Analysis of Bevacizumab Activity Following Treatment of Patients with Ovarian Cancer or Glioblastoma
Main Article Content
Highly sensitive reporter-gene assays have been developed that allow the precise quantification of both the direct vascular endothelial growth factor-A neutralizing activity of bevacizumab and the ability of bevacizumab to activate antibody dependent cellular cytotoxicity. The use of these assays to analyzes samples from patients with ovarian cancer following four cycle of bevacizumab treatment revealed a close correlation between bevacizumab neutralizing activity and antibody dependent cellular cytotoxicity activity, and a reasonably good correlation between both activities and circulating drug levels determined using an enzyme-linked immunosorbent assay. Analysis of longitudinal samples from a small cohort of patients with glioblastoma treated with bevacizumab revealed a lower correlation between these parameters. We report herein that reanalysis of the grouped samples from the two studies using the nonparametric Spearman rank correlation coefficient revealed a surprisingly good correlation between the two facets of bevacizumab activity, and between both activities and circulating drug levels despite the different indications and treatment regimens, revealing new insights into the action of bevacizumab in neoplastic disease.
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
 Wenger KJ, Wagner M, You SJ, Franz K, Harter PN, Burger MC, et al. Bevacizumab as last-line treatment for glioblastoma following failure of radiotherapy, temozolomide and lomustine. Oncol Lett. (2017) 14:1141–1146. doi: 10.3892/ol.2017.6251
 Panares RL & Garcia AA. Bevacizumab in the management of solid tumors Expert Reviews of Anticancer Therapy (2014) 7:433-445.
 Oza, AM, Dubois F, Hegg R, Hernandez CA, Finocchiaro G, Ghirighelli F, et al. Along-term study of bevacizumab in patients with solid tumors. The Oncologist. (2021) 26:2254-2264.
 Garcia J, Hurwitz HI, Sandler AB, Miles D, Coleman RL, Deurloo R, et al. bevacizumab (Avastin ® ) in cancer treatment: a review of 15 years of clinical experience and future outlook. Cancer Treat Rev. (2017) 86:1-18. 102017. doi:10.1016/j.ctrv.2020.102017
 Wang A, Fei D, Vanderlaan M, Song A. Biological activity of bevacizumab, a humanized anti-VEGF antibody in vitro. Angiogenesis.(2004) 7:335–345. doi:10.1007/10456-04-8272-2
 Lallemand C, Ferrando-Miguel R, Auer M, Iglseder S, Czech T, Gaber-Wagener A, et al. Quantification of Bevacizumab Activity Following Treatment of Patients with Ovarian Cancer or Glioblastoma. Frontiers in Immunology (2020) 11:1-9, Article 515556
 Lallemand C,Liang F, Staub F, Simansour M, Vallette B, Huang L, Ferrando-Miguel R, Tovey MG. A Novel System for the Quantification of the ADCC Activity of Therapeutic Antibodies. Journal of Immunology Research (2017) 10:1-19
 Louis DN, Ohgaki H, Wiestler OD, WK C. WHO classification of tumors of the central nervous system. Acta Neuropathol. (2016) 6:803-820.
 Schweighofer B, Schultes J, Pomyje J, Hofer E. Signals and genes induced by angiogenic growth factors in comparison to inflammatory cytokines in endothelial cells. Clin Hemorheol Microcirc. (2007) 37:57–62.
 Lee A & Shirley M. Ranibizumab: A review in retinopathy of prematurity. Pediatric Drugs (2021) 23:111-117 doi: 10.1007/s40272-020-00433-z.
 Ferrara N, Adams AP. Ten years of anti-vascular endothelial growth factor therapy. Nat Rev Drug Ther. (2016) 15:385–403. doi: 10.1038/nrd.2015.17
 Baish JW, Jain RK. Fractals and cancer. Cancer Res. (2000) 60: 3683–3688.
 Yang AD, Bauer TW, Camp ER, Somcio BS, Liu W, Fan BS. Improving delivery of antineoplastic agents with anti-vascular endothelial growth factor therapy. Cancer (2005) 103:1561-1570
 Paley PJ, Staskus KA, Gebhard K, Mohanraj D, Twiggs LB, Carson LF, et al ; Vascular endothelial growth factor expression in early stage ovarian carcinoma. Cancer (1997) 80: 98-106
 Flyn RJ, Wang L, Gillespie DL, Stoddard GL, Reid JK, Owens J; et al Hypoxia-regulated protein expression, patient characteristics, and previous imaging as predictors of survival in adults with glioblastoma. Cancer (2008) 113:1032-1042
 Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med (2014) 370(8):709–22. https://doi.org/10.1056/NEJMoa1308345.
 Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H et al N Engl J Med (2011) 365(26):2473-2483. DOI: 10.1056/NEJMoa1104390
 Jain RK. Anti-angiogenesis strategies revisited: from starving tumors to alleviating. hypoxia. Cancer Cell (2014) 26 (5):605–622. https://doi.org/10.1016/j.ccell 10.006
 Ramjiawan RR, Griffioen AW, Duda DG. Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy? Angiogenesis (2017);20(2):185–204
 Folkins C, Man S, Xu P, Shaked S, Hicklin DJ, Kerbel RS, Anticancer Therapies Combining Antiangiogenic and Tumor Cell Cytotoxic Effects Reduce the Tumor Stem-Like
Cell Fraction in Glioma Xenograft Tumors Cancer Res (2007) 67: (8). 3560-3564
 Souberan, A., Brustlein, S., Couarne, G., Chasson, L., Tchoghandjian, A. Effects of VEGF blockade on the dynamics of the inflammatory landscape in glioblastoma-bearing mice. J Neuroinflammation (2019) 16:191-206.
 Charles NA, Holland EC, Gilbertson R, Glass R, Kettenmann H. The brain tumor microenvironment. Glia (2012) 60:502–14
 Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumor activity. Nat Rev Cancer (2008) 8:579-91
 Marcucci F, Bellone M, Rumio C, Corti A. Approaches to improve tumor accumulation and interactions between monoclonal antibodies and immune cells. MAbs (2013) 5:34–46.
 Pereira NA, Chan KF, Lin PC, Song Z. The less is more in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity. MAbs (2018) 10:693–711.
 Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P, Watier H. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor gamma RIIIa gene. Blood. (2002) 99:754–758. doi:10.1182/blood.V99.3.754. PMID:11806974.
 Musolino A, Naldi N, Bortesi B, Pezzuolo D, Capelletti M, Missale G, Laccabue D, Zerbini A, Camisa R, Bisagni G, et al. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive meta- static breast cancer. J Clin Oncol. (2008) 26:1789–1796. doi:10.1200/ JCO.2007.14.8957. PMID:18347005.
 Weng WK, Levy R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol. (2003) 21:3940–3947. doi:10.1200/JCO.2003.05.013. PMID:12975461.
 Steenholdt C, Bendtzen K, Brynskov J, Thomsen OØ, Ainsworth MA. Cut-off levels and diagnostic accuracy of infliximab trough levels and anti-infliximab antibodies in Crohn’s disease. Scand J Gastroenterol. (2011) 46:310-318.
 Lipsky PE, van der Heiide DM, ST Clair EW, Furst DE, Breedveld FC, Kalden JT, et al Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-tumor necrosis trail in rheumatoid arthritis with concomitant therapy study group. N. Eng. J. Med. (2000). 343:1594-1602 doi: 10.1056/NEJM200011303432202.