to recognize the TAAs as foreign, an immune response can be mounted against the tumor. Several TAAs have been identified that are found in specific types of cancers, but not in normal cells. By targeting these TAAs with cancer vaccines, cancer vaccines can induce the immune system to attack cancer cells while leaving normal, healthy cells largely intact. Currently, cancer vaccines targeting cancers of the breast, prostate, liver, kidney, pancreas, and lung, as well as melanoma and certain types of leukemias and lymphomas are in clinical trials.
Some cancers are known to be associated with viral infections. Infection with human papilloma virus has been shown to be a cause of cervical cancer. Hepatitis B and C viruses are known to cause a certain type of liver cancer. New vaccines against the human papilloma virus (HPV) help prevent women from getting cervical, vaginal, and vulvar cancer. Vaccines that prevent infection from these viruses would help to prevent their associated cancers. 1 While these vaccines may ultimately prevent cancer, these are not cancer vaccines. These vaccines are actually vaccines against viruses, rather than cancer itself. Prevention of cancer is merely a consequence of the prevention of the viral infection.
Cancer vaccines need to be directed at antigens that are expressed by the tumor but not by the normal cells. If the antigen that is used is also expressed in normal cells, the immune response generated by the vaccine can attack normal tissue as well. This cross-reactivity can increase the toxicity of the treatment, interfering with one of the biggest potential advantages of cancer vaccines: the ability to specifically target the cancer cells without damaging the normal cells.
Co-stimulation of the immune response must occur for there to be a vigorous immune response. Tumor cells secrete chemical factors that interfere with co-stimulation of the immune response. Even if an APC is able to present antigens to T-cells, the immune response is often limited without co-stimulatory signals. Cancer vaccines that present the TAA to the immune system without increasing co-stimulation run into the same problem. The immune response is often too weak for any significant effect on the tumor to occur. In order to solve this problem, cancer vaccines are often designed to provide co-stimulation in addition to the TAA in order to increase the immune response.
When individual cancer cells are found, the immune system can easily clear them from the body. Unfortunately, by the time most cancer vaccines are given, the tumors are large and much more difficult to treat. In addition to the sheer number of cells that need to be destroyed, as tumors grow, there are areas within the tumor that become difficult for the immune system to reach. These areas become protected from the effect of the cancer vaccine.
The thymus is an organ in the chest that functions to produce T-cells (the T stands for thymus). It functions in childhood and slows down with time, eventually becoming smaller and inactive in adults. This is one of the reasons that vaccines are often given in infancy and childhood. The immune response of adults is dependent on the population of T-cells that was produced during childhood. Over time, this response becomes less vigorous. Cancer vaccines face the challenge of inducing immune responses in a population of patients whose immune systems are naturally slowing down.
Cancer cells can suppress the immune system in a number of ways. They can block co-stimulation, preventing a vigorous immune response. Cancer cells can inhibit the maturation or function of APCs, blocking the presentation of TAAs to lymphocytes. In addition, cancer cells can directly block the activation of lymphocytes, preventing a response after the antigens have been presented.
A number of different approaches have been used to introduce TAAs to the immune system and produce an adequate immune response to destroy the cancer cells. Each has its own advantages and disadvantages.
Similar to vaccines against infectious agents, these vaccines usually utilize whole, inactivated tumor cells to generate the immune response. The advantage of this is that a number of antigens are presented that the immune system can target. However, this wide range of antigens compromises the specificity of the vaccine. Also, the immune response is often weak due to the lack of co-stimulatory signals.
A peptide is a fragment of a protein that can be used as the antigen in a cancer vaccine. By introducing the appropriate peptide directly to the APCs, the vaccine can induce an immune response to cells producing that antigen. Oftentimes, the peptide vaccine is given simultaneously with chemical signals (such as hapten) that act as co-stimulatory signals for the immune system, improving the immune response. The peptides can also be engineered to elicit strong immune responses by altering specific portions of the peptide. These alterations result in stronger immune reactions than unaltered peptides do. Potential disadvantages of the peptide vaccines include the need for the peptide to be taken up by the APC. If, this does not occur, no immune response is seen. In addition, cells within a tumor are frequently changing. If the peptide that is used in the vaccine is not essential to the tumor, the cells can frequently stop making that protein and avoid detection by the immune system.
In order to ensure that the dendritic cells (the most notable APCs) adequately take up peptides, these cells can be exposed directly to high levels of the appropriate antigen. The patient's own dendritic cells are removed and can be bombarded with either peptide fragments or whole proteins. When the dendritic cells are introduced back into the patient, they present large amounts of the antigen to the immune system and stimulate an immune response. Alternatively, the genes that encode the antigens can be introduced directly into the dendritic cell. Again, dendritic cells are removed from the patient and the genes introduced to the cells by either directly injecting them into the cell or by stimulating the cell to take up the genes through pulses of electricity. Either way, once the gene is taken up by the dendritic cell and reintroduced to the patient, the cell can potentially produce large amounts of the antigen and induce a strong immune response. Currently, an alternative method in which dendritic cells are fused with tumor cells is under research. All of these methods are very cumbersome and expensive, making their widespread use difficult.
Viral vectors utilize a modified virus that remains mildly infectious. The gene that encodes the TAA is placed inside the virus, and when the virus infects a dendritic cell, it can induce the cell to produce large amounts of the antigen. This method has the advantage of being a much cheaper and easier way of introducing genes into dendritic cells than direct injection or electrical manipulation. The dendritic cells can be altered directly in the patient and do not need to first be removed from the patient and later reintroduced. In addition, current viral vaccines also include genes encoding co-stimulatory signals so that the dendritic cells will also produce these proteins, improving the immune response. However, one disadvantage of this system is the possibility of generating an immune response to the virus itself. If the viral antigens are recognized by the immune system, the virus can be cleared from the body before it has a chance to infect the dendritic cell. If the virus is cleared to quickly, no immune response against the cancer is mounted.
Heat shock proteins (HSPs) are produced by all cells when they undergo environmental stresses. When these proteins move outside of the cell, they act as stimulatory signals to the immune system and induce an immune response. Heat shock protein vaccines work by extracting HSPs directly from tumor cells. HSPs often contain tumor-specific antigens which are recognized by the immune system. When the HSPs are reintroduced to the patients, they both generate an immune response and direct that response to the specific antigens that they carry. However, a number of different HSPs can be produced by a tumor, and they can carry antigens that are found in normal tissue. In order for these vaccines to be clinically useful, only HSPs that carry tumor-specific antigens can be used.
There have been a number of clinical studies that have tested cancer vaccines. Thus far, there is only one cancer vaccine found to improve overall survival. Sipuleucel-T (Provenge®) is approved for use in some men with metastatic prostate cancer. It stimulates an immune response to prostatic acid phosphatase (PAP), an antigen present on most prostate cancers. In a clinical trial, Provenge increased the survival of men with hormone refractory metastatic prostate cancer by about 4 months.2 The vaccine is customized for each patient. Using leukopheresis, the patient's APCs are harvested and then cultured with a protein called PAP-GM-CSF. This protein consists of PAP linked to another protein called granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF stimulates the immune system and enhances antigen presentation. APC cells cultured with PAP-GM-CSF are then infused into the patient with three treatments, usually two weeks apart. The exact mechanism of action of sipuleucel-T is unknown but, it is likely that that the APCs that have taken up PAP-GM-CSF stimulate T cells to kill tumor cells that express PAP. Common side effects included fever, chills, fatigue, back and joint pain, nausea, and headache. These most often started during the cell infusions and resolved within one to two days.
Even the studies of vaccines that did ultimately not work have taught us important lessons:
Cancer vaccines remain an important and growing area of cancer research. A number of phase III trials are currently underway to further evaluate the effectiveness of these vaccines in improving patients' outcomes. A number of key questions and areas of research remain:
We are still quite a ways away from incorporating cancer vaccines into the routine care of cancer patients. Nevertheless, the possibility of using the body's own immune system to destroy cancer cells remains an appealing possibility and results of early trials are promising. Research into new ways of treating cancer, such as cancer vaccines, remains critical in our ongoing fight against cancer.
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