Lymphoma Vaccine Enters Large-Scale Clinical Trials

    For the first time, results of a recently completed lymphoma cancer vaccine study show that there is a clear anti-tumor 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 NCI said that on the basis of these promising results, it will launch a large-scale, randomized, phase III clinical trial in the near future to definitively test the experimental vaccine, which is custom-made from patients' own tumors.

   In the October Nature Medicine, *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 fifty-fifty 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.

*The article is titled "Complete Molecular Remissions Induced by Patient-Specific Vaccination Plus Granulocyte-Monocyte Colony-Stimulating Factor Against Lymphoma." The authors are Maurizio Bendandi, Christopher D. Gocke, Carol B. Kobrin, Floyd A. Benko, Lars A. Sternas, Robin Pennington, Thelma M. Watson, Craig W. Reynolds, Barry L. Gause, Patricia L. Duffy, Elaine S. Jaffe, Stephen P. Creekmore, Dan L. Longo, and Larry W. Kwak. It appears in Nature Medicine, Vol. 5, No. 10, October 1999.*

For more information about cancer visit NCI's Web site for patients, public, and the mass media at:  http://www.nci.nih.gov.

Phase II Cancer Vaccine for B-Cell Lymphoma

   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 about cancer visit NCI's Web site for patients, public and the mass media at:  http://rex.nci.nih.gov or NCI's main Web site at:  http://www.nci.nih.gov