Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden.
J Transl Med. 2010 Jun 7;8:53. doi: 10.1186/1479-5876-8-53.
Adjuvant trastuzumab (Herceptin) treatment of breast cancer patients significantly improves their clinical outcome. Vaccination is an attractive alternative approach to provide HER-2/neu (Her2)-specific antibodies and may in addition concomitantly stimulate Her2-reactive T-cells. Here we report the first administration of a Her2-plasmid DNA (pDNA) vaccine in humans.
The vaccine, encoding a full-length signaling-deficient version of the oncogene Her2, was administered together with low doses of GM-CSF and IL-2 to patients with metastatic Her2-expressing breast carcinoma who were also treated with trastuzumab. Six of eight enrolled patients completed all three vaccine cycles. In the remaining two patients treatment was discontinued after one vaccine cycle due to rapid tumor progression or disease-related complications. The primary objective was the evaluation of safety and tolerability of the vaccine regimen. As a secondary objective, treatment-induced Her2-specific immunity was monitored by measuring antibody production as well as T-cell proliferation and cytokine production in response to Her2-derived antigens.
No clinical manifestations of acute toxicity, autoimmunity or cardiotoxicity were observed after administration of Her2-pDNA in combination with GM-CSF, IL-2 and trastuzumab. No specific T-cell proliferation following in vitro stimulation of freshly isolated PBMC with recombinant human Her2 protein was induced by the vaccination. Immediately after all three cycles of vaccination no or even decreased CD4+ T-cell responses towards Her2-derived peptide epitopes were observed, but a significant increase of MHC class II restricted T-cell responses to Her2 was detected at long term follow-up. Since concurrent trastuzumab therapy was permitted, lambda-subclass specific ELISAs were performed to specifically measure endogenous antibody production without interference by trastuzumab. Her2-pDNA vaccination induced and boosted Her2-specific antibodies that could be detected for several years after the last vaccine administration in a subgroup of patients.
This pilot clinical trial demonstrates that Her2-pDNA vaccination in conjunction with GM-CSF and IL-2 administration is safe, well tolerated and can induce long-lasting cellular and humoral immune responses against Her2 in patients with advanced breast cancer.
曲妥珠单抗（赫赛汀）辅助治疗乳腺癌患者可显著改善其临床结局。疫苗接种是一种有吸引力的替代方法，可以提供 HER-2/neu（Her2）特异性抗体，并可能同时刺激 Her2 反应性 T 细胞。在此，我们报告了首例 Her2 质粒 DNA（pDNA）疫苗在人体中的应用。
该疫苗编码的是 Her2 致癌基因的全长信号缺失型，与低剂量 GM-CSF 和 IL-2 联合用于转移性 Her2 表达型乳腺癌患者，这些患者也接受了曲妥珠单抗治疗。入组的 8 名患者中有 6 名完成了所有 3 个疫苗周期。在另外 2 名患者中，由于肿瘤快速进展或与疾病相关的并发症，在完成 1 个疫苗周期后停止了治疗。主要目的是评估疫苗方案的安全性和耐受性。次要目标是通过测量抗体产生以及针对 Her2 衍生抗原的 T 细胞增殖和细胞因子产生来监测治疗诱导的 Her2 特异性免疫。
在 GM-CSF、IL-2 和曲妥珠单抗联合使用 Her2-pDNA 后，未观察到急性毒性、自身免疫或心脏毒性的临床表现。接种疫苗后，用重组人 Her2 蛋白体外刺激新鲜分离的 PBMC 后，未诱导出特定的 T 细胞增殖。在接种后的所有 3 个周期后，立即观察到针对 Her2 衍生肽表位的 CD4+T 细胞反应减弱甚至消失，但在长期随访中检测到 MHC Ⅱ类限制的 T 细胞对 Her2 的反应显著增加。由于允许同时使用曲妥珠单抗治疗，因此进行了 lambda 亚类特异性 ELISA 检测，以特异性测量内源性抗体产生，而不会受到曲妥珠单抗的干扰。Her2-pDNA 疫苗接种可诱导并增强 Her2 特异性抗体，在最后一次疫苗接种后数年，可在患者亚组中检测到这些抗体。
这项临床试验表明，Her2-pDNA 疫苗与 GM-CSF 和 IL-2 联合应用在晚期乳腺癌患者中是安全的、耐受良好的，并可诱导针对 Her2 的长期细胞和体液免疫反应。
