S. Jack Wei, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: July 2, 2004
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.