title: Induction of tumor inhibitory anti-angiogenic response through immunization with interferon Gamma primed placental endothelial cells: ValloVax™.
abstract: BACKGROUND
  While the concept of angiogenesis blockade as a therapeutic intervention for cancer has been repeatedly demonstrated, the full promise of this approach has yet to be realized. Specifically, drugs such as VEGF-blocking antibodies or kinase inhibitors suffer from the drawbacks of resistance development, as well as off-target toxicities. Previous studies have demonstrated feasibility of specifically inducing immunity towards tumor endothelium without consequences of systemic autoimmunity in both animal models and clinical settings.
  
  
  METHODS
  Placenta-derived endothelial cells were isolated and pretreated with interferon gamma to enhance immunogenicity. Syngeneic mice received subcutaneous administration of B16 melanoma, 4 T1 mammary carcinoma, and Lewis Lung Carcinoma (LLC), followed by administration of control saline, control placental endothelial cells, and interferon gamma primed endothelial cells (ValloVax™). Tumor volume was quantified. An LLC metastasis model was also established and treated under similar conditions. Furthermore, a safety analysis in non-tumor bearing mice bracketing the proposed clinical dose was conducted.
  
  
  RESULTS
  ValloVax™ immunization led to significant reduction of tumor growth and metastasis as compared to administration of non-treated placental endothelial cells. Mitotic inactivation by formalin fixation or irradiation preserved tumor inhibitory activity. Twenty-eight day evaluation of healthy male and female mice immunized with ValloVax™ resulted in no abnormalities or organ toxicities.
  
  
  CONCLUSIONS
  Given the established rationale behind the potential therapeutic benefit of inhibiting tumor angiogenesis as a treatment for cancer, immunization against a variety of endothelial cell antigens may produce the best clinical response, enhancing efficacy and reducing the likelihood of the development of treatment resistance. These data support the clinical evaluation of irradiated ValloVax™ as an anti-angiogenic cancer vaccine.
authors.affiliation: Batu Biologics Inc, San Diego, 9255 Towne Centre Drive, Suite 450, San Diego, CA, 92121, USA. thomas.ichim@gmail.com.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Ichim
authors.affiliation: Department of Endocrinology, The Affiliated Zhongshan Hospital of Dalian University, Dalian, 116001, China. shuanglqw1109@163.com.
authors.forename: Shuang
authors.initials: S
authors.lastname: Li
authors.affiliation: Batu Biologics Inc, San Diego, 9255 Towne Centre Drive, Suite 450, San Diego, CA, 92121, USA. hongma2008@gmail.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Ma
authors.affiliation: Nova Southeastern University, Fort Lauderdale, Florida, USA. yy21@nova.edu.
authors.forename: Yuliya V
authors.initials: YV
authors.lastname: Yurova
authors.affiliation: Batu Biologics Inc, San Diego, 9255 Towne Centre Drive, Suite 450, San Diego, CA, 92121, USA. julszymanski@gmail.com.
authors.forename: Julia S
authors.initials: JS
authors.lastname: Szymanski
authors.affiliation: Department of Surgery, University of Utah, Salt Lake City, Utah. amit.patel@hsc.utah.edu.
authors.forename: Amit N
authors.initials: AN
authors.lastname: Patel
authors.affiliation: Department of Neurosciences, University of California San Diego, 9500 Gilman Dr., MSC 0752, La Jolla, San Diego, CA, 92093-0752, USA. skesari@ucsd.edu.|Translational Neuro-Oncology Laboratories, Moores Cancer Center, University of California San Diego, 3855 Health Sciences Dr., MSC 0819, La Jolla, San Diego, CA, 92093-0819, USA. skesari@ucsd.edu.
authors.forename: Santosh
authors.initials: S
authors.lastname: Kesari
authors.affiliation: Department of Immunology, University of Western Ontario, London, Ontario, Canada. ameeek@gmail.com.
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Min
authors.affiliation: Batu Biologics Inc, San Diego, 9255 Towne Centre Drive, Suite 450, San Diego, CA, 92121, USA. samuel.wagner@batubiologics.com.
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Wagner
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology*; D005260:Female; D007109:Immunity; D007114:Immunization; D007371:Interferon-gamma / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D008546:Melanoma, Experimental / Q000098:blood supply / Q000276:immunology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008938:Mitosis / Q000187:drug effects; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000098:blood supply* / Q000276:immunology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010920:Placenta / Q000166:cytology*; D011247:Pregnancy
chemical_list: D019496:Cancer Vaccines; D007371:Interferon-gamma