title: A cancer treatment based on synergy between anti-angiogenic and immune cell therapies.
abstract: A mathematical model integrating tumor angiogenesis and tumor-targeted cytotoxicity by immune cells was developed to identify the therapeutic window of two distinct modes to treat cancer: (1) an anti-angiogenesis treatment based on the monoclonal antibody bevacizumab that targets tumor vasculature, and (2) immunotherapy involving the injection of unlicensed dendritic cells to boost the anti-tumor adaptive response. The angiogenic cytokine Vascular Endothelial Growth Factor (VEGF) contributes to the immunosuppressive tumor microenvironment, which is responsible for the short-lived therapeutic effect of cancer-targeted immunotherapy. The effect of immunosuppression on the width of the therapeutic window of each treatment was quantified. Experimental evidence has shown that neutralizing immunosuppressive cytokines results in an enhanced immune response against infections and chronic diseases. The model was used to determine treatment protocols involving the combination of anti-VEGF and unlicensed dendritic cell injections that enhance tumor regression. The model simulations predicted that the most effective method to treat tumors involves administering a series of biweekly anti-VEGF injections to disrupt angiogenic processes and limit tumor growth. The simulations also verified the hypothesis that reducing the concentration of the immunosuppressive factor VEGF prior to an injection of unlicensed dendritic cells enhances the cytotoxicity of CD8+ T cells and results in complete tumor elimination. Feasible treatment protocols for tumors that are diagnosed late and have grown to a relatively large size were identified.
authors.affiliation: Department of Mathematics, East Los Angeles College, 1301 Avenida Cesar Chavez, Monterey Park, CA 91754, USA. Electronic address: lsoto@alumni.caltech.edu.
authors.forename: Luis
authors.initials: L
authors.lastname: Soto-Ortiz
authors.affiliation: Department of Biomedical Engineering, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Stacey D
authors.initials: SD
authors.lastname: Finley
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000276:immunology; D002452:Cell Count; D049109:Cell Proliferation; D003198:Computer Simulation; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D057131:Immune Evasion; D007165:Immunosuppression Therapy; D007167:Immunotherapy; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D020533:Angiogenesis Inhibitors; D000951:Antigens, Neoplasm; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A
keywords: Immunosuppression; Immunotherapy; Mathematical modeling; Monoclonal antibody; Tumor angiogenesis; VEGF
references.citation: J Exp Med. 2005 Oct 17;202(8):1075-85
references.pmid: 16230475
references.citation: J Theor Biol. 2009 Aug 21;259(4):820-7
references.pmid: 19446568
references.citation: J Theor Biol. 2014 Jun 21;351:74-82
references.pmid: 24594371
references.citation: Anticancer Res. 2009 Mar;29(3):881-8
references.pmid: 19414323
references.citation: Ann Oncol. 2011 Sep;22(9):1939-1947
references.pmid: 21289366
references.citation: CPT Pharmacometrics Syst Pharmacol. 2014 May 07;3:e113
references.pmid: 24806032
references.citation: PLoS One. 2015 Mar 18;10(3):e0120007
references.pmid: 25785600
references.citation: Bull Math Biol. 2011 Jan;73(1):2-32
references.pmid: 20225137
references.citation: Biochem Biophys Res Commun. 2005 Jul 29;333(2):328-35
references.pmid: 15961063
references.citation: Clin Cancer Res. 2007 Feb 15;13(4):1253-9
references.pmid: 17317837
references.citation: J Exp Clin Cancer Res. 2012 May 16;31:47
references.pmid: 22592077
references.citation: Bull Math Biol. 2012 Jul;74(7):1485-500
references.pmid: 22438084
references.citation: New J Sci. 2014 Jan 5;2014:
references.pmid: 24634791
references.citation: Immunol Cell Biol. 2005 Oct;83(5):451-61
references.pmid: 16174093
references.citation: Int J Radiat Oncol Biol Phys. 2001 Feb 1;49(2):597-604
references.pmid: 11173160
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: Gynecol Oncol. 2010 Dec;119(3):564-70
references.pmid: 20822802
references.citation: Cancer Metastasis Rev. 2006 Sep;25(3):323-31
references.pmid: 16983515
references.citation: J Clin Oncol. 2007 Apr 20;25(12):1489-97
references.pmid: 17372278
references.citation: J Clin Oncol. 2005 Mar 20;23(9):2078-93
references.pmid: 15774796
references.citation: Int J Biol Sci. 2012;8(7):964-78
references.pmid: 22811618
references.citation: Blood. 2003 Jun 15;101(12):4878-86
references.pmid: 12586633
references.citation: Vaccine. 2014 Apr 17;32(19):2241-50
references.pmid: 24530151
references.citation: Front Immunol. 2013 Dec 25;4:490
references.pmid: 24400010
references.citation: Br J Cancer. 2012 Nov 20;107(11):1869-75
references.pmid: 23169339
references.citation: Eur J Surg Oncol. 2006 May;32(4):363-70
references.pmid: 16520018
references.citation: Blood. 2000 Nov 1;96(9):3102-8
references.pmid: 11049990
references.citation: Int J Cancer. 2014 Oct 15;135(8):1983-8
references.pmid: 24604357
references.citation: Br J Cancer. 2004 Aug 31;91(5):817-21
references.pmid: 15266309
references.citation: Mol Cancer. 2010 May 26;9:122
references.pmid: 20504320
references.citation: J Immunol. 2014 Oct 15;193(8):3914-24
references.pmid: 25200950
references.citation: FEBS J. 2014 Sep;281(17):3882-93
references.pmid: 25041128
references.citation: Front Pharmacol. 2013 May 07;4:57
references.pmid: 23675348
references.citation: J Exp Med. 2005 Oct 3;202(7):919-29
references.pmid: 16186184
references.citation: Oncologist. 2007 Jan;12(1):20-37
references.pmid: 17227898
references.citation: Cancer Immunol Immunother. 2008 Aug;57(8):1115-24
references.pmid: 18193223
references.citation: PLoS Med. 2008 Aug 19;5(8):e170
references.pmid: 18715113
references.citation: J Oncol. 2013;2013:835956
references.pmid: 23577028
references.citation: Circulation. 2013 Oct 22;128(17):1927-95
references.pmid: 24081971
references.citation: Cancer Epidemiol Biomarkers Prev. 2010 Aug;19(8):1893-907
references.pmid: 20647400
references.citation: Oncologist. 2007 Dec;12(12):1443-55
references.pmid: 18165622
references.citation: Immunology. 2007 May;121(1):1-14
references.pmid: 17386080
references.citation: Korean J Anesthesiol. 2014 Jul;67(1):4-7
references.pmid: 25097731
references.citation: J Theor Biol. 2012 Feb 7;294:56-73
references.pmid: 22051568
references.citation: J Exp Med. 2002 Jun 17;195(12):1575-84
references.pmid: 12070285
references.citation: Br J Clin Pharmacol. 2015 Jan;79(1):56-71
references.pmid: 24134068
references.citation: Vaccine. 2012 Jan 5;30(2):368-77
references.pmid: 22075086
references.citation: Front Oncol. 2014 Apr 02;4:70
references.pmid: 24765614
references.citation: Curr Pharm Des. 2014;20(30):4934-40
references.pmid: 24283955
references.citation: Oncologist. 1999;4(1):45-54
references.pmid: 10337370
references.citation: Br J Cancer. 1998 Dec;78(12):1573-7
references.pmid: 9862566
references.citation: Pharmacol Rev. 2004 Dec;56(4):549-80
references.pmid: 15602010
references.citation: Int J Radiat Oncol Biol Phys. 2007 Nov 1;69(3):751-60
references.pmid: 17560735
references.citation: Chin J Cancer Res. 2012 Jun;24(2):130-7
references.pmid: 23359769
references.citation: J Clin Oncol. 1995 Jan;13(1):283-92
references.pmid: 7799032
references.citation: Oncology. 2005;68(2-3):276-84
references.pmid: 16015045
references.citation: J Immunol. 1998 Feb 1;160(3):1224-32
references.pmid: 9570538
references.citation: Clin Breast Cancer. 2000 Sep;1 Suppl 1:S80-4
references.pmid: 11970755
references.citation: Radiology. 1999 Aug;212(2):551-60
references.pmid: 10429717
references.citation: Nat Rev Immunol. 2002 Jan;2(1):46-53
references.pmid: 11905837
references.citation: Nat Med. 1996 Oct;2(10):1096-103
references.pmid: 8837607
references.citation: Nat Rev Cancer. 2008 Aug;8(8):618-31
references.pmid: 18633355
references.citation: Biomed Res Int. 2014;2014:683068
references.pmid: 25309919
references.citation: PLoS One. 2014 Oct 30;9(10):e110126
references.pmid: 25356878
references.citation: Clin Exp Immunol. 2014 Oct;178(1):1-8
references.pmid: 24828133
references.citation: J Exp Med. 2015 Feb 9;212(2):139-48
references.pmid: 25601652
references.citation: Immunology. 2001 Jun;103(2):131-6
references.pmid: 11412299
references.citation: Front Oncol. 2013 Jul 30;3:196
references.pmid: 23908970
references.citation: Transl Lung Cancer Res. 2012 Mar;1(1):14-25
references.pmid: 25806151
references.citation: J Clin Oncol. 2008 Mar 10;26(8):1239-46
references.pmid: 18323547
references.citation: Clin Ther. 2006 Nov;28(11):1779-802
references.pmid: 17212999