Augmenting immunity via HER2-targeted immunotherapy and PSK M.Disis/L.Standish

目的：评估PSK的TLR激动剂活性与HER-2/neu（HER 2）定向单克隆抗体治疗（使用HER 2特异性疫苗）联合治疗晚期乳腺癌患者的效果。我们将在第1年和第2年进行临床前基因签名生物标志物工作，然后在第3年和第4年进行安慰剂对照的II期随机对照临床试验。 假设：PSK加入HER 2疫苗后，将改善晚期HER 2过表达乳腺癌女性的免疫应答和生存率。 研究方法：1）确定PSK与HER 2靶向疫苗同时施用是否可以增强肿瘤抗原特异性免疫应答并预防或延迟neu转基因小鼠中的疾病进展; 2）鉴定预测接受PSK、曲妥珠单抗和HER 2靶向疫苗的neu转基因小鼠中的临床应答的基因特征;和3）确定PSK作为晚期（IV期）乳腺癌患者的联合免疫疗法的组分的安全性和免疫原性。 临床试验设计：30名接受曲妥珠单抗+HER 2肽疫苗治疗的晚期HER-2/neu过表达乳腺癌女性将随机接受PSK或安慰剂口服（3000 mg/天）联合疫苗治疗。主要终点将是分子间表位扩散、TGF-b血清水平变化和neu转基因小鼠中鉴定的外周血生物标志物，可预测接受HER 2 ICD疫苗的乳腺癌患者的临床应答。

Purpose: To assess the effects of combining the TLR agonist activity of PSK to HER-2/neu (HER2) directed monoclonal antibody therapy using a HER2 specific vaccine for the treatment of patients with advanced stage breast cancer. We will conduct pre-clinical gene-signature biomarker work in year 1 and 2 then conduct a placebo-controlled phase II randomized controlled clinical trial in years 3 and 4. Hypothesis: PSK, when added to a HER2 vaccine will improve immune response and Survival in women with advanced HER2 overexpressing breast cancer. Methods: 1) Determine whether PSK administered concurrently with HER2-targeted vaccine can enhance tumor antigen-specific immune response and prevent or delay disease progression in neu-transgenic mice; 2) Identify a gene signature that predicts clinical response in neu-transgenic mice receiving PSK, trastuzumab, and a HER2-tergeted vaccine; and 3) Determine the safety and immunogenicity of PSK as a component of combination immunotherapy in patients with advanced stage (stage IV) breast cancer. Clinical Trial Design: 30 women with advanced HER-2/neu overexpressing breast cancer who receive trastuzumab + HER2 peptide vaccine therapy will be randomized to receive PSK or placebo orally (3000 mg/day) concomitant with vaccine therapy. Primary endpoints will be intermolecular epitope spreading, changes in TGF-b serum levels and peripheral blood biomarkers identified in neu-transgenic mice as predictive of clinical response in breast cancer patients receiving HER2 ICD vaccine.