Researchers at the National Cancer Institute (NCI) have reported an antitumor effect in a small group of patients with lymphoma who were vaccinated with an experimental B-cell lymphoma vaccine over a 5-year period. These promising results have prompted the NCI to launch a large-scale, randomized, phase III clinical trial to definitively test the vaccine.
Vaccination Achieved 75% Complete Remission in Phase II Study
In the phase II study, published in the October 1999 issue of Nature Medicine, 20 patients who had minimal lymphoma or were in chemotherapy-induced first remission were treated with an initial injection of the B-cell lymphoma vaccine, followed by booster shots for 4 months. After 4 years, 18 of the 20 patients remained in complete remission, with no evidence of microscopic disease. Following vaccination, complete molecular remissions were documented, using polymerase chain reaction (PCR) analysis, in 75% of patients.
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, md, phd, a senior investigator in NCIs Division of Clinical Sciences, and the studys principal investigator. Kwak said that researchers maximized the likelihood that the vaccine would produce a positive immune response by selecting only newly diagnosed patients.
Researchers created the lymphoma vaccine by fusing tumor cells culled from individual patients to antibody-producing mouse cells, which, in turn, acted as mini-factories, churning out numerous tumor proteins. The proteins were then shed into a tissue culture fluid, from which a particular protein was collectedin this case, a receptor molecule located on the coating of the immune systems 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 the malignant B cell will have this [receptor molecule] marker. The B-cell lymphoma vaccine mixture also included a highly immunogenic carrier protein and an adjuvant or immune system booster.
PCR Used to Measure the Vaccines Effect
Because lymphomas can recur after many years in remission, the phase II study established surrogate end points to measure the vaccines success. Using PCR, investigators measured chromosomal or molecular changes in peripheral blood for evidence of residual tumor cells or microscopic disease.
Eleven patients in the phase II study were suitable for molecular analysis. Despite being in complete remissiona common finding in many lymphoma patients whose persistent circulating tumor cells pose an increased risk of relapseall 11 patients were PCR positive before and at the start of vaccination. However, following vaccination, 8 of the 11 patients converted to PCR negative status, which persisted for an average of 18 months.
Kwak said the long-term clinical importance of these molecular remissions remains to be determined. However, he said, it seems clear that the vaccine either further reduces patient tumor burden beyond that achieved by chemotherapy, or redistributes residual tumor cells to sites other than the peripheral blood, such as the lymph nodes.
Investigators also reported antitumor activity in 19 of the 20 vaccinated patientsspecifically, the induction of tumor-specific cytotoxic T cells.
Study Design of Upcoming Pivotal Trial
Researchers at the NCI expect to enroll 390 patients with low-grade follicular lymphoma into the large-scale, randomized, phase III trial. Testing will begin at several clinics in North America and at the Warren G. Magnuson Clinical Center at the National Institutes of Health. Patients in the control arm will receive the carrier protein and granulocyte colony-stimulating factor (Neupogen) to stimulate or boost an immune system response. Two-thirds of the participants will enter the experimental arm of the trial, thereby allowing more patients to obtain the vaccine than the 50% usually given an experimental therapy in clinical trials. Kwak believes this attractive tactic will increase the number of trial enrollees.
Kwak expects the trial to last from 6 to 8 years, depending on patient accrual and the vaccines continued effectiveness.