Lymphoma Vaccine Enters Large-Scale Clinical Trials
For the first time, results of a lymphoma cancer vaccine study show that there is a clear antitumor effect in a small group of patients who were vaccinated over the course of five years, according to researchers at the National Cancer Institute (NCI). The results were published in the October 1999 issue of Nature Medicine (see the journal abstract).
The NCI said that on the basis of these promising results, it will launch a large-scale, randomized, phase III clinical trial to definitively test the experimental vaccine, which is custom-made from patients' own tumors (see the trial's protocol summary).
NCI researchers reported that 18 of 20 patients who were vaccinated against this common blood-cell tumor remain in complete remission an average of four years after vaccine therapy began -- and have no evidence of microscopic disease.
Prior to vaccination, all of the patients in the phase II study had minimal disease or were in a chemotherapy-induced first remission. Complete molecular remissions were documented, using the high technology tool of polymerase chain reaction (PCR), in 75 percent of patients after vaccination.
"Essentially, what we have done is present a tumor protein to patients in such a way that their immune systems recognize it and then destroy any cells bearing that protein," said Larry W. Kwak, M.D., Ph.D., a senior investigator in NCI's Division of Clinical Sciences in Bethesda, Md., and the study's principal investigator. By selecting only newly diagnosed patients, Kwak added, researchers maximized the likelihood that the vaccine would produce a positive immune response.
To create the vaccine, researchers fused tumor cells taken from individual patients to antibody-producing mouse cells that act as mini-factories, churning out large quantities of tumor proteins. These proteins were then shed into a tissue culture fluid, from which a particular protein of interest was plucked -- in this case a receptor molecule on the outer coating of the immune system's B cells.
The receptor molecule is "exquisitely specific for this type of tumor because it is an immunoglobulin," Kwak said. "And since it is unique to a given B cell, any tumor derived from that malignant B cell will have this [receptor molecule] marker."
The vaccine mixture also included a highly immunogenic carrier protein and an "adjuvant" or immune system booster. Patients received an initial injection, followed by booster shots for four months.
In the forthcoming pivotal trial, NCI hopes to enroll 390 patients who have been diagnosed with low-grade follicular lymphoma -- the most common form of this cancer -- at a consortium of several clinical centers in North America, to be announced, as well as at the Warren G. Magnuson Clinical Center at the National Institutes of Health in Bethesda, Md.
Patients in the control arm of this large-scale study will not get the tumor-specific antigen (the receptor molecule) in their vaccine mixture, but they will receive the carrier protein and granulocyte colony-stimulating factor to stimulate or boost an immune system response.
Also, Kwak said, two-thirds of participants will go into the experimental arm of the trial, a departure from the traditional 50-50 randomized split seen in most clinical trials. The hope is that by making the odds higher for getting the treatment vaccine "we will make the trial more attractive to patients," Kwak said.
Depending on the rate of patient accrual and whether or not the vaccine continues to prove effective, he added, the trial will take anywhere from six to eight years.
B-cell lymphoma, which strikes an estimated 41,000 Americans each year, is a cancer of the lymph glands caused by an unruly growth of B cells, white blood cells that produce the body's disease-fighting antibodies. Perhaps as many as 25,000 of these cancers are low-grade lymphomas -- slow-growing tumors with a high rate of recurrence.
Because these tumors can recur after many years in remission, in the Nature Medicine study Kwak and his colleagues established surrogate endpoints to measure the vaccine's success. Using PCR, the investigators measured chromosomal or molecular changes in the peripheral blood for evidence of residual tumor cells or microscopic disease. Cancerous cells are PCR-positive for these molecular or chromosomal changes; noncancerous cells are not. Eleven patients in the initial vaccine study were suitable for molecular analysis.
All 11 patients were PCR-positive at the beginning of the study, as well as before vaccination, despite being in complete remission -- a common finding for many lymphoma patients whose persistent circulating tumors cells place them at increased risk of relapse. However, eight of the 11 patients converted to PCR-negative status after receiving the treatment vaccine and have remained so an average of 18 months after vaccination.
The long-term clinical importance of these "molecular remissions," Kwak said, has yet to be determined, but it seems clear that the vaccine either further reduces patients' tumor burden beyond that achieved by chemotherapy or redistributes residual tumors to sites other than the peripheral blood, such as the lymph nodes.
The investigators also found that, as a result of vaccination, 19 of 20 patients showed anti-tumor activity -- specifically the induction of tumor-specific cytotoxic T cells. T cells are the white blood cells that orchestrate the immune response and have the capacity to directly kill tumor cells.
Anti-cancer vaccines are a high priority of research for NCI. Unlike conventional vaccines, which are used to prevent illness, the B-cell lymphoma vaccine represents a therapeutic approach, which seeks to strengthen the body's natural defenses against diseases such as cancer that have already developed.
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