NCI Plans a Large Phase III Trial of Lymphoma Vaccine

BETHESDA, Md—The National Cancer Institute (NCI) has announced plans for a large-scale, randomized phase III trial of a patient-specific therapeutic vaccine against B-cell lymphoma. The decision came as the result of findings from a recently completed phase II study at the NCI.

In the phase II trial, 20 follicular lymphoma patients in first complete remission following chemotherapy were vaccinated with a protein from their own cancer cells; 18 of the 20 patients remained in remission and had no evidence of microscopic disease an average of 4 years after they began therapy.

Because these tumors can recur after many years in remission, the researchers established surrogate endpoints to measure the vaccine’s success. Using polymerase chain reaction (PCR), they measured chromosomal changes—specifically, the t(14;18) gene translocation marker for lymphoma—in the peripheral blood for evidence of residual tumor cells or microscopic disease. Cancerous cells are PCR-positive for these molecular 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 tumor cells place them at increased risk of relapse. However, 8 of the 11 patients (75%) 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,” has yet to be determined, Larry W. Kwak, MD, PhD, a senior investigator in the Institute’s Division of Clinical Trials and the study’s principal investigator, said in an NCI press release. But, Dr. Kwak added, 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 antitumor activity, specifically, the induction of tumor-specific cytotoxic T lymphocytes.

The New Study

The NCI plans to enroll 390 patients in the forthcoming study, which will be conducted at the National Institutes of Health’s Warren G. Magnuson Clinical Center and at a consortium of North American medical centers. Consortium members will be announced later.

Two thirds of the patients will be randomized to the vaccine group. NCI departed from the usual 50-50 randomization format to “make the trial more attractive to patients,” Dr. Kwak said.

The study will enroll patients diagnosed with low-grade follicular lymphoma. (About 25,000 of the 41,000 B-cell lymphomas diagnosed annually in the United States are low-grade cases.) Depending on the accrual rate and whether the vaccine continues to prove effective, the trial will last 6 to 8 years.

Creating the Vaccine

Researchers create the vaccine by fusing tumor cells taken from individual patients to antibody-producing mouse cells, which then produce large quantities of tumor protein. From this mix, they extract a specific protein—the surface receptor (M protein) molecule on the outer coating of B cells.

“This receptor molecule is exquisitely specific for this type of tumor because it is an immunoglobulin,” Dr. 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 surface receptor molecule is then mixed with a highly immunogenic carrier protein (keyhole limpet hemocyanin) and an immune system adjuvant to create an individualized vaccine for each patient.

“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,” Dr. Kwak said. By selecting only newly diagnosed patients, he added, researchers maximize the likelihood that the vaccine will produce a positive immune response.

The new study will test this approach against a control arm, which will not receive the B-cell receptor molecule, but will get the carrier protein and granulocyte colony-stimulating factor (G-CSF) to boost the immune system. Following their initial injection, participants will receive booster shots for 4 months.

Findings of the initial NCI vaccine study were published in the October 1999 issue of Nature Medicine (Bendandi M, Gocke CD, Kobrin CB, et al: Complete molecular remissions induced by patient-specific vaccination plus granulocyte-monocyte colony-stimulating factor against lymphoma).