HOUSTON - Researchers at The University of Texas M. D. Anderson CancerCenter and the National Cancer Institute have found that anexperimental vaccine can prime the immune system to help fight anaggressive form of lymphoma, even though prior therapy had eliminatedvirtually all of the B cells thought necessary to mount such a defense.
Their study, published in the September issue of Nature Medicine,has both important basic science and clinical implications, researcherssay. It demonstrates that few, if any, B cells are needed to trigger aneffective T-cell immune response - a finding which overturns thecommonly accepted notion that both are needed to prime the human immunesystem. The article will be available online on Aug. 21, 2005, at noonCDT.
Their research also tests the use of personalized vaccines tohelp lymphoma patients fend off a recurrence of their cancer aftertreatment. Several such cancer vaccines are in human testing. In thisstudy, conducted at the Center for Cancer Research, National CancerInstitute, treatment with a B-cell depleting treatment regimen followedby an experimental vaccine resulted in an impressive 89 percentsurvival 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-cellresponses in the absence of B cells, and this paves the way to usevaccines in a number of hematological cancers that are treated byeliminating diseased B cells," says the study's first author, SattvaNeelapu, M.D., an assistant professor in the Department of Lymphoma atM. D. Anderson.
Those cancers include forms of lymphoma and leukemia in whichthe cancer evolves in B-cell lymphocytes, white blood cells whose jobis to produce antibodies that activate a response by the immune system.New treatments, such as rituximab, are designed to completely wipe outdiseased (as well as healthy) B cells and can prolong patient survival.However, because researchers were concerned that B-cell depletion fromrituximab may impede immune responses to cancer vaccines, and animalstudies were contradictory, rituximab has been omitted from lymphomavaccine studies, according to Wyndham Wilson, M.D., Ph.D., the study'sprincipal investigator and Chief, Lymphoid Malignancies TherapeuticSection, NCI.
This question has now been answered, says senior author LarryKwak, M.D., Ph.D., professor and chair of the Department of Lymphoma atM. D. Anderson. "We were frankly surprised to find that B cells werecoming back in patients that were already primed to fight theirtumors," he says. "Now we know B cells are not needed for T-cellimmunity."
The study was designed to address the immunological effects ofB-cell depletion and to assess the use of idiotype vaccine in mantlecell lymphoma, a rare type of non-Hodgkin's lymphoma for which there isno effective long-term therapy - the majority of patients relapse andsuccumb to their disease. Kwak helped develop the vaccine while heworked 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 Bcells. The vaccine is designed to alert a patient's immune system tothose antigens, and train it to destroy these cells whenever theyappear.
The vaccine was originally tested for use in follicularlymphoma, and was subsequently licensed by the NCI to AccentiaBiopharmaceuticals. That company, for which Kwak now consults, istesting it in a Phase III clinical trial. Besides that vaccine, knownby the name Biovaxid, two other customized lymphoma vaccines are nowbeing tested in the United States, and each differs only in the waythat they are produced.
In this Phase I study, researchers prepared an individualizedvaccine for each patient based on the specific antigens present ontheir cancerous B cells. The vaccine was given to the patients threemonths after chemotherapy/rituximab treatment, and five doses in allwere 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 wasseen after the fourth or fifth vaccination," says Neelapu.
That antibody response was unexpected, researchers say. "Wedon't know how it happened," Neelapu says. "It may be that someprecursor B cells were being primed or that there were very smallnumbers of B cells remaining in lymph nodes or other compartments thatwere not depleted. Or other immune cells, such as dendritic cells, mayhave taken up antigen presenting cell function."
Although several patients have relapsed for reasons that areunclear, "so many of these patients continue to be alive that it isquite possible the vaccine did modify the natural history of thedisease," Kwak says. "We can't over interpret this single study, butthese 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 studyinclude, from the NCI: Carol Kobrin, Ph.D.; Craig Reynolds, Ph.D.; JohnJanik, M.D.; Kieron Dunleavy, M.D.; Therese White; Linda Harvey; RobinPennington; 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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