ReviewCombined yeast-derived β-glucan with anti-tumor monoclonal antibody for cancer immunotherapy
Introduction
Humanized anti-tumor monoclonal antibody (mAb) therapy has been widely used to treat cancer (Adams et al., 2005). The effector mechanisms mediated by these anti-tumor mAbs are diverse and include antagonizing receptor tyrosine kinases that are vital for tumor cell proliferation and transformation (Zhang et al., 2003), directly inducing tumor cell apoptosis (Johnson et al., 2003), and eliciting immunological effects such as Ab-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) (Gelderman et al., 2004). However, mAb therapy is not uniformly effective, even in patients whose tumors express a high level of tumor antigen. Most of these mAbs are used in combination with chemotherapy drugs to further their therapeutic efficacy (Sobrero et al., 2008). However, combination therapy of anti- tumor mAb with such agents also significantly increases severalty of adverse effects, thus limiting its utilization in a greater number of cancer patients.
Many efforts have been made to maximize therapeutic efficacy of anti-tumor mAb with limited adverse effect. For example, tetravalent anti-tumor mAb can increase its half-life in the circulation and augment its anti-tumor efficacy (Li, 2008, Meng, 2004). In addition, anti-tumor mAbs can be conjugated with toxin to increase tumor killing activity (Senter et al., 1989). Studies are also being carried out to augment the immunological effect of anti-tumor mAbs, such as in ADCC and/or CDC (Gelderman, 2004, Hinton, 2004, Hinton, 2006). Over the past decade, we have demonstrated that yeast-derived β-glucan is capable of augmenting anti-tumor mAb efficacy to treat cancer (Hong, 2003, Hong, 2004, Yan, 1999). Other investigators have showed that barley β-glucan has similar effects (Cheung et al., 2002a, Cheung et al., 2002b, Modak, 2005). Further mechanistic studies demonstrate that β-glucan in combination with complement-activating mAbs elicits complement receptor 3 (CR3)-dependent cellular cytotoxicity (CR3-DCC) (Hong, 2004, Li, 2006).
β-glucans are biological response modifiers (BRMs) and have been used for cancer treatment for more than 40 years particularly in Asia with varying and unpredictable efficacy (Yan et al., 2005). In vitro and in vivo studies have shown that soluble, low molecular weight β-glucan binds to its receptor CR3 (CD11b/CD18, Mac-1, αMβ2-integrin) (Thornton, 1996, Xia, 1999). CR3, a member of the β2-integrin family, is a multifunctional adhesion molecule in which a common β2 (CD18) subunit is non-covalently bound to the αM subunit (CD11b) (Ross, 2000). A previous study demonstrated that the ability of CR3 to bind diverse ligands is mainly contributed to a consensus-binding site within CD11b (Yakubenko et al., 2002). Ligands for the inserted (I) domain of CD11b include complement activation component iC3b, intercellular adhesion molecule-1 (ICAM-1), fibrinogen, factor X, and heparin (Diamond, 1995, Diamond, 1993). Lectin-like domain (LLD), which is located proximal to the membrane, binds microbial polysaccharides such as β(1,3)-linked glucose polymers (β-glucan). Dual ligation of CR3 leads to degranulation and cytotoxic effects (Li et al., 2006).
Combined therapy of β-glucan with anti-tumor mAbs has been studied in a variety of murine syngeneic tumors (Hong, 2003, Hong, 2004, Yan, 1999) as well as human carcinoma xenograft models (Cheung et al., 2002a, Cheung et al., 2002b, Li, 2007a, Modak, 2005, Salvador, 2008) to demonstrate its therapeutic efficacy. The FDA has approved its clinical investigation in Phase I/II trials. In this review, we focus on yeast-derived β-glucan and discuss its composition, mechanism of action, and preclinical animal studies.
Section snippets
β-glucan sources and structure
β-glucans are polysaccharides found as constituents in a variety of plants and microorganisms, including oat, barley, mushroom, seaweed, some bacteria, and yeast (Gawronski, 1999, Wasser, 1999). β-glucans from various sources are differential in their structure, conformation, and thus biological activity. Oat and barley β-glucans are primarily linear with large regions of β(1,4) linkages; mushroom and fungus β-glucans have the β(1,3) backbone branched with short β(1,6)-linked side chains (
Mechanisms of action for the combined β-glucan and anti-tumor mAb immunotherapy
CR3-DCC is a critical mechanism for killing microorganisms (Ross et al., 1987). Following mAb binding to the surface antigen, the activated complement pathway leads to iC3b deposition on the microorganisms. The iC3b-opsonized microorganisms can be efficiently recognized by leukocyte CR3. However, induction of CR3-DCC requires dual occupation of CR3 to both iC3b and β-glucan, which exists in the cell walls of microorganisms. The binding of CR3 to iC3b is not sufficient for leukocytes to kill
Pre-clinical human carcinoma xenograft models
Immunotherapy with β-glucan substantially enhances the therapeutic efficacy of anti-tumor mAb in the experimental murine breast, lung and lymphoma tumor models. To facilitate translation from preclinical models to clinical application, human carcinoma-challenged xenograft models were established in severe combined immunodeficient (SCID) mice. The human non-small cell lung carcinoma (NSCLC) cell line NCI-H23 was implanted in SCID mice to study the therapeutic efficacy of the combined therapy of
Neutrophils are the effector cells for β-glucan-mediated antitumor therapy
Although β-glucan has been found to prime CR3 of macrophages, neutrophils and NK cells in vitro, neutrophils have been distinguished as the primary effector cells in the immune response elicited by combined β-glucan plus anti-tumor mAb therapy (Allendorf, 2005, Hong, 2003). This was illustrated by the observed reversal of combined β-glucan with anti-tumor mAb therapeutic effectiveness in GR-1 treated, granulocyte-depleted animals (Allendorf et al., 2005). The critical components for enlisting
Another potential therapeutic benefit of β-glucan treatment
Thus far, neutrophils have proven to be efficient tumor cell killing innate effector cells when primed with β-glucan and administered in conjunction with anti-tumor mAbs. The addition of PGG β-glucan to mAb cancer treatment adds therapeutic advantages without adverse side effects to the patients. Studies are showing that not only may β-glucan aid in tumor targeting and destruction for eradication, but after chemotherapeutic treatment or radiation therapy, β-glucan can hasten bone marrow
Current and future challenges
β-glucan has demonstrated its synergistic effect with currently clinically available anti-tumor mAbs in tumor therapy. The novel mechanism mediated by this combination therapy via innate effector neutrophil CR3-DCC would not interfere with other killing mechanisms elicited by anti-tumor mAb itself. Any anti-tumor mAb that is capable of activating complement could be used in combination with β-glucan for tumor therapy. In addition to current FDA-approved anti-tumor Abs, there are also more and
Acknowledgments
This research was supported by grants from the National Institutes of Health R01 CA86412 and the Kentucky Lung Cancer Research Board.
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