Induction of tumor inhibitory anti-angiogenic response through immunization with interferon Gamma primed placental endothelial cells: ValloVax™

Abstract

BackgroundWhile 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.MethodPlacenta-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.ResultsValloVax™ 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.ConclusionGiven 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0441-0) contains supplementary material, which is available to authorized users.

Gas Plasma-Treated Prostate Cancer Cells Augment Myeloid Cell Activity and Cytotoxicity

“…One reason for that might be the low initial cell number used, and the ability of the cells to internalize extracellular chemokines and cytokines produced during the 96 h-period of incubation. The unchanged levels of TGFβ and the significantly decreased levels of VEGF need to be emphasized because both are potent tumor-promoting effectors in the tumor microenvironment [58,59]. This was also observed in our co-culture experiments, pointing to a potentially beneficial effect of the plasma treatment.…”

Induction and characterization of anti-tumor endothelium immunity elicited by ValloVax therapeutic cancer vaccine

“…Previously we demonstrated that ValloVax vaccination inhibits growth of lung cancer, melanoma, and breast cancer [7]. In this study we utilized the GL261 glioma model and demonstrated suppression of tumor growth (Figure 2A).…”

Alternative Strategies to Inhibit Tumor Vascularization

“…However, both in preclinical and in clinical studies, the efficacy and the observed adverse events were variable, according to vaccine type, route of administration and to the adjuvant choice [98][99][100][101][102]. At present, different anti-angiogenic vaccination protocols, involving the use of peptide-based vaccines, are undergoing clinical trials, as summarized in Table 3 [101][102][103][104][105][106][107][108].…”

“…However, TEC genetic instability, together with the activation of compensatory pathways, may lead to an incomplete response to vaccination therapies against specific targets. Therefore, further clinical studies using whole endothelial [106] or placental cells [107] to induce a polyvalent immune response are currently under evaluation.…”