Ichim Thomas E, Li Shuang, Ma Hong, Yurova Yuliya V, Szymanski Julia S, Patel Amit N, Kesari Santosh, Min Wei-Ping, Wagner Samuel C
Batu Biologics Inc, San Diego, 9255 Towne Centre Drive, Suite 450, San Diego, CA, 92121, USA.
Department of Endocrinology, The Affiliated Zhongshan Hospital of Dalian University, Dalian, 116001, China.
J Transl Med. 2015 Mar 14;13:90. doi: 10.1186/s12967-015-0441-0.
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.
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.
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.
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.
虽然血管生成阻断作为癌症治疗干预手段的概念已得到反复验证，但这种方法的全部潜力尚未实现。具体而言，诸如VEGF阻断抗体或激酶抑制剂等药物存在耐药性发展以及脱靶毒性等缺点。先前的研究已在动物模型和临床环境中证明了特异性诱导针对肿瘤内皮的免疫反应而不产生全身性自身免疫后果的可行性。
分离胎盘来源的内皮细胞，并用γ干扰素进行预处理以增强免疫原性。同基因小鼠皮下接种B16黑色素瘤、4T1乳腺癌和Lewis肺癌（LLC），随后分别给予对照生理盐水、对照胎盘内皮细胞和经γ干扰素预处理的内皮细胞（ValloVax™）。对肿瘤体积进行量化。还建立了LLC转移模型并在类似条件下进行治疗。此外，对接近拟用临床剂量的未荷瘤小鼠进行了安全性分析。
与未处理的胎盘内皮细胞给药相比，ValloVax™免疫导致肿瘤生长和转移显著减少。福尔马林固定或照射导致的有丝分裂失活保留了肿瘤抑制活性。对用ValloVax™免疫的健康雄性和雌性小鼠进行的28天评估未发现异常或器官毒性。
鉴于抑制肿瘤血管生成作为癌症治疗潜在治疗益处背后的既定原理，针对多种内皮细胞抗原进行免疫接种可能产生最佳临床反应，提高疗效并降低产生治疗耐药性的可能性。这些数据支持将经照射的ValloVax™作为抗血管生成癌症疫苗进行临床评估。
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