Institute of Specific Prophylaxis and Tropical Medicine, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.
Clin Cancer Res. 2021 Jul 1;27(13):3649-3660. doi: 10.1158/1078-0432.CCR-20-3742. Epub 2021 Apr 20.
HER2/neu is overexpressed in up to 30% of gastroesophageal adenocarcinomas (GEA) and linked to poor prognosis. Recombinant mAbs to treat HER2/neu-overexpressing cancers are effective with limitations, including resistance and toxicity. Therefore, we developed a therapeutic B-cell epitope vaccine (IMU-131/HER-Vaxx) consisting of three fused B-cell epitopes from the HER2/neu extracellular domain coupled to CRM197 and adjuvanted with Montanide. This phase Ib study aimed to evaluate the optimal/safe dose leading to immunogenicity and clinical responses (https//clinicaltrials.gov/ct2/show/NCT02795988).
A total of 14 patients with HER2/neu-overexpressing GEA were enrolled, and dose escalation (10, 30, 50 μg) was performed in three cohorts (C). Immunogenicity was evaluated by HER2-specific Abs and cellular responses, clinical responses by CT scans according to RECIST version 1.1.
IMU-131 was safe without vaccine-related significant local/systemic reactions or serious adverse events. A total of 11 of 14 patients were evaluable for changes in tumor size and vaccine-specific immune responses. One patient showed complete, 5 partial responses, and 4 stable diseases as their best response. HER2-specific IgG levels were dose dependent. In contrast to patients in C1 and C2, all patients in C3 mounted substantial HER2-specific Ab levels. In addition, cellular vaccine responses, such as Th1-biased cytokine ratios and reduced regulatory T cell numbers, were generated. Progression-free survival was prolonged in C3, correlating with the vaccine-specific humoral and cellular responses.
IMU-131 was well tolerated and safe. The induced HER2-specific Abs and cellular responses were dose dependent and correlated with clinical responses. The highest dose (50 μg) was recommended for further evaluation in a phase II trial, with chemotherapy + IMU-131 or chemotherapy alone, which is currently ongoing.
HER2/neu 在高达 30%的胃食管腺癌（GEA）中过表达，并与预后不良相关。用于治疗 HER2/neu 过表达癌症的重组单克隆抗体具有一定的疗效，但存在局限性，包括耐药性和毒性。因此，我们开发了一种治疗性 B 细胞表位疫苗（IMU-131/HER-Vaxx），由 HER2/neu 细胞外结构域的三个融合 B 细胞表位组成，与 CRM197 偶联，并辅以 Montanide 佐剂。这项 Ib 期研究旨在评估最佳/安全剂量，以产生免疫原性和临床反应（https//clinicaltrials.gov/ct2/show/NCT02795988）。
共纳入 14 例 HER2/neu 过表达的 GEA 患者，在三个队列（C）中进行剂量递增（10、30、50μg）。通过 HER2 特异性抗体和细胞反应评估免疫原性，根据 RECIST 版本 1.1 通过 CT 扫描评估临床反应。
IMU-131 是安全的，没有与疫苗相关的明显局部/全身反应或严重不良事件。14 例患者中有 11 例可评估肿瘤大小变化和疫苗特异性免疫反应。1 例患者完全缓解，5 例部分缓解，4 例疾病稳定为最佳反应。HER2 特异性 IgG 水平呈剂量依赖性。与 C1 和 C2 中的患者相比，C3 中的所有患者均产生了大量的 HER2 特异性 Ab 水平。此外，还产生了细胞疫苗反应，如 Th1 偏向细胞因子比值和调节性 T 细胞数量减少。C3 中的无进展生存期延长，与疫苗特异性体液和细胞反应相关。
IMU-131 耐受性良好且安全。诱导的 HER2 特异性 Abs 和细胞反应呈剂量依赖性，并与临床反应相关。推荐使用最高剂量（50μg）进行进一步评估，在一项正在进行的 II 期试验中，联合化疗和 IMU-131 或单独化疗。
