Cancer Vaccines: Training the Immune System to Fight Cancer
Researchers have spent more than a century trying to develop a vaccine that jump-starts the body's immune system in an effort to either prevent or treat cancer. Although understanding of the immune system's role and function in cancer initiation and progression has improved, researchers have had limited success translating that improved knowledge into better results in early-phase cancer vaccine clinical trials. That does not mean researchers have lost hope of getting some vaccines to pass Food and Drug Administration (FDA) muster for use in patients. If anything, it has forced them to be more creative in their efforts to teach the immune systems to treat cancer cells like the unwelcome intruders they are.
The use of cancer vaccines to date has almost uniformly focused on patients already undergoing treatment - so-called therapeutic vaccines. Through mechanisms researchers are now beginning to understand, the immune system often fails to recognize cancerous cells, and simply leaves them to potentially take root and form tumors. Therapeutic cancer vaccines are meant to reverse this course, unmasking active cancer cells and bringing them to immune cells' attention.
"The best settings are for treating people who have minimal disease or a high risk of recurrence," explains Dr. Jeffrey Schlom, chief of NCI's Laboratory of Tumor Immunology and Biology, and a leader in cancer vaccine development. "But at this time, most therapeutic cancer vaccines are being studied in people who have failed other therapies."
About a dozen therapeutic vaccines currently are being studied in advanced clinical trials, according to Dr. Steven Hirschfeld, a medical officer in the FDA Center for Biologics Evaluation and Research. The vaccines, says Dr. Hirschfeld, "are designed to be specific, targeting only the cancer cells without harming the healthy ones."
Although many of the therapeutic vaccines under investigation are made with cancer antigens - unique proteins or protein bits on the surface of cancer cells that can elicit some immune response - the antigens' presence is not always sufficient to fuel a robust immune response. So Dr. Schlom and other researchers have enhanced the potency of their vaccines. For example, Dr. Schlom's lab has developed a vaccine, CEA-TRICOM, in which genes for the tumor antigen called CEA are put into a weakened vaccinia virus, or vector, that delivers genetic materials to antigen-presenting and/or cancer cells, making the tumor antigen more visible to the immune system. The genes for three "costimulatory molecules" are also added to the vaccine to serve as signaling beacons that make the vaccine more potent than it would be if the antigen were used alone.
The most recent findings from a CEA-TRICOM vaccine clinical trial were published in December in the Journal of Clinical Oncology. In the phase I trial (the primary goal of which is to prove safety), 58 patients received the CEA-TRICOM vaccine regimen, which includes an initial vaccination along with "booster" vaccinations. After 4 months, 40 percent of patients had stable disease, with more than half maintaining stability beyond 6 months, and one patient had a pathologic complete response.
In a commentary published last November in Nature Medicine, Dr. Steven Rosenberg, chief of the NCI Surgery Branch, and NCI colleagues, discussed the lack of pathologic response and tumor regression in trials testing cancer vaccines against solid tumors. Using peptide vaccines, Dr. Rosenberg's group has shown that tumor progression persists even when more than 10 percent of cells demonstrate anti-tumor activity in response to the vaccine. "This is an exciting area of research, but there is still a lot of work to be done," says Dr. Rosenberg. "Unfortunately, as of today, there are no vaccines that are effective in patients with solid tumors."
Vaccines are also being tested against several blood cancers, and have yielded some positive results. One such vaccine relies on white blood cells called dendritic cells, which are mixed with genetic material taken from a patient's tumor. Dendritic cells are like bloodhounds: They sniff out the tumor antigens and show them to the hunter T cells, and researchers have discovered how to dramatically expand the number of dendritic cells in a vaccine. "Employing millions of 'pumped-up' dendritic cells can help elicit a strong immune response," says Dr. Kim Lyerly, director of the Duke Comprehensive Cancer Center, whose research team has been developing dendritic cell-based vaccines.
In a 2002 study at Stanford University, use of a dendritic cell-based vaccine to treat 19 patients with B-cell lymphoma yielded 4 complete tumor regressions and an objective tumor regression rate of nearly 32 percent.
"For decades, people thought it wasn't even fundamentally possible to develop cancer vaccines, and here we are," says Dr. Lyerly. "The science behind cancer vaccines is leading us to believe that we will find the answers."
[This story was adapted, in part, from an article that ran in the Sept.-Oct. 2004 issue of FDA Consumer magazine.]
By Carmen Phillips