© 2003 by Oxford University Press
Journal of the National Cancer Institute, Vol. 95, No. 7, 548-555,
April 2, 2003
© 2003 Oxford University Press
ARTICLE |
Antitumor Immunity After Vaccination With B Lymphoma Cells Overexpressing a Triad of Costimulatory Molecules
Affiliations of authors: J. Briones, J. M. Timmerman, R. Levy, Division of Oncology, Stanford University School of Medicine, Stanford, CA; D. L. Panicalli, Therion Biologics Corporation, Cambridge, MA.
Correspondence to: Ronald Levy, M.D., Division of Oncology, CCSR 1126, 269 Campus Dr., Stanford University School of Medicine, Stanford, CA 94305-5151 (e-mail: levy{at}stanford.edu).
Background: The costimulatory molecules B7-1, intercellular adhesion molecule-1 (ICAM-1), and leukocyte function-associated antigen-3 (LFA-3) play pivotal roles in the activation of T cells. We investigated whether in vivo vaccination with lymphoma cells infected with a recombinant, nonreplicating fowlpox (FP) virus encoding this triad of costimulatory molecules (TRICOM) could stimulate lymphoma-specific immunity. Methods: TRICOM-infected A20 B lymphoma cells were analyzed for expression of B7-1, ICAM-1, and LFA-3. Mice (10 per group) were vaccinated with irradiated A20 cells infected with either the TRICOM vector or the wild-type FP virus (WT-FP), challenged with live A20 tumor cells, and followed for survival. Mice with established A20 tumors were also treated with irradiated TRICOM-infected A20 cells. Survival curves were compared with the log-rank statistic. The mechanism of the antitumor effect was studied by in vivo depletion of CD4+ and CD8+ T cells and in vitro cytotoxicity assays. All statistical tests were two-sided. Results: A20 tumor cells infected with TRICOM expressed high levels of B7-1, ICAM-1, and LFA-3. Mice vaccinated with irradiated TRICOM-infected A20 cells had prolonged survival relative to mice vaccinated with WT-FP-infected cells (80% versus 20% survival at 110 days; P<.001). In mice with established tumors, tumor growth was slower in those treated with TRICOM-infected tumor cells than in those treated with WT-FP-infected cells, and this treatment provided a survival advantage (P<.001). Depletion of CD4+ or CD8+ T cells reduced the antitumor immunity provided by the tumor cell–TRICOM vaccine, and lymphocytes from vaccinated mice displayed in vitro cytotoxic activity toward A20 cells. Conclusions: Increasing expression of costimulatory molecules on B lymphoma cells by infection with a recombinant FP virus encoding B7-1, ICAM-1, and LFA-3 stimulates antitumor immune responses in vivo and may provide a novel strategy for treating patients with B-cell malignancies.
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