IMMUNOTHERAPEUTIC MODULATION OF ANGIOGENESIS IN CANCER

该项目的目标是开发和临床应用抗血管生成与肿瘤特异性免疫治疗相结合的协同策略来治疗神经母细胞瘤。这一提议将验证一种抗血管生成、血管特异性整合素α - v肽拮抗剂与肿瘤特异性抗体-白细胞介素-2融合蛋白协同作用的假设，这在临床前转移模型中被证明非常有效地抑制播散性肿瘤的生长。其基本原理是，整合素α - v肽拮抗剂是血管生成的有效抑制剂，可减少原发肿瘤和转移瘤的血液供应，随后促进肿瘤腔室的免疫治疗攻击。肿瘤特异性抗体-白细胞介素-12融合蛋白的作用和机制也将被评估，该蛋白在一个分子中结合了抗血管生成和免疫调节，并在异种移植模型中抑制肿瘤转移。我们的假设的有效性得到了初步数据的支持，表明只有肽拮抗剂与融合蛋白联合使用才能诱导原发性肿瘤消退和根除自发性肝神经母细胞瘤转移。血管密度的同时降低和肿瘤浸润性白细胞的增加仅在用这种组合治疗的动物中得到证实。第一年，我们将进一步优化和表征整合素α v肽拮抗剂联合抗体白介素-2融合蛋白的治疗效果，并在同基因动物模型上评估抗体-白介素-12融合蛋白的作用和机制。在第二年，我们将启动一项I-II期临床试验，以研究肽拮抗剂/融合蛋白组合在4期神经母细胞瘤患者中的毒性和免疫反应及其对疾病临床病程的影响。这些临床前和临床研究将有助于我们了解抗血管生成与主动特异性癌症免疫治疗之间的协同作用，并进一步优化癌症的辅助治疗。

The goal of this project is to develop and clinically apply synergistic strategies combining anti-angiogenesis with tumor-specific immunotherapy for the treatment of neuroblastoma. This proposal will test the hypothesis that an anti-angiogenic, vasculature-specific integrin alpha v peptide antagonist synergizes with tumor-specific antibody-interleukin-2 fusion proteins, that proved very efficient in suppressing growth of disseminated tumors in preclinical metastasis models. The underlying rationale is that integrin alpha v peptide antagonists are potent inhibitors of angiogenesis, which may reduce blood supply to primary tumors and metastases and subsequently facilitate an immunotherapeutic attack in the tumor compartment. Effects and mechanisms of a tumor-specific anti body- interleukin-12 fusion protein will also be evaluated, that combines both anti-angiogenesis with immunomodulation in one molecule, and suppressed tumor metastasis in xenograft models. The validity of our hypothesis is supported by preliminary data, indicating that only the combination of peptide antagonists with fusion proteins induced primary tumor regressions and eradication of spontaneous hepatic neuroblastoma metastases. A simultaneous reduction in blood vessel density and increase in tumor infiltrating leukocytes was demonstrated only in animals treated with this combination. In the first year, we will further optimize and characterize the therapeutic effect of combining integrin alpha v peptide antagonists with antibody interleukin-2 fusion proteins and evaluate effect and mechanism of antibody-interleukin-12 fusion proteins in syngeneic animal models. In the second year, we will initiate a phase I-II clinical trial to investigate the toxicity and immune response of the peptide antagonist/fusion protein combination in patients with stage 4 neuroblastoma and its effect on the clinical course of the disease. These preclinical and clinical studies should contribute to our understanding of the synergy between anti-angiogenesis and active specific cancer immunotherapy and lead to further optimization of adjuvant treatment of cancer.