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Synergism between cytosine-guanine oligodeoxynucleotides and monoclonal antibody in the treatment of lymphoma.

Synthetic oligodeoxynucleotides containing unmethylated cytosine-guanine dinucleotides (CpG ODN) are potent immunostimulatory agents that can activate various immune cell subsets. We have found that CpG ODN show a variety of effects that could be useful in enhancing the efficacy of antibody therapy of lymphoma. In a mouse model, CpG ODN alone had no effect on survival of animals inoculated with lymphoma. In contrast, CpG ODN plus monoclonal antibody (MAb) was more effective at inhibiting tumor growth than MAb alone or MAb plus control ODN. Cytosine-guanine ODN plus MAb cured mice with a large tumor burden that could not be cured with MAb therapy alone. We also evaluated the effects of CpG ODN on the phenotype of human malignant B cells. Cytosine-guanine ODN upregulated the expression of a number of antigens, including CD20. The upregulation of CD20 was most extensive in cells that had low baseline expression of this antigen. We conclude that CpG ODN enhances the efficacy of MAb in a murine lymphoma model, most likely by activating effector cells, and upregulates expression of CD20 on primary human malignant B cells. Given the effects of CpG ODN on both target antigen expression and effector-cell function, further evaluation of the combination of CpG ODN plus rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA) and CpG ODN plus other MAbs is warranted.