Newspapers around the country have touted cancer vaccines as offering new hope for cancer treatment. A National Cancer Institute Web site lists nine phase III clinical trials and 64 phase II trials testing cancer vaccines. Excitement is building in the cancer vaccine field.
"The notion that somehow we can use the immune system to recognize and destroy cancer is not a new idea, but it has been very difficult to make it work," said Edgar Engleman, M.D., professor of pathology and of medicine at Stanford University.
Similar to vaccines against viruses like poliovirus, a cancer vaccine seeks to show the body what it should be battling. Bacteria and viruses produce antigens that are very different from those on the patients normal cells. Because of this, the antigens are easily recognized by the immune system.
In contrast, tumor antigens are likely to be similar or even identical to antigens on normal cells and are therefore harder for the immune system to recognize. The tumor antigens are weak antigens; they have already escaped the immune systems detection. The challenge is to make the weak cancer antigen more recognizable by the immune system.
"There was a tremendous amount of skepticism about this for many years," said Engleman. "I think the evidence is pretty clear now that . . . we can, in fact, introduce tumor-associated antigens in a way that does make them immunogenic."
When to Treat?
The obvious requirement that a patient have an optimally functioning immune system cannot always be met. For example, the way that drugs for cancer are tested, for ethical reasons, is to initially test them in advanced cases that have failed other treatments, said Jeffrey Schlom, Ph.D., chief of the Laboratory of Tumor Immunology and Biology at NCI. He noted that patients who have had other therapies will have a suppressed immune system, "and that is not the best place to test the efficacy of a vaccine."
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Despite obstacles, the successes are mounting. "I think its true that any therapy, including immunotherapy, will work best in those patients who are the healthiest, who have the lowest tumor burden, whose immune systems are in intact," said Engleman.
Which Tumor Antigen?
Research laboratories around the world have invested much time and effort in discovering cancer antigens. The question of which antigen is going to produce the best immune response is pivotal to the success of a cancer vaccine.
"To develop a cancer vaccine, you have to know what the antigens are on the cancer that the immune system reacts against," said Steven Rosenberg, M.D., Ph.D., chief of the Surgery Branch at NCI. "So we have spent many years trying to clone genes that code for cancer antigens. We have identified well over a dozen right now."
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"In the post-human genome era, there are gene products that are potential antigens for vaccines just emerging now," said Schlom. The expectation is that an explosion of potential new antigens is forthcoming. "We will have a lot of tumor antigens as candidates to develop as [targets for] cancer vaccines," said Larry Kwak, M.D., Ph.D., head of the Vaccine Biology Section at NCI. "One of our challenges is going to be prioritizing these and having efficient methods for determining which of the candidates are most promising because we are going to have a lot to choose from."
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Mode of Delivery
Once an antigen has been identified as a possible target for a cancer vaccine, the researcher must find a way to present it to the patients immune system in such a way as to enhance the immune response. Schlom and his colleagues are using vaccinia virusthe virus used in the smallpox vaccineto deliver their antigen. "When a person gets the smallpox vaccine," explained Schlom, "he or she gets this pustule, this inflammation. That is the body responding to the virus. Its in that environment, with the immune systems cytokines being released and the T-cells coming in, that we present this weak tumor antigen."
Schloms group is also making use of costimulatory molecules, secondary signals that activate the immune system. "Its been found very recently that the more of these costimulatory molecules that you use, the better response you get," said Schlom. "Weve been able to put together a virus vector with the antigen and three costimulatory moleculesall in the same vectorto load it up."
Schloms animal model studies have shown that the combination of the antigen and the costimulatory molecules are much more potent in attacking tumors than just the antigen alone. "With DNA vectors, like plasmids, you can only put in one gene," explained Schlom. "But with these big viral vectors you can put in four, five, six genes. Thats why weve used them."
Other delivery systems show promise as well. "The delivery vehicle that were most excited about is a fusion protein of tumor antigens and chemokine molecules," said Kwak. Chemokines are attracted to receptors located on dendritic cellskey components of the immune system. By creating a fusion protein, Kwak has coerced the chemokine into delivering the antigen to the immune system. Kwak added that the work is all in animal models and pre-clinical studies. "Were hoping to translate this into phase I clinical trials within the year," he added.
Like many in the cancer vaccine field, Rosenberg and colleagues are exploring many avenues for delivery of antigens. "Weve explored a whole variety of ways to immunize. Weve put them into recombinant viruses, and we are engineering recombinant adenoviruses and vaccinia viruses," said Rosenberg.
"But what weve found is that the most effective way to immunize patients is by immunizing with peptidessmall pieces of the antigen," he said. "When one does that, one can raise very high levels of antitumor immunity in patients."
Dendritic Cells
Engleman and his colleagues have concentrated efforts on understanding and exploiting dendritic cells. "The only reason we did this is because we had figured out a way to isolate these very rare cells from the blood," said Engleman.
Their studies showed that dendritic cells are the only cells that are able to sensitize naïve T-cells to antigens. Engleman observed an immunologic response as the dendritic cells activated and educated the T-cells. "So we were able to create an immune response in the test tube that we couldnt do with other cells," said Engleman.
This observation resulted in a collaboration with Ron Levy, M.D., professor of medicine and chief of oncology at Stanford University. The investigators found they could remove a small number of dendritic cells from a patient, introduce the cells to the antigen in vitro, and then return the educated cells to the patient. Early studies showed an antitumor response in some patients. "I think that experience ignited a lot of interest in this general approach," said Engleman.
Although the manipulation of dendritic cells is promising, it is also very expensive and labor-intensive. "These are patient-specific treatments using the patients own cells. Its very costly," said Engleman. "Eventually, we may have to get beyond this approach to a more cost-effective approach."
Future Directions
Despite the obstacles and the time involved in researching, developing, and testing cancer vaccines, the researchers most knowledgeable about the field are optimistic about the future of this immunotherapy.
"I think the general wisdom is that the best approach to cancer is one that uses multiple approaches: surgery and chemotherapy to reduce the tumor and immunological approaches to perhaps clean up residual cancer because the immune system is pretty efficient," said Engleman.
Others hope that cancer vaccines will one day replace the more toxic standard therapies. "What Im really excited about is that eventually we will probably be able to combine a bunch of different vaccines," said Schlom. "If there are three or four antigens that are overexpressed in, for example, most colon cancers or breast cancers, you would just mix them in the vialjust like the DTP [diphtheria, tetanus, and pertussis] vaccine. With vaccines, you start a response. Then, adding another vaccine at the same time or later magnifies that whole response, which makes it more synergistic.
"I think the day is going to come soon where maybe 10 or 15 antigens are identified that are shared among most breast cancers, most colon cancers," he added. "You will make a vaccine against all of them. It will be easy to use and cost effective. In animal models, we are just starting to do this. Thats where the field is going. Thats where its going for sure."
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