Phase II Cancer Vaccine Trial for B-Cell Lymphoma

National Cancer Institute
Tuesday, 8 December 1998

Since launching the nation's first phase II cancer vaccine trial for B-cell lymphoma in 1994, researchers at the National Cancer Institute (NCI) have vaccinated 21 patients with this common blood-cell tumor that strikes an estimated 41,000 Americans each year. An additional 30 patients will be vaccinated over the next two years.

The treatment vaccine, which is custom-made from a patient's own tumor, is approved for experimental use by the U.S. Food and Drug Administration for low-grade B-cell lymphomas. These tumors, while slow-growing, have a high rate of recurrence and account for roughly two-thirds of all lymphomas.

All of the patients treated to date had minimal disease or were in complete remission after a standard four-drug chemotherapy regimen at the time vaccine therapy began.

"Essentially, what we're doing is presenting 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. By selecting only newly diagnosed patients, Kwak added, researchers maximized the likelihood that the vaccine would produce a positive immune response.

B-cell lymphoma is a cancer of the lymph glands caused by unruly growth of B cells, white blood cells that produce the body's disease fighting antibodies. To produce a vaccine against the disease, Kwak and his colleagues fused cells taken from the tumors of individual patients to antibody-producing mouse cells which "immortalize" production of tumor proteins. These proteins were then shed into a tissue culture fluid, from which researchers plucked out a particular protein of interest — in this case a receptor molecule on the outer coating of 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 marker."

After obtaining the individual receptor molecule from each patient's tumor, the investigators coupled it to a highly immunogenic carrier protein. Then, to heighten visibility of these marked B cells and to provoke a vigorous immune response, they also added an adjuvant or immune system booster.

For the phase II trials, the immunogenic receptor molecule was coupled with granulocyte colony-stimulating factors (GM-CSF) a substance that stimulates blood-cell production and had the "most promise" in preclinical animal studies, according to Kwak. GM-CSF is a potent adjuvant and has elicited strong T-cell responses, he said. T cells are the white blood cells that orchestrate the immune response.

Patients receiving the experimental vaccine were given an initial injection after six months of chemotherapy, followed by booster shots for six months. Perhaps as many as 25,000 of the 41,000 patients diagnosed each year with lymphoma are eligible for the study, Kwak said. There were several exclusion criteria: Patients could not be positive for the human immunodeficiency virus; they had to have abnormal lymph nodes accessible for biopsy to make the vaccine; and they were newly diagnosed with no prior cancer treatment These same exclusion criteria will apply to the remaining 30 patients being enrolled in the trial.

Because lymphomas can recur after many years in remission, Kwak and his colleagues have established surrogate endpoints by which to measure the vaccine's success. By using the technology tool of the polymerase chain reaction (PCR) to detect chromosomal or molecular changes, researchers determined that they have been successful in eradicating microscopic disease. Cancerous cells are PCR positive for these changes; noncancerous cells are not.

The development of anti-cancer vaccines is a high priority area 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 that have already developed. Moreover, this approach "establishes a principle [for a therapeutic vaccine] that some day may be applied to more common tumors," such as prostate, breast, and lung cancers, Kwak said.

For more information, or to contact National Cancer Institute, see their website at: www.cancer.gov