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）：乳腺癌是美国妇女最常见的恶性肿瘤，也是这一群体中癌症死亡的第二大原因。虽然在乳腺癌的诊断方面已经有了显著的改进，并且因此早期疾病的治疗已经有了显著的改进，但是转移性乳腺癌不能通过目前的疗法治愈。治疗转移性乳腺癌的最乐观的新疗法是化疗与生物反应调节剂曲妥珠单抗的组合。这种方法增加了转移性乳腺癌诊断后的生存时间，但并未导致患者完全缓解率的显著增加。 我们的团队率先使用来自HER-2/neu蛋白的表位的树突状细胞疫苗治疗转移性乳腺癌女性。虽然HER-2/neu仅在25%的患者肿瘤中过表达，但过表达HER-2/neu的肿瘤预后较差，因此这些肿瘤更常见于转移性疾病患者。我们最初的疫苗试验表明，肽脉冲的DC可以在转移性乳腺癌患者中成功产生，并且这些细胞的输注不会导致任何治疗患者的II级以上毒性。然而，单独使用疫苗治疗仅在轻微疾病患者中诱导临床应答，并且这种应答在治疗完成后不持续。因此，单独的疫苗治疗不足以诱导大块肿瘤患者的临床应答。 在目前的临床试验中，我们试图解决与我们最初的疫苗治疗相关的许多问题。使用HER-2/neu转基因动物，并因此对表达该蛋白的肿瘤耐受，我们发现给予曲妥珠单抗和长春瑞滨的多表位DC疫苗导致A2 Kb x Neu转基因小鼠中所有肿瘤完全消退。与单独使用长春瑞滨、抗Neu mAb或DC疫苗接种相比，这是显著改善的应答。由于这些数据，我们已经产生了一个II期临床试验，其中转移性乳腺癌妇女每周接受长春瑞滨治疗两次，联合曲妥珠单抗和DC疫苗，使用来自HER-2/neu的两个表位，在A2 Kb x Neu小鼠中诱导最稳健的CD 8 + T细胞应答。我们将评估这种治疗在表达HLA-A0201的转移性乳腺癌患者中的毒性和疗效。最后，我们将评估这种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治疗方法，以诱导转移性乳腺癌女性的完全缓解。