BETHESDA, MdThe 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
vaccines success. Using polymerase chain reaction (PCR), they
measured chromosomal changesspecifically, the t(14;18) gene
translocation marker for lymphomain 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 remissiona 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 Institutes Division of Clinical
Trials and the studys 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 Healths 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 proteinthe 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
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