Their study, published in the September issue of Nature Medicine, has both important basic science and clinical implications, researchers say. It demonstrates that few, if any, B cells are needed to trigger an effective T-cell immune response - a finding which overturns the commonly accepted notion that both are needed to prime the human immune system. The article will be available online on Aug. 21, 2005, at noon CDT.
Their research also tests the use of personalized vaccines to help lymphoma patients fend off a recurrence of their cancer after treatment. Several such cancer vaccines are in human testing. In this study, conducted at the Center for Cancer Research, National Cancer Institute, treatment with a B-cell depleting treatment regimen followed by an experimental vaccine resulted in an impressive 89 percent survival rate at 46 months for 26 patients with mantle cell lymphoma, which is difficult to control.
"This is the first human cancer vaccine study to see T-cell responses in the absence of B cells, and this paves the way to use vaccines in a number of hematological cancers that are treated by eliminating diseased B cells," says the study's first author, Sattva Neelapu, M.D., an assistant professor in the Department of Lymphoma at M. D. Anderson.
Those cancers include forms of lymphoma and leukemia in which the cancer evolves in B-cell lymphocytes, white blood cells whose job is to produce antibodies that activate a response by the immune system. New treatments, such as rituximab, are designed to completely wipe out diseased (as well as healthy) B cells and can prolong patient survival. However, because researchers were concerned that B-cell depletion from rituximab may impede immune responses to cancer vaccines, and animal studies were contradictory, rituximab has been omitted from lymphoma vaccine studies, according to Wyndham Wilson, M.D., Ph.D., the study's principal investigator and Chief, Lymphoid Malignancies Therapeutic Section, NCI.
This question has now been answered, says senior author Larry Kwak, M.D., Ph.D., professor and chair of the Department of Lymphoma at M. D. Anderson. "We were frankly surprised to find that B cells were coming back in patients that were already primed to fight their tumors," he says. "Now we know B cells are not needed for T-cell immunity."
The study was designed to address the immunological effects of B-cell depletion and to assess the use of idiotype vaccine in mantle cell lymphoma, a rare type of non-Hodgkin's lymphoma for which there is no effective long-term therapy - the majority of patients relapse and succumb to their disease. Kwak helped develop the vaccine while he worked at the National Cancer Institute (NCI) before moving to M. D. Anderson. The so-called "idiotype" vaccine is tailored to each patient, based on the specific antigens present on the outside of the diseased B cells. The vaccine is designed to alert a patient's immune system to those antigens, and train it to destroy these cells whenever they appear.
The vaccine was originally tested for use in follicular lymphoma, and was subsequently licensed by the NCI to Accentia Biopharmaceuticals. That company, for which Kwak now consults, is testing it in a Phase III clinical trial. Besides that vaccine, known by the name Biovaxid, two other customized lymphoma vaccines are now being tested in the United States, and each differs only in the way that they are produced.
In this Phase I study, researchers prepared an individualized vaccine for each patient based on the specific antigens present on their cancerous B cells. The vaccine was given to the patients three months after chemotherapy/rituximab treatment, and five doses in all were given at monthly intervals.
"After the third vaccination, we began to see T-cell responses. An antibody response to the tumor produced by recovering B cells was seen after the fourth or fifth vaccination," says Neelapu.
That antibody response was unexpected, researchers say. "We don't know how it happened," Neelapu says. "It may be that some precursor B cells were being primed or that there were very small numbers of B cells remaining in lymph nodes or other compartments that were not depleted. Or other immune cells, such as dendritic cells, may have taken up antigen presenting cell function."
Although several patients have relapsed for reasons that are unclear, "so many of these patients continue to be alive that it is quite possible the vaccine did modify the natural history of the disease," Kwak says. "We can't over interpret this single study, but these patients may have done better than expected."
Typical overall survival for mantle cell lymphoma is 50 percent at three years, Wilson says.
M. D. Anderson researchers are already working on improving the vaccine before testing it further.
Co-authors of the study include, from the NCI: Carol Kobrin, Ph.D.; Craig Reynolds, Ph.D.; John Janik, M.D.; Kieron Dunleavy, M.D.; Therese White; Linda Harvey; Robin Pennington; Maryalice Stetler-Stevenson, M.D., Ph.D.; Elaine Jaffe, M.D.; Seth Steinberg, Ph.D.; Ronald Gress, M.D.; and Fran Hakim, Ph.D.
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