Multimodality Therapy for Metastatic Breast Cancer

转移性乳腺癌的多学科治疗

• 批准号: 6938142
• 负责人: Jonathan S. Serody
• 金额: $ 28.84万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-15 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6938142
• 关键词: MHC class I antigen; antineoplastics; breast neoplasms; clinical research; clinical trial phase II; combination cancer therapy; dendritic cells; human subject; human therapy evaluation; immune response; immunologic assay /test; metastasis; monoclonal antibody; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; neoplasm /cancer vaccine; patient oriented research; statistics /biometry

DESCRIPTION (provided by applicant): Breast cancer is the most common malignancy in women in the Untied States and the number two cause of death from cancer in this group. While there has been significant improvement in the diagnosis of breast cancer, and as a result treatment of early stage disease, metastatic breast cancer cannot be cured by current therapies. The most optimistic new therapy for the treatment of metastatic breast cancer is the combination of chemotherapy with the biological response modifier trastuzumab. This approach has increased the survival time after the diagnosis of metastatic breast cancer but has not resulted in a significant increase in the complete response rate for patients. Our group has pioneered the use of dendritic cell vaccines using epitopes from the protein HER-2/neu in the treatment of women with metastatic breast cancer. While HER-2/neu is overexpressed in only 25% of tumors from patients, tumors that overexpress HER-2/neu have a poorer prognosis, thus these tumors are more commonly found in patients with metastatic disease. Our initial vaccine trial demonstrated that peptide-pulsed DCs can be generated successfully in patients-with metastatic breast cancer and that infusion of these cells did not result in greater than grade II toxicity in any patient treated. However, treatment with the vaccine alone induced clinical responses only in patients with minimal disease and this response did not persist after completion of therapy. Thus, vaccine therapy alone was not sufficient for induction of clinical responses in patients with bulk tumor. In the current clinical trial, we have attempted to remedy many of the problems associated with our initial vaccine therapy. Using animals that are transgenic for HER-2/neu and as a consequence tolerant to tumors expressing this protein, we have found that a multi-epitope DC vaccine given with trastuzumab and vinorelbine resulted in complete regression of all tumors in A2Kb x Neu transgenic mice. This was a markedly improved response compared to the use of vinorelbine, anti-Neu mAb or DC vaccination alone. As a result of these data, we have generated a phase II clinical trial in which women with metastatic breast cancer receive vinorelbine weekly for two treatments combined with trastuzumab and a DC vaccine using two epitopes from HER-2/neu that induced the most robust CD8+ T cell response in A2Kb x Neu mice. We will evaluate the toxicity and efficacy of this treatment in women with metastatic breast cancer who express HLA-A0201. Finally, we will assess the ability of this strategy to induce antigen-specific T cells in the blood after vaccination. The long-term goals of this work are to evaluate safe and effective therapies that induce a complete remission for the treatment of women with metastatic breast cancer.

描述（由申请人提供）：乳腺癌是女性最常见的恶性肿瘤，也是该组中癌症的第二名死亡原因。尽管乳腺癌的诊断有了显着改善，并且由于早期疾病的治疗方法，但当前疗法无法治愈转移性乳腺癌。用于治疗转移性乳腺癌的最乐观的新疗法是化学疗法与生物反应修饰剂曲妥珠单抗的结合。这种方法增加了诊断转移性乳腺癌后的生存时间，但并未导致患者的完全反应率显着提高。 我们的小组率先使用了使用蛋白质HER-2/NEU的表位的树突状细胞疫苗在治疗转移性乳腺癌的女性中。尽管Her-2/neu在患者中只有25％的肿瘤中过表达，但过表达Her-2/neu的肿瘤的预后较差，因此这些肿瘤在转移性疾病的患者中更常见。我们最初的疫苗试验表明，可以在转移性乳腺癌的患者中成功产生肽脉冲的DC，并且在任何接受治疗的患者中，这些细胞的输注不会使这些细胞大于II毒性。但是，单独使用疫苗治疗仅在最小疾病的患者中引起临床反应，并且在治疗完成后这种反应并未持续。因此，仅疫苗治疗不足以诱导大量肿瘤患者的临床反应。 在当前的临床试验中，我们试图纠正与初始疫苗疗法相关的许多问题。使用对表达这种蛋白的肿瘤的HER-2/NEU转基因的动物，我们发现用曲妥珠单抗和vinorelbine给予的多角膜直流疫苗会导致A2KB X NEU转基因小鼠中所有肿瘤的所有肿瘤完全回归。与仅使用Vinorelbine，Anti-Neu MAB或DC疫苗接种相比，这是一种明显改善的反应。由于这些数据，我们已经生成了一项II期临床试验，其中转移性乳腺癌的女性每周接受两种与曲妥珠单抗结合和DC疫苗的治疗，并使用HER-2/NEU的两个表位诱导了A2KB X Neu小鼠中最健壮的CD8+ T细胞反应。我们将评估这种疗法对表达HLA-A0201的转移性乳腺癌女性的毒性和功效。最后，我们将评估该策略在疫苗接种后诱导血液中抗原特异性T细胞的能力。 这项工作的长期目标是评估安全有效的疗法，这些疗法可以完全缓解转移性乳腺癌女性的完全缓解。