Carolina Salvador1, Bing Li, Richard Hansen, Daniel E Cramer, Maiying Kong, Jun Yan. 1. Tumor Immunobiology Program of the James Graham Brown Cancer Center and Division of Hematology/Oncology, Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Abstract
PURPOSE: Bevacizumab is a recombinant IgG1 humanized monoclonal antibody against vascular endothelial growth factor (VEGF). Its proposed mechanism of action is independent of immune effector functions. Many human carcinomas not only secrete VEGF but also express membrane-bound VEGF. In addition, VEGF receptors are expressed on tumor cells. It is hypothesized that bevacizumab could bind membrane-bound VEGF or VEGF-VEGF receptor complexes on tumors, thereby initiating potential immunologic consequences. We previously showed that yeast-derived beta-glucan functions with antitumor antibodies that activate complement to recruit complement receptor 3-expressing leukocytes capable of mediating complement receptor 3-dependent cellular cytotoxicity of tumors opsonized with iC3b. In the current study, the therapeutic efficacy mediated by combining bevacizumab with yeast-derived beta-glucan was studied in human carcinoma xenograft models. EXPERIMENTAL DESIGN: Human tumor cell lines were screened for membrane-bound VEGF expression both in vitro and in vivo. Complement activation mediated by bevacizumab was examined. Tumor cell lines positive or negative for membrane-bound VEGF expression were implanted in severe combined immunodeficient mice to establish xenograft models. Tumor-bearing mice were treated with different regimens. Tumor regression and long-term survival were recorded. RESULTS: Human ovarian carcinoma SKOV-3 cells expressed membrane-bound VEGF both in vitro and in vivo. Bevacizumab was bound to membrane-bound VEGF, activated complement, and synergized with beta-glucan to elicit cellular cytotoxicity in vitro. In vivo study showed that beta-glucan could significantly augment the therapeutic efficacy mediated by bevacizumab. CONCLUSIONS: Yeast-derived beta-glucan can synergize with anti-VEGF monoclonal antibody bevacizumab for the treatment of cancer with membrane-bound VEGF expression.
PURPOSE:Bevacizumab is a recombinant IgG1 humanized monoclonal antibody against vascular endothelial growth factor (VEGF). Its proposed mechanism of action is independent of immune effector functions. Many humancarcinomas not only secrete VEGF but also express membrane-bound VEGF. In addition, VEGF receptors are expressed on tumor cells. It is hypothesized that bevacizumab could bind membrane-bound VEGF or VEGF-VEGF receptor complexes on tumors, thereby initiating potential immunologic consequences. We previously showed that yeast-derived beta-glucan functions with antitumor antibodies that activate complement to recruit complement receptor 3-expressing leukocytes capable of mediating complement receptor 3-dependent cellular cytotoxicity of tumors opsonized with iC3b. In the current study, the therapeutic efficacy mediated by combining bevacizumab with yeast-derived beta-glucan was studied in humancarcinoma xenograft models. EXPERIMENTAL DESIGN:Humantumor cell lines were screened for membrane-bound VEGF expression both in vitro and in vivo. Complement activation mediated by bevacizumab was examined. Tumor cell lines positive or negative for membrane-bound VEGF expression were implanted in severe combined immunodeficientmice to establish xenograft models. Tumor-bearing mice were treated with different regimens. Tumor regression and long-term survival were recorded. RESULTS:Humanovarian carcinoma SKOV-3 cells expressed membrane-bound VEGF both in vitro and in vivo. Bevacizumab was bound to membrane-bound VEGF, activated complement, and synergized with beta-glucan to elicit cellular cytotoxicity in vitro. In vivo study showed that beta-glucan could significantly augment the therapeutic efficacy mediated by bevacizumab. CONCLUSIONS:Yeast-derived beta-glucan can synergize with anti-VEGF monoclonal antibody bevacizumab for the treatment of cancer with membrane-bound VEGF expression.
Authors: Alexei V Salnikov; Nils-Erik Heldin; Linda B Stuhr; Helge Wiig; Hanspeter Gerber; Rolf K Reed; Kristofer Rubin Journal: Int J Cancer Date: 2006-12-15 Impact factor: 7.396
Authors: Bing Li; Daniel J Allendorf; Richard Hansen; Jose Marroquin; Chuanlin Ding; Daniel E Cramer; Jun Yan Journal: J Immunol Date: 2006-08-01 Impact factor: 5.422
Authors: Christopher G Willett; Yves Boucher; Emmanuelle di Tomaso; Dan G Duda; Lance L Munn; Ricky T Tong; Daniel C Chung; Dushyant V Sahani; Sanjeeva P Kalva; Sergey V Kozin; Mari Mino; Kenneth S Cohen; David T Scadden; Alan C Hartford; Alan J Fischman; Jeffrey W Clark; David P Ryan; Andrew X Zhu; Lawrence S Blaszkowsky; Helen X Chen; Paul C Shellito; Gregory Y Lauwers; Rakesh K Jain Journal: Nat Med Date: 2004-01-25 Impact factor: 53.440
Authors: Feng Hong; Richard D Hansen; Jun Yan; Daniel J Allendorf; Jarek T Baran; Gary R Ostroff; Gordon D Ross Journal: Cancer Res Date: 2003-12-15 Impact factor: 12.701
Authors: Bing Li; Yihua Cai; Chunjian Qi; Richard Hansen; Chuanlin Ding; Thomas C Mitchell; Jun Yan Journal: Clin Cancer Res Date: 2010-09-20 Impact factor: 12.531
Authors: Anissa S H Chan; Takashi O Kangas; Xiaohong Qiu; Mark T Uhlik; Ross B Fulton; Nadine R Ottoson; Keith B Gorden; Yumi Yokoyama; Michael E Danielson; Trinda M Jevne; Kyle S Michel; Jeremy R Graff; Nandita Bose Journal: Front Oncol Date: 2022-05-26 Impact factor: 5.738
Authors: Shakeel Modak; Brian H Kushner; Kim Kramer; Andrew Vickers; Irene Y Cheung; Nai-Kong V Cheung Journal: Oncoimmunology Date: 2013-03-01 Impact factor: 8.110
Authors: M Thomas; P Sadjadian; J Kollmeier; J Lowe; P Mattson; J R Trout; M Gargano; M L Patchen; R Walsh; M Beliveau; J F Marier; N Bose; K Gorden; F Schneller Journal: Invest New Drugs Date: 2017-03-16 Impact factor: 3.850
Authors: Anissa S H Chan; Adria Bykowski Jonas; Xiaohong Qiu; Nadine R Ottoson; Richard M Walsh; Keith B Gorden; Ben Harrison; Peter J Maimonis; Steven M Leonardo; Kathleen E Ertelt; Michael E Danielson; Kyle S Michel; Mariana Nelson; Jeremy R Graff; Myra L Patchen; Nandita Bose Journal: PLoS One Date: 2016-11-03 Impact factor: 3.240