IMMUNOTHERAPEUTIC MODULATION OF ANGIOGENESIS IN CANCER

癌症血管生成的免疫治疗调节

• 批准号: 2907651
• 负责人: RALPH A. REISFELD
• 金额: $ 13.36万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2907651
• 关键词: RNase protection assay; SCID mouse; SDS polyacrylamide gel electrophoresis; angiogenesis; angiogenesis inhibitors; clinical research; combination cancer therapy; drug interactions; drug screening /evaluation; enzyme linked immunosorbent assay; flow cytometry; human subject; human therapy evaluation; immunomodulators; integrins; interleukin 12; interleukin 2; laboratory mouse; metastasis; neoplasm /cancer immunotherapy; neuroblastoma; nonhuman therapy evaluation; pediatric neoplasm /cancer; polymerase chain reaction; tissue /cell culture

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.

该项目的目的是在临床上采用抗血管生成与肿瘤特异性免疫疗法相结合的神经母细胞瘤治疗的协同策略。该提案将检验以下假设：抗血管生成的，脉络膜特异性整联蛋白αV肽拮抗剂与肿瘤特异性抗体 - 互晶-2融合蛋白协同，证明在临床上的转移模型中抑制了传播肿瘤的生长方面非常有效。 根本的理由是整联蛋白αV肽拮抗剂是血管生成的有效抑制剂，可以减少对原发性肿瘤和转移的血液供应，然后促进肿瘤室中的免疫治疗攻击。还将评估肿瘤特异性抗体 - 白细胞介素12融合蛋白的作用和机制，将两种抗血管生成与一个分子中的免疫调节结合在一起，并抑制异种移植模型中的肿瘤转移。我们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诱导的原发性肿瘤回归和消除自发性肝神经母细胞瘤转移的组合。 仅在使用这种组合治疗的动物中证明了血管密度同时降低血管密度和肿瘤浸润的白细胞。 在第一年，我们将进一步优化和表征将整联蛋白αV肽拮抗剂与抗体白介素-2融合蛋白相结合的治疗效果，并评估合成动物模型中抗体 - 互化素-12融合蛋白的效果和机制。 在第二年，我们将启动一项I-II期临床试验，以研究4期神经母细胞瘤患者肽拮抗剂/融合蛋白组合的毒性和免疫反应及其对疾病临床过程的影响。 这些临床前研究和临床研究应有助于我们理解抗血管生成与主动特异性癌症免疫疗法之间的协同作用，并导致对癌症辅助治疗的进一步优化。