Research Abstract
β-Glucan Functions as an Adjuvant for Monoclonal Antibody Immunotherapy by Recruiting Tumoricidal Granulocytes as Killer Cells
Feng Hong,1,2 Richard D. Hansen,1 Jun Yan,1,2 Daniel J. Allendorf,2 Jarek T. Baran,1 Gary R. Ostroff,3 and Gordon D. Ross1,2
1James Graham Brown Cancer Center and 2Department of Microbiology and Immunology, University of Louisville, Louisville, Kentucky, and 3Biopolymer Engineering, Inc., Eagan, Minnesota
Cancer Research 63, 9023–9031, December 15, 2003]
The tumor-killing mechanisms available to monoclonal antibodies (mAbs; e.g., antagonism of growth factor receptors, antibody-dependent cell-mediated cytotoxicity) limit efficacy. Previous studies suggested that i.v. β-glucan might function as an adjuvant for antitumor mAbs. β- Glucan had been shown to function via the iC3b-receptor complement receptor 3 (CR3; CD11b/CD18) thereby enhancing leukocyte killing of tumor cells coated with iC3b via naturally occurring antitumor antibodies. Therapy with β-glucans was limited by levels of natural antibodies and by tumor escape through elimination of antigen-positive cells. Accordingly, it was hypothesized that β-glucan responses could be improved by combined administration with antitumor mAbs. Five tumor models were explored in BALB/c or C57Bl/6 mice using tumors that expressed either high levels of naturally occurring antigens (e.g., GD2 ganglioside) or recombinant human MUC1. In comparison with antitumor mAb or β-glucan alone, combined treatment with mAb plus β-glucan produced significantly greater tumor regression in all models that included mammary, s.c., and hepatic tumors. Tumor-free survival only occurred in models that incorporated stable expression of the target antigen. β-Glucan enhancement of the mAb tumoricidal response did not occur in mice deficient in either leukocyte CR3 (CD11b-/-) or serum C3, confirming the requirement for CR3 on leukocytes and iC3b on tumors. Granulocytes appeared to be primarily responsible for tumoricidal activity, because β-glucan therapeutic responses did not occur in granulocyte-depleted mice. These data suggest that the therapeutic efficacy of mAbs known to activate complement (e.g., Herceptin, Rituxan, and Erbitux) could be significantly enhanced if they were combined with β-glucan.