Prevention of Epstein-Barr virus-induced human B-cell lymphoma in severe combined immunodeficient mice treated with CD3xCD19 bispecific antibodies, CD28 monospecific antibodies, and autologous T cells.

Abstract

Bispecific CD3 x antitumor antibodies in combination with coactivating CD28 antibodies can induce resting T cells to proliferate and to lyse syngeneic tumor cells (M. Azuma et al., J. Immunol., 150: 2091-2101, 1993; M. Azuma et al., J. Exp. Med., 177: 845-850, 1993). This combination of antibodies may therefore be useful for active immunotherapy of malignant tumors. In this study, we present a preclinical model to evaluate CD3xCD19 bispecific antibodies. We investigated whether bispecific antibodies prevent the development of malignant EBV-induced lymphomas in severe combined immunodeficient (SCID) mice which lack functional B and T lymphocytes (G. C. Bosma et al., Immunogenetics, 29: 54-57, 1989). SCID mice were engrafted (i.p.) with peripheral blood lymphocytes and EBV and treated after 3 days with CD3xCD19 bispecific antibodies and CD28 antibodies. Our data demonstrate that the growth of B cell lymphomas can be prevented in SCID mice by treatment with CD3xCD19 bispecific antibodies and that B-lymphoma-specific T cells can be recruited. In contrast to in vitro experiments, there was no clear effect of CD28 administration which is due to high expression of B7-1 on the transplanted B cells. Lymphoma-bearing mice had elevated titers of interleukin10 in the serum, in contrast to tumor-free animals. As shown by PCR analysis, there was no evidence of dormant B-lymphoma cells in specimens from surviving mice. In the spleen of surviving mice, rearranged human T-cell receptor gamma gene segments were detectable. Furthermore, mice that were initially treated with CD3xCD19 and CD28 antibodies did not develop lymphomas upon rechallenge with EBV-infected mononuclear cells of the same donor, whereas control animals did. Our results obtained from this autologous human B-lymphoma model have implications for the design and evaluation of new immunotherapeutic modalities for the treatment of human B-cell lymphoma with bispecific antibodies.