Review
Combined yeast-derived β-glucan with anti-tumor monoclonal antibody for cancer immunotherapy

https://doi.org/10.1016/j.yexmp.2009.01.006Get rights and content

Abstract

β-glucan is an immuno-stimulating agent that has been used to treat cancer and infectious disease for many years with varying and unpredictable efficacy. Recent studies have unraveled the action mode of yeast-derived β-glucan in combination with anti-tumor monoclonal antibodies (mAbs) in cancer therapy. It has demonstrated that particulate or large molecular weight soluble β-glucans are ingested and processed by macrophages. These macrophages secrete the active moiety that primes neutrophil complement receptor 3 (CR3) to kill iC3b-opsonized tumor cells. In vitro and in vivo data demonstrate that successful combination therapy requires complement activation and deposition on tumors and CR3 expression on granulocytes. Pre-clinical animal studies have demonstrated the efficacy of combined β-glucan with anti-tumor mAb therapy in terms of tumor regression and long-term survival. Clinical trials are underway using anti-epidermal growth factor receptor mAb (cetuximab) in combination with β-glucan for metastatic colorectal cancer. This review provides a brief overview of this combination therapy in cancer and describes in detail the β-glucan composition and structure, mechanism of action, and preclinical studies in human carcinoma xenograft models. It is proposed that the addition of β-glucan will further improve the therapeutic efficacy of anti-tumor mAbs in cancer patients.

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.

References (74)

  • LobergR.D.

    Inhibition of decay-accelerating factor (CD55) attenuates prostate cancer growth and survival in vivo

    Neoplasia

    (2006)
  • MacorP.

    Complement as effector system in cancer immunotherapy

    Immunol. Lett.

    (2007)
  • ModakS.

    Rituximab therapy of lymphoma is enhanced by orally administered (1–>3),(1–>4)-D-beta-glucan

    Leuk. Res.

    (2005)
  • YakubenkoV.P.

    A molecular basis for integrin alphaMbeta 2 ligand binding promiscuity

    J. Biol. Chem.

    (2002)
  • YanJ.

    Critical role of Kupffer cell CR3 (CD11b/CD18) in the clearance of IgM-opsonized erythrocytes or soluble beta-glucan

    Immunopharmacology

    (2000)
  • AdamsG.P.

    Monoclonal antibody therapy of cancer

    Nat. Biotechnol.

    (2005)
  • AllendorfD.J.

    C5a-mediated leukotriene B4-amplified neutrophil chemotaxis is essential in tumor immunotherapy facilitated by anti-tumor monoclonal antibody and {beta}-glucan

    J. Immunol.

    (2005)
  • BaranJ.

    Oral beta-glucan adjuvant therapy converts nonprotective Th2 response to protective Th1 cell-mediated immune response in mammary tumor-bearing mice

    Folia Histochem. Cytobiol.

    (2007)
  • BellamyW.T.

    Expression of vascular endothelial growth factor and its receptors in hematopoietic malignancies

    Cancer Res.

    (1999)
  • BjorgeL.

    Complement-regulatory proteins in ovarian malignancies

    Int. J. Cancer

    (1997)
  • BoscardinS.B.

    Antigen targeting to dendritic cells elicits long-lived T cell help for antibody responses

    J. Exp. Med.

    (2006)
  • BrownG.D.

    Immune recognition. A new receptor for beta-glucans

    Nature

    (2001)
  • BrownG.D.

    Dectin-1 mediates the biological effects of beta-glucans

    J. Exp. Med.

    (2003)
  • BuettnerR.

    Activated signal transducers and activators of transcription 3 signaling induces CD46 expression and protects human cancer cells from complement-dependent cytotoxicity

    Mol. Cancer Res.

    (2007)
  • CheungN.K.

    Oral (1–>3),(1–>4)-beta-D-glucan synergizes with antiganglioside GD2 monoclonal antibody 3F8 in the therapy of neuroblastoma

    Clin. Cancer Res.

    (2002)
  • CheungN.K.

    Orally administered beta-glucans enhance anti-tumor effects of monoclonal antibodies

    Cancer Immunol. Immunother.

    (2002)
  • CramerD.E.

    Mobilization of hematopoietic progenitor cells by yeast-derived beta-glucan requires activation of matrix metalloproteinase-9

    Stem Cells

    (2008)
  • DavisI.D.

    A phase I multiple dose, dose escalation study of cG250 monoclonal antibody in patients with advanced renal cell carcinoma

    Cancer Immun.

    (2007)
  • DecaussinM.

    Expression of vascular endothelial growth factor (VEGF) and its two receptors (VEGF-R1-Flt1 and VEGF-R2-Flk1/KDR) in non-small cell lung carcinomas (NSCLCs): correlation with angiogenesis and survival

    J. Pathol.

    (1999)
  • Di GaetanoN.

    Synergism between fludarabine and rituximab revealed in a follicular lymphoma cell line resistant to the cytotoxic activity of either drug alone

    Br. J. Haematol.

    (2001)
  • DiamondM.S.

    Heparin is an adhesive ligand for the leukocyte integrin Mac-1 (CD11b/CD1)

    J. Cell. Biol.

    (1995)
  • DiamondM.S.

    The I domain is a major recognition site on the leukocyte integrin Mac-1 (CD11b/CD18) for four distinct adhesion ligands

    J. Cell. Biol.

    (1993)
  • DonevR.M.

    p53 regulates cellular resistance to complement lysis through enhanced expression of CD59

    Cancer Res.

    (2006)
  • DuttaT.

    Robust ability of IFN-gamma to upregulate class II MHC antigen expression in tumor bearing rat brains

    J. Neurooncol.

    (2003)
  • FoonK.A.

    Immune response to the carcinoembryonic antigen in patients treated with an anti-idiotype antibody vaccine

    J. Clin. Invest.

    (1995)
  • GantnerB.N.

    Collaborative induction of inflammatory responses by dectin-1 and Toll-like receptor 2

    J. Exp. Med.

    (2003)
  • GawronskiM.

    Microfibrillar structure of PGG-glucan in aqueous solution as triple-helix aggregates by small angle x-ray scattering

    Biopolymers

    (1999)
  • Cited by (0)

    View full text