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The role played by B cells in cancer biology is complex and somewhat controversial. Previous studies using genetically engineered mice suggest that B cells may be immunosuppressive and inhibit tumor rejection. However, the effects of B-cell depletion employing an antibody in mice bearing solid tumors has not been tested owing to difficulties in making an effective antimouse CD20 antibody (similar to rituximab). Injection of a newly developed antimouse CD20 antibody was effective in depleting circulating B cells from blood and lymph nodes, although depletion was less complete in the spleen. B-cell depletion slowed the growth of new solid tumors (not expressing CD20) and retarded the growth of established tumors but did not induce tumor regression. However, when the antibody was combined with an active immunotherapy approach using an adenovirus vaccine expressing the human papilloma virus-E7 gene (Ad.E7) in mice bearing TC1 tumors (murine lung cancer cells expressing human papilloma virus-E7), we noted enhanced antitumor effects and increased numbers of tetramer+/CD8+ T cells within the spleens and activated CD8+ T cells within tumors. B-cell depletion using an anti-CD20 antibody was thus effective in retarding tumor growth in multiple solid tumor models and augmenting immunotherapy in a tumor vaccine model. These studies raise the possibility that B-cell depletion may be a useful adjunct in human immunotherapy trials.