Multimodality Therapy for Metastatic Breast Cancer

描述(申请人提供)：乳腺癌是美国女性最常见的恶性肿瘤，也是这一群体中死于癌症的第二大原因。虽然乳腺癌的诊断和早期疾病的治疗有了显著的进步，但转移性乳腺癌不能用目前的治疗方法治愈。治疗转移性乳腺癌最乐观的新疗法是将化疗与生物反应调节剂曲妥珠单抗相结合。这种方法延长了转移性乳腺癌诊断后的生存时间，但并未导致患者的完全应答率显着增加。 我们小组率先使用树突状细胞疫苗治疗转移性乳腺癌妇女，使用的是HER-2/neu蛋白的表位。虽然HER-2/neu只在25%的患者肿瘤中过度表达，但过度表达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的患者。我们最初的疫苗试验表明，在转移性乳腺癌患者中可以成功地产生多肽冲击的DC，并且这些细胞的输注在任何接受治疗的患者中都不会导致大于II级的毒性。然而，单独使用疫苗治疗只在病情较小的患者中产生临床反应，并且这种反应在治疗完成后不会持续。因此，疫苗治疗本身并不足以诱导大块肿瘤患者的临床反应。 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HER-2/neu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A2Kb x Neu转基因小鼠的所有肿瘤完全消退。与单独使用长春瑞滨、抗Neu单抗或DC疫苗相比，这是一种显著改善的反应。作为这些数据的结果，我们产生了一项II期临床试验，在该试验中，转移性乳腺癌患者每周接受长春瑞滨两次治疗，联合曲妥珠单抗和DC疫苗，该疫苗使用HER-2/neu的两个表位，在A2Kb x Neu小鼠中诱导最强劲的CD8+T细胞反应。我们将评估这种疗法在表达HLA-A0201的转移性乳腺癌患者中的毒性和疗效。最后，我们将评估这一策略在接种后在血液中诱导抗原特异性T细胞的能力。 这项工作的长期目标是评估导致转移性乳腺癌女性治疗完全缓解的安全和有效的治疗方法。

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.