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和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。这项提议将测试一种抗血管生成、血管特异性整合素αv肽拮抗剂与肿瘤特异性抗体-白介素2融合蛋白协同作用的假设，事实证明，在临床前转移模型中，这一融合蛋白在抑制播散性肿瘤生长方面非常有效。其基本原理是，整合素αv肽拮抗剂是有效的血管生成抑制剂，可能会减少对原发肿瘤和转移瘤的血液供应，从而促进肿瘤间隔区的免疫治疗攻击。还将评估肿瘤特异性抗体-白介素12融合蛋白的作用和机制，该融合蛋白将抗血管生成和免疫调节结合在一个分子中，并在异种移植模型中抑制肿瘤转移。我们的假设得到了初步数据的支持，表明只有多肽拮抗剂和融合蛋白的结合才能诱导原发肿瘤的消退和自发性肝神经母细胞瘤转移的根除。血管密度的降低和肿瘤浸润性白细胞的增加，只有在接受这种联合治疗的动物中才被证实。在第一年，我们将进一步优化和表征整合素αv肽拮抗剂与抗体IL-2融合蛋白的治疗效果，并评价抗体-IL-12融合蛋白在同基因动物模型中的作用和机制。在第二年，我们将启动一项I-II期临床试验，研究多肽拮抗剂/融合蛋白组合对4期神经母细胞瘤患者的毒性和免疫反应及其对临床病程的影响。这些临床前和临床研究将有助于我们理解抗血管生成和主动的肿瘤特异性免疫治疗之间的协同作用，并导致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.