| Beta-glucans, biological response modifiers (BRMs) derived from the cell walls of yeast, cereal grains, mushrooms, and seaweed, have been used for decades throughout Asia for the treatment of a variety of malignancies. There is growing evidence at both the cellular and molecular levels that the mechanism of action of these compounds is the activation of leukocyte complement receptor 3 (CR3, CD11b/CD18, Mac-1, alphambeta2 integrin) thus enabling these cells to kill tumors opsonized with the complement fragment iC3b.; Many tumors activate complement via the classical pathway as a consequence of the expression of surface antigens (Ags) that are recognized by natural antibodies (Abs). Ab recognition of tumors has been optimized clinically through the development of monoclonal antibodies (mAbs) directed against tumor associated antigens (TAA). Trastuzumab is a mAb that recognizes Her-2/neu, a TAA that is over-expressed in up to one third of breast and ovarian cancers. Over-expression of Her-2/neu is uniformly a poor prognostic factor. Trastuzumab has been observed clinically to induce significant tumor regression and prolong survival in combination with paclitaxel in patients with Her-2+ metastases. However, the effector mechanism of trastuzumab, as it is utilized currently, is the inhibition of growth factor receptor activity. Immune effector mechanisms including ADCC and CDC are not believed to mediate trastuzumab efficacy in vivo. However, the addition of beta-glucan re-engages the immune system as an effector mechanism of trastuzumab, and other anti-tumor mAbs, by mediating CR3-dependent cellular cytotoxicity (CR3-DCC).; The mechanism of action of large molecular weight beta-glucans was shown to be dependent on the processing of the parent molecules into small molecular weight b-glucan moieties that were capable of priming neutrophil CR3 for cytotoxicity. In addition, neutrophils were determined to be necessary for beta-glucan immunotherapy because of their role in mediating CR3-DCC of iC3b-opsonized tumors. Furthermore, an important role for neutrophil chemotaxis in beta-glucan immunotherapy was described, and a novel relationship between C5a and LTB4 was described.; These mechanistic studies were applied to a xenograft model of human Her-2+ cancer. Among the differences noted between the Her-2 + xenograft and syngeneic tumors that had been utilized previously in the lab was the dramatic immunosuppression mediated by the human tumor cells. To that end, beta-glucan immunotherapy was modified with the intent of altering the tumor microenvironment from a phenotype of cancer promoting chronic inflammation, to a phenotype of acute inflammation that would promote effective anti-tumor immunity. These observations provided useful mechanistic and pre-clinical data that will contribute to the means by which beta-glucan immunotherapy will be utilized clinically. |
