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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.
Highlights
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
ValloVaxTM immunization led to significant reduction of tumor growth and metastasis as compared to administration of non-treated placental endothelial cells
Immunological targeting of tumor endothelium is appealing based on: a) For every tumor endothelial cell therapeutically neutralized approximately 200–300 tumor cells perish, reducing ability of tumors to lose expression of antigens; b) The immune system is in direct contact with the tumor endothelium, while immune access inside tumors is difficult due to areas of necrosis and high interstitial pressure; and c) Demonstrated prior efficacy of other anti-angiogenesis inhibitory compounds such as bevacizumab [11,12]
Summary
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 Drugs such as VEGF-blocking antibodies or kinase inhibitors suffer from the drawbacks of resistance development, as well as off-target toxicities. Immune-mediated destruction of the tumor endothelium has been shown to significantly increase TILs in mouse models, which was correlated with tumor regression [14] Another further potential benefit of targeting the tumor associated vasculature is the potential of sensitizing tumors to radiotherapy [15], in part due to the selective thrombotic and apoptotic effects irradiation has on the tumor vasculature [16,17,18,19]. A more effective anti-angiogenesis approach may be to stimulate selective killing of the tumor endothelium through immunotherapeutic vaccines
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