This proposal is a phase I trial of orally administered beta-glucan that can enhance the anti-tumor effects of anti-GD2 monoclonal antibody. (MoAb) in the therapy of neuroblastoma (NB). Beta-glucans are polysaccharides of low toxicity found in many common foods. Herbal medicines containing beta-glucans are used clinically as anti-tumor treatments by alternative medicine practitioners. In the laboratory, pure beta-glucans are used clinically as anti-tumor treatments by alternative medicine practitioners. In the laboratory, pure beta-glucans have been demonstrated to prime CR3 )C-receptor type 3, an iC3b-receptor) of circulating leukocytes (neutrophils, monocyte/macrophages, NK cells). These primed leukocytes can kill tumor cells targeted with iC3b through the activation fo complement by anti-cancer antibodies. Previous reports have shown that barley beta-glucans could prime leukocyte CR3 (CD11b/CD18; Mac-1; alphaMbeta2-integrin) for cytotoxicity of tumor cells in vitro, but only if the target cells were coated with iC3b, one of the ligands for CR3. In murine models, highly successful therapy with intravenous yeast beta-glucan required anti-tumor antibodies that could deposit IC3b, plus white cells that express CR3 receptors. The translation of these findings to the clinic has been hindered by the difficulty of isolating pharmaceutical grade soluble beta-glucans of the appropriate molecular weight for patient trials. Moreover, there are concerns about the practicality of a clinical drug that needs to be administered i.v. on a daily basis over prolonged periods of time. We have identified a beta-glucan, extracted from barley (Hordeum vulgare), that strongly enhances the effects of anti-cancer MoAbs. This effect is independent of tumor type. Human NB, melanoma, lymphoma, breast cancer and epidermoid carcinoma xenografts respond in the presence of anti-GD2, anti-GD3, anti-CD2-, anti-HER2 and anti-EGFR MoAbs, respectively. While complement activation is essential, the effect is independent of antibody dependent cell-mediated cytotoxicity (ADCC). Barley beta-glucan is highly soluble in water, extremely sable against heat and protease, inexpensive, easy to produce and purify, relatively non-allergenic, and has an excellent safety record when ingested. 3F8 is a murine IgG3 MoAb previously shown to activate human complement and ADCC. It targets efficiently to NB in patients and is clinically safe and efficacious. We plan to define the clinical toxicity of beta-glucan plus 3F8 and test if barley beta-glucan can enhance 3F8, in killing a tumor (i.e. NB) deficient in membrane complement resistance factors and thus allowing complement activation. These findings will have general implications for antibody and vaccine strategies in human cancer models, and the role of polysaccharides as complementary/herbal medicine in immune-based therapies.
|Modak, Shakeel; Kushner, Brian H; Kramer, Kim et al. (2013) Anti-GD2 antibody 3F8 and barley-derived (1 ? 3),(1 ? 4)-?-D-glucan: A Phase I study in patients with chemoresistant neuroblastoma. Oncoimmunology 2:e23402|
|Cheung, Nai-Kong V; Modak, Shakeel (2002) Oral (1-->3),(1-->4)-beta-D-glucan synergizes with antiganglioside GD2 monoclonal antibody 3F8 in the therapy of neuroblastoma. Clin Cancer Res 8:1217-23|
|Cheung, Nai-Kong V; Modak, Shakeel; Vickers, Andrew et al. (2002) Orally administered beta-glucans enhance anti-tumor effects of monoclonal antibodies. Cancer Immunol Immunother 51:557-64|